[Federal Register Volume 85, Number 172 (Thursday, September 3, 2020)]
[Notices]
[Pages 55017-55019]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-19519]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-D-1530]


Control of Nitrosamine Impurities in Human Drugs; 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, the Agency, or we) is 
announcing the availability of a final guidance for industry, entitled 
``Control of Nitrosamine Impurities in Human Drugs.'' This guidance 
recommends steps manufacturers of active pharmaceutical ingredients and 
drug products should take to detect and prevent objectionable levels of 
nitrosamine impurities in pharmaceutical products. The guidance also 
describes conditions that may introduce nitrosamine impurities. The 
recent unexpected finding of nitrosamine impurities, which are probable 
human carcinogens, in drugs such as angiotensin II receptor blockers, 
ranitidine, nizatidine, and metformin, has made clear the need for a 
risk assessment strategy to identify and minimize nitrosamines in any 
pharmaceutical product at risk for their presence.

DATES: The announcement of the guidance is published in the Federal 
Register on September 3, 2020.

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 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-2020-D-1530 for ``Control of Nitrosamine Impurities in Human 
Drugs.'' 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, 240-402-7500.
     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

[[Page 55018]]

FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/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, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the guidance to the 
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. Send two self-addressed adhesive labels to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Dongmei Lu, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 75, Rm. 6649, Silver Spring, MD 20993, 240-402-7966.

SUPPLEMENTARY INFORMATION:

I. Background

    We are announcing the availability of a guidance for industry 
entitled ``Control of Nitrosamine Impurities in Human Drugs.'' We are 
issuing this guidance consistent with our good guidance practices (GGP) 
regulation (Sec.  10.115 (21 CFR 10.115)). We are implementing this 
guidance without prior public comment because we have determined that 
prior public participation is not feasible or appropriate (Sec.  
10.115(g)(2)). We made this determination because of the importance of 
providing timely information to manufacturers regarding risk 
assessments, testing, and other appropriate actions they should take to 
reduce and mitigate nitrosamine impurities in active pharmaceutical 
ingredients (APIs) and drug products. Although this guidance document 
is immediately in effect, it remains subject to comment in accordance 
with FDA's GGP regulation (Sec.  10.115(g)(3)(D)).
    Nitrosamines have been classified as probably carcinogenic to 
humans by the World Health Organization. This guidance recommends steps 
manufacturers of APIs and drug products should take to detect and 
prevent objectionable levels of nitrosamine impurities in 
pharmaceutical products. The guidance also describes conditions that 
may introduce nitrosamine impurities.
    The recent discovery of nitrosamine impurities in some types of 
drug products, including angiotensin II receptor blockers, ranitidine, 
nizatidine, and metformin, led FDA and other international regulators 
to conduct a detailed analysis of these impurities in affected APIs and 
drug products. Recently, preliminary results from FDA stability testing 
raised concerns that N-Nitrosodimethylamine (NDMA) levels in some 
ranitidine products stored at room temperature can increase with time 
to unacceptable levels. Results from other tests FDA conducted suggest 
that the NDMA levels increase with storage time. On April 1, 2020, FDA 
requested that all ranitidine products be withdrawn from the U.S. 
market.
    Based on the testing results and the Agency's current understanding 
of the chemistry, FDA has developed this guidance to provide API and 
drug product manufacturers information on the potential root causes of 
nitrosamine formation. It recommends ways API and drug product 
manufacturers can conduct risk assessments of their products, whether 
approved, marketed, or with pending applications. The guidance also 
suggests actions they should take to reduce or prevent the presence of 
nitrosamines in APIs and drug products.
    API and drug product manufacturers should assess the risk of 
nitrosamine contamination or formation in their drugs. These risk 
assessments should be conducted in a timely manner. Manufacturers do 
not need to submit risk assessment documents to the Agency, but they 
should retain them so that they are available if requested. FDA may 
request an expedited risk assessment, confirmatory testing, or other 
regulatory action based on information available to the Agency.
    For products at the pre-submission stage, FDA recommends that 
applicants conduct a risk assessment for nitrosamine impurities in APIs 
and proposed drug products and conduct confirmatory testing as needed 
prior to submission of an original application. However, the risk 
assessment and submission of any confirmatory testing or changes to the 
drug master file or application may be submitted in an amendment if 
they are not available at the time of the original submission filing. 
For applications that are pending with the Agency, applicants should 
conduct the risk assessment expeditiously and inform FDA if 
confirmatory testing finds nitrosamine levels above the recommended 
acceptable daily intake (ADI) limit. If a nitrosamine impurity is 
detected above the limit of quantitation but is within the ADI limit, 
the applicant should amend the application as appropriate. The Agency 
will work with the applicant to resolve issues during the review cycle 
or immediately after approval, and before distribution, if determined 
to be necessary by the Agency.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (Sec.  10.115). The guidance represents the 
current thinking of FDA on the ``Control of Nitrosamine Impurities in 
Human Drugs.'' 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.

II. Paperwork Reduction Act of 1995

    This guidance refers to previously approved FDA collections of 
information. These collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (44 U.S.C. 3501-3521). The collections of information in 21 
CFR parts 210 and 211 have been approved under OMB control number 0910-
0139; the collections of information in 21 CFR part 312 have been 
approved under OMB control number 0910-0014; the collections of 
information in 21 CFR part 314 have been approved under OMB control 
number 0910-0001; the collections of information in 21 CFR part 601 
have been approved under OMB control number 0910-0338; the collections 
of information for the permanent discontinuation or interruption in 
manufacturing of certain drug and biological products have been 
approved under OMB control number 0910-0759; the collections of 
information pertaining to the guidance for industry entitled 
``Controlled Correspondence Related to Generic Drug Development'' have 
been approved under OMB control number 0910-0797.

III. Electronic Access

    Persons with access to the internet may obtain the document at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm or 
https://www.regulations.gov. Use the FDA website listed in the previous 
sentence to find the most current version of the guidance.


[[Page 55019]]


    Dated: August 28, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-19519 Filed 9-2-20; 8:45 am]
BILLING CODE 4164-01-P


