[Federal Register Volume 83, Number 153 (Wednesday, August 8, 2018)]
[Notices]
[Pages 39103-39105]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-16984]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-1692]


Elemental Impurities in Drug Products; Guidance for Industry; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled ``Elemental 
Impurities in Drug Products.'' This guidance finalizes the draft 
guidance issued July 1, 2016, which provides recommendations regarding 
the control of elemental impurities of human drug products marketed in 
the United States consistent with the implementation of International 
Council for Harmonisation (ICH) guidance for industry entitled ``Q3D 
Elemental Impurities'' (ICH Q3D). This guidance will also assist 
manufacturers of compendial drug products in responding to the issuance 
of the United States Pharmacopeia (USP) requirement for the control of 
elemental impurities.

DATES: The announcement of the guidance is published in the Federal 
Register on August 8, 2018.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that

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identifies you in the body of your comments, that information will be 
posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for Written/Paper 
Submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-D-1692 for ``Elemental Impurities in Drug Products.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002; or to the Office of 
Communication, Outreach and Development, Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Danae Christodoulou, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 21, Rm. 2602, Silver Spring, MD 20993-0002, 301-
796-1342; or Stephen Ripley, Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Elemental Impurities in Drug Products.'' This guidance 
provides recommendations regarding the control of elemental impurities 
of human drug products marketed in the United States consistent with 
implementation of ICH Q3D. The guidance will also assist manufacturers 
of compendial drug products in responding to the issuance of the USP 
chapters for the control of elemental impurities.
    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 finished 
drug products, and (2) update the methodology used to test for 
elemental impurities in drug products to include modern analytical 
procedures. ICH Q3D contains recommendations for manufacturers of human 
drugs and biologics on applying a risk-based approach to control 
elemental impurities and permitted daily exposure. USP worked closely 
with ICH to align its new General Chapters with ICH Q3D.
    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 USP-National Formulary requirements. 
This guidance outlines approaches for implementation of USP <232>, 
<233>, and ICH Q3D in new and existing products.
    This guidance finalizes the draft guidance issued July 1, 2016 (81 
FR 43211). Since the draft guidance was issued, USP <232> was 
harmonized with ICH Q3D with respect to the all elements and their 
limits. Originally, prior to issuance of the draft guidance, USP <232> 
included a fraction (15) of elemental impurities (EIs) listed in ICH 
Q3D. A number of stakeholder comments to the draft guidance referred to 
the update and harmonization of USP <232> with ICH Q3D, which is now 
reflected in the final guidance. In addition, a number of stakeholder 
comments requested clarification regarding the applicability of the 
guidance to biologics license applications (BLAs). The final guidance 
now states that ``for control of EIs in approved or pending BLAs, see 
ICH Q3D.'' This differs from the draft, where it was stated that the 
guidance pertained to biotechnology products covered by new drug 
applications (NDAs).
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
current thinking of FDA on ``Elemental Impurities in Drug Products.'' 
It does not establish any rights for any person and is not binding on 
FDA or the public.

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You can use an alternative approach if it satisfies the requirements of 
the applicable statutes and regulations. This guidance is not subject 
to Executive Order 12866.

II. Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). The collections of information in 21 CFR part 314 for submitting 
NDAs and abbreviated new drug applications, including supplemental 
applications and annual reports, have been approved under OMB control 
number 0910-0001. The collections of information in 21 CFR parts 211 
and 212 (current good manufacturing practices) have been approved under 
OMB control numbers 0910-0139 and 0910-0667.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
https://www.regulations.gov.

    Dated: August 3, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-16984 Filed 8-7-18; 8:45 am]
 BILLING CODE 4164-01-P


