82 FR 34537 - Recommendations for the Permitted Daily Exposures for Two Solvents, Triethylamine and Methylisobutylketone, According to the Maintenance Procedures for the Guidance Q3C Impurities: Residual Solvents; International Council for Harmonisation; Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 82, Issue 141 (July 25, 2017)

The Food and Drug Administration (FDA or Agency) is announcing the availability of recommendations for a new permitted daily exposure (PDE) for the residual solvent triethylamine and a revised PDE for the residual solvent methylisobutylketone. The PDEs were developed according to the methods for establishing exposure limits included in the guidance for industry entitled ``Q3C Impurities: Residual Solvents.'' The recommendations were prepared under the auspices of the International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation. The document is intended to recommend acceptable amounts for the listed residual solvents in pharmaceuticals for the safety of the patient.

[Federal Register Volume 82, Number 141 (Tuesday, July 25, 2017)]
[Notices]
[Pages 34537-34538]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2017-15537]



[[Page 34537]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-D-3474]


Recommendations for the Permitted Daily Exposures for Two 
Solvents, Triethylamine and Methylisobutylketone, According to the 
Maintenance Procedures for the Guidance Q3C Impurities: Residual 
Solvents; International Council for Harmonisation; 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 recommendations for a new permitted daily exposure 
(PDE) for the residual solvent triethylamine and a revised PDE for the 
residual solvent methylisobutylketone. The PDEs were developed 
according to the methods for establishing exposure limits included in 
the guidance for industry entitled ``Q3C Impurities: Residual 
Solvents.'' The recommendations were prepared under the auspices of the 
International Council for Harmonisation (ICH), formerly the 
International Conference on Harmonisation. The document is intended to 
recommend acceptable amounts for the listed residual solvents in 
pharmaceuticals for the safety of the patient.

DATES: Submit either electronic or written comments on Agency guidances 
at any time.

ADDRESSES: You may submit comments 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-2015-D-3474 for ``Recommendations for the Permitted Daily Exposures 
for Two Solvents, Triethylamine and Methylisobutylketone, According to 
the Maintenance Procedures for the Guidance Q3C Impurities: Residual 
Solvents; International Council for Harmonisation; Guidance for 
Industry; Availability.'' 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.thefederalregister.org/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.
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research 
(CDER), Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002; or 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. The guidance may also be obtained by mail by calling 
CBER at 800-835-4709 or 240-402-8010. See the SUPPLEMENTARY INFORMATION 
section for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guidance: Timothy J. McGovern, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6300, Silver Spring, MD 20993-0002, 240-
402-0477.
    Regarding the ICH: Amanda Roache, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 1176, Silver Spring, MD 20993-0002, 301-796-4548.

SUPPLEMENTARY INFORMATION:

I. Background

    In recent years, many important initiatives have been undertaken by 
regulatory authorities and industry associations to promote 
international harmonization of regulatory requirements. FDA has 
participated in many meetings designed to enhance harmonization and is 
committed to seeking scientifically based harmonized technical 
procedures for pharmaceutical

[[Page 34538]]

development. One of the goals of harmonization is to identify and then 
reduce differences in technical requirements for drug development among 
regulatory agencies.
    ICH was organized to provide an opportunity for harmonization 
initiatives to be developed with input from both regulatory and 
industry representatives. FDA also seeks input from consumer 
representatives and others. ICH is concerned with harmonization of 
technical requirements for the registration of pharmaceutical products 
for human use among regulators around the world. The six founding 
members of the ICH are: The European Commission; the European 
Federation of Pharmaceutical Industries Associations; the Japanese 
Ministry of Health, Labour, and Welfare; the Japanese Pharmaceutical 
Manufacturers Association; CDER and CBER, FDA; and the Pharmaceutical 
Research and Manufacturers of America. The Standing Members of the ICH 
Association include Health Canada and Swissmedic. Any party eligible as 
a Member in accordance with the ICH Articles of Association can apply 
for membership in writing to the ICH Secretariat. The ICH Secretariat, 
which coordinates the preparation of documentation, operates as an 
international nonprofit organization and is funded by the Members of 
the ICH Association. The ICH Assembly is the overarching body of the 
Association and includes representatives from each of the ICH members 
and observers.
    In the Federal Register of December 24, 1997 (62 FR 67377), FDA 
published a notice announcing the availability of the ICH guidance for 
industry entitled ``Q3C Impurities: Residual Solvents.'' The guidance 
makes recommendations as to what amounts of residual solvents are 
considered toxicologically acceptable for some residual solvents. Upon 
issuance in 1997, the text and appendix 1 of the guidance contained 
several tables and a list of solvents categorizing residual solvents by 
toxicity, classes 1 through 3, with class 1 being the most toxic. The 
ICH Quality Expert Working Group (EWG) agreed that the PDE could be 
modified if reliable and more relevant toxicity data were brought to 
the attention of the group and the modified PDE could result in a 
revision of the tables and list.
    In 1999, ICH instituted a Q3C maintenance agreement and formed a 
maintenance EWG (Q3C EWG). The agreement provided for the revisitation 
of solvent PDEs and allowed for minor changes to the tables and list 
that include the existing PDEs. The agreement also provided for new 
solvents and PDEs that could be added to the tables and list based on 
adequate toxicity data. In the Federal Register of February 12, 2002 
(67 FR 6542), FDA briefly described the process for proposing future 
revisions to the PDE. In the same notice, the Agency announced its 
decision to delink the tables and list from the Q3C guidance and create 
a stand-alone document entitled ``Q3C: Tables and List'' to facilitate 
making changes recommended by ICH, available at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073395.pdf. The ``Q3C: Tables and List'' has been updated as of 
January 2017 to include the recommended PDE for triethylamine and 
methylisobutylketone.
    In the Federal Register of October 16, 2015 (80 FR 62537), FDA 
published a notice announcing the availability of draft recommendations 
for the PDEs for two solvents, trimethylamine and methylisobutylketone, 
according to the maintenance procedures for the guidance entitled ``Q3C 
Impurities: Residual Solvents,'' available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm073394.pdf. The notice gave interested persons an opportunity to 
submit comments by December 15, 2015. After consideration of the 
comments received and revisions to the guidance, a final draft of the 
recommendations was submitted to the ICH Assembly and endorsed by the 
regulatory agencies in November 2016.
    The guidance provides a new PDE for the solvent trimethylamine and 
a revised PDE for the solvent methylisobutylketone. In addition, the 
data used to derive the PDEs are summarized. Revisions made to the 
final guidance as a result of comments include a modification of the 
PDE for methylisobutylketone from 22.6 milligrams (mg)/day to 45 mg/day 
based on reconsideration of the severity of effects identified in rat 
studies and the human relevance of effects identified in mouse 
carcinogenicity study. The recommendation to place methylisobutylketone 
into class 2 remains. The ``Q3C: Tables and List'' has been updated as 
of January 2017 to include the recommended PDE for triethylamine and 
methylisobutylketone.
    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 ``Q3C Impurities: Residual Solvents.'' 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. Electronic Access

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

    Dated: July 18, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-15537 Filed 7-24-17; 8:45 am]
 BILLING CODE 4164-01-P