[Federal Register Volume 88, Number 248 (Thursday, December 28, 2023)]
[Notices]
[Pages 89703-89705]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-28675]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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:
     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-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 https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.

[[Page 89704]]

     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.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 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, [email protected].

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 https://www.fda.gov/media/133650/download) 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, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    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