Control of Nitrosamine Impurities in Human Drugs; Guidance for Industry; Availability
| Published date | 03 September 2020 |
| Citation | 85 FR 55017 |
| Record Number | 2020-19519 |
| Section | Notices |
| Court | Food And Drug Administration |
Federal Register, Volume 85 Issue 172 (Thursday, September 3, 2020)
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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
