Notice2023-28675
Reformulating Drug Products That Contain Carbomers Manufactured With Benzene; Guidance for Industry; Availability
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Published
December 28, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled "Reformulating Drug Products That Contain Carbomers Manufactured With Benzene." The purpose of this guidance is to provide recommendations to applicants and manufacturers on what tests should be performed and what documentation should be submitted or available to support the reformulation of drug products that use carbomers manufactured with benzene. Certain United States Pharmacopeia (USP) carbomer monographs currently allow for unacceptable levels of benzene, which raises safety concerns. FDA has requested that the USP omit (or remove) these monographs, and applicants and manufacturers may need to reformulate their drug products to avoid use of these carbomers. This guidance provides recommendations for tests and documentation related to reformulation based on various routes of administration and dosage forms of affected drug products, and provides recommendations for application holders on the appropriate submission types to notify the Agency of reformulation changes. The intended effect of this guidance is to, as appropriate, provide a less burdensome risk-based approach to reformulation submissions relative to existing guidances on scale-up and post-approval changes (SUPAC), and address the immediate public health need to expedite the discontinuation of the use of carbomers manufactured with high levels of benzene in drug products.
Full Text
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<title>Federal Register, Volume 88 Issue 248 (Thursday, December 28, 2023)</title>
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[Federal Register Volume 88, Number 248 (Thursday, December 28, 2023)]
[Notices]
[Pages 89703-89705]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-28675]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2023-D-5408]
Reformulating Drug Products That Contain Carbomers Manufactured
With Benzene; 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
``Reformulating Drug Products That Contain Carbomers Manufactured With
Benzene.'' The purpose of this guidance is to provide recommendations
to applicants and manufacturers on what tests should be performed and
what documentation should be submitted or available to support the
reformulation of drug products that use carbomers manufactured with
benzene. Certain United States Pharmacopeia (USP) carbomer monographs
currently allow for unacceptable levels of benzene, which raises safety
concerns. FDA has requested that the USP omit (or remove) these
monographs, and applicants and manufacturers may need to reformulate
their drug products to avoid use of these carbomers. This guidance
provides recommendations for tests and documentation related to
reformulation based on various routes of administration and dosage
forms of affected drug products, and provides recommendations for
application holders on the appropriate submission types to notify the
Agency of reformulation changes. The intended effect of this guidance
is to, as appropriate, provide a less burdensome risk-based approach to
reformulation submissions relative to existing guidances on scale-up
and post-approval changes (SUPAC), and address the immediate public
health need to expedite the discontinuation of the use of carbomers
manufactured with high levels of benzene in drug products.
DATES: The announcement of the guidance is published in the Federal
Register on December 28, 2023.
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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2023-D-5408 for ``Reformulating Drug Products That Contain
Carbomers Manufactured With Benzene; Guidance for Industry.'' Received
comments will be placed in the docket and, except for those submitted
as ``Confidential Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
[[Page 89704]]
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 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. 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: Pallavi Nithyanandan, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 4156, Silver Spring, MD 20993-0002, 301-
796-7546, <a href="/cdn-cgi/l/email-protection#aefecfc2c2cfd8c780e0c7dac6d7cfc0cfc0cacfc0eec8cacf80c6c6dd80c9c1d8"><span class="__cf_email__" data-cfemail="346455585855425d1a7a5d405c4d555a555a50555a745250551a5c5c471a535b42">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Reformulating Drug Products That Contain Carbomers
Manufactured With Benzene.'' FDA is issuing this guidance consistent
with its good guidance practices (GGP) regulation (Sec. 10.115 (21 CFR
10.115)). The Agency is implementing this guidance without prior public
comment because it has determined that prior public participation is
not feasible or appropriate (Sec. 10.115(g)(2) and (3)). FDA made this
determination because benzene is a known human carcinogen, and the
Agency seeks to facilitate the transition away from using carbomers
manufactured with high levels of benzene. Publishing this guidance
without prior public comment addresses the immediate public health need
to expedite the discontinuation of the use of these carbomers and
provides a less burdensome risk-based approach to applicant
submissions, relative to existing guidances on SUPAC. Although this
guidance document is immediately in effect, it remains subject to
comment in accordance with FDA's GGP regulation.
The purpose of this guidance is to provide recommendations to
applicants and manufacturers on what tests should be performed and what
documentation should be submitted or available to support the
reformulation of drug products that use carbomers manufactured with
benzene. Certain USP carbomer monographs currently allow for
unacceptable levels of benzene, which raises safety concerns. FDA has
requested that the USP omit (or remove) these monographs, and
applicants and manufacturers may need to reformulate their drug
products to avoid use of these carbomers.
Carbomers are a group of polymers composed of acrylic acid. They
are widely used as inactive ingredients in drug products as fillers,
emulsifiers, gelling agents, and binding agents. There are carbomers
currently used as inactive ingredients that are manufactured using
benzene as a polymerization solvent. Benzene is a known human
carcinogen. As such, both the International Conference for
Harmonisation (ICH) guidance for industry entitled ``Q3C--Tables and
List'' (available at <a href="https://www.fda.gov/media/133650/download">https://www.fda.gov/media/133650/download</a>) and USP
General Chapter <467> ``Residual Solvents'' designate benzene as a
Class 1 solvent (i.e., solvents that should be avoided) and recommend
that benzene should not be employed in the manufacture of drug
substances, excipients, and drug products. However, there are still
several grades of carbomers that are manufactured using benzene as a
solvent being used in pharmaceutical products even though alternative
grades of carbomers are available that are manufactured without the use
of benzene.
At the time of publication, carbomers manufactured with benzene may
fall under the United States Pharmacopeia-National Formulary (USP-NF)
monographs Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, or
Carbomer 1342. These monographs permit benzene levels as high as 5,000
parts per million (ppm), which is significantly higher than the limit
of 2 ppm on benzene as an impurity in the USP-NF Carbomer Homopolymer,
Carbomer Copolymer, and Carbomer Interpolymer monographs. To avoid
confusion, and because of the safety concerns associated with these
unacceptable levels of benzene permitted by these monographs, FDA has
asked the USP to remove (or ``omit'') the Carbomer 934P, Carbomer 940,
Carbomer 934, Carbomer 1342, and Carbomer 941 monographs from the USP-
NF compendium.
The guidance represents the current thinking of FDA on
``Reformulating Drug Products That Contain Carbomers Manufactured With
Benzene.'' 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
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved 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 part 314 pertaining to the submission of new drug applications have
been approved under OMB control number 0910-0001. The collections of
information in 21 CFR parts 210 and 211 pertaining to current good
manufacturing practice requirements have been approved under OMB
control number 0910-0139.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
https://www.fda.gov/drugs/guidance-
[[Page 89705]]
compliance-regulatory-information/guidances-drugs, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Dated: December 21, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-28675 Filed 12-27-23; 8:45 am]
BILLING CODE 4164-01-P
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