Document ID: FDA-2015-D-3474-0001
Agency: fda
Document Type: Notice
Title: Draft 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 Conference on Harmonisation; Availability
Posted Date: 2015-10-16T04:00Z

[Federal Register Volume 80, Number 200 (Friday, October 16, 2015)]
[Notices]
[Pages 62537-62538]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-26361]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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

Draft 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 Conference on Harmonisation; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of draft recommendations for a new permitted daily 
exposure (PDE) for the residual solvent triethylamine and a revised PDE 
for the residual solvent methylisobutylketone, according to the 
maintenance procedures for the guidance for industry entitled ``Q3C 
Impurities: Residual Solvents.'' The draft recommendations were 
prepared under the auspices of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The document is intended to 
recommend acceptable amounts for the listed residual solvents in 
pharmaceuticals for the safety of the patient.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on the 
draft recommendations before it begins work on the final 
recommendations, submit either electronic or written comments on the 
document by December 15, 2015.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, 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 ``Draft 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 Conference on 
Harmonisation; Availability.'' Received comments will be placed in the 
docket and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at http://www.regulations.gov or at the Division of 
Dockets Management 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 http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    Submit written requests for single copies of the draft 
recommendations to the Division of Drug Information (HFD-240), 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 the office in processing your requests. The draft 
recommendations may also be obtained by mail by calling CBER at 1-800-
835-4709 or 240-402-8010. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the draft recommendations.

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: Michelle Limoli, CBER International Programs, 
Food and

[[Page 62538]]

Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7212, 
Silver Spring, MD 20993-0002, 301-796-8377.

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 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 tripartite 
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 among three regions: Europe, Japan, and North 
America. The eight ICH sponsors 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; the 
Pharmaceutical Research and Manufacturers of America; Health Canada; 
and Swissmedic. The ICH Secretariat, which coordinates the preparation 
of documentation, is provided by the International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization.
    In the Federal Register of December 24, 1997 (62 FR 67377), FDA 
published the ICH guidance for industry entitled ``Q3C Impurities: 
Residual Solvents.'' The guidance makes recommendations as to what 
amounts of residual solvents are considered to be 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 that new 
solvents and PDEs 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.
    In June 2015, the ICH Steering Committee agreed that draft 
recommendations for a new PDE for the residual solvent triethylamine 
and a revised PDE for the residual solvent methylisobutylketone should 
be made available for public comment. The draft recommendations are the 
product of the Quality Expert Working Group of the ICH. Comments about 
this draft will be considered by FDA and the Quality Expert Working 
Group.
    The draft recommendations provide guidance on the new PDE for the 
solvent trimethylamine and the revised PDE for the solvent 
methylisobutylketone. In addition, the data used to derive the PDEs are 
summarized. The document is intended to recommend acceptable amounts 
for the listed residual solvents in pharmaceuticals for the safety of 
the patient.
    The draft recommendations are being issued consistent with FDA's 
good guidance practices regulation (21 CFR 10.115). The draft 
recommendations for the solvents trimethylamine and 
methylisobutylketone, when finalized, will represent the current 
thinking of FDA on this topic. They do not establish any rights for any 
person and are 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 
http://www.regulations.gov, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

    Dated: October 9, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-26361 Filed 10-15-15; 8:45 am]
 BILLING CODE 4164-01-P