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)
Food and Drug Administration
Federal Register Volume 82, Issue 141 (July 25, 2017)
| Page Range | 34537-34538 | |
| FR Document | 2017-15537 |
[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]] ----------------------------------------------------------------------- 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. ----------------------------------------------------------------------- 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
![Federal Register / Vol. 82, No. 141 / Tuesday, July 25, 2017 / Notices 34537
DEPARTMENT OF HEALTH AND comments, that information will be ‘‘confidential.’’ Any information marked
HUMAN SERVICES posted on https://www.regulations.gov. as ‘‘confidential’’ will not be disclosed
• If you want to submit a comment except in accordance with 21 CFR 10.20
Food and Drug Administration with confidential information that you and other applicable disclosure law. For
[Docket No. FDA–2015–D–3474]
do not wish to be made available to the more information about FDA’s posting
public, submit the comment as a of comments to public dockets, see 80
Recommendations for the Permitted written/paper submission and in the FR 56469, September 18, 2015, or access
Daily Exposures for Two Solvents, manner detailed (see ‘‘Written/Paper the information at: https://www.gpo.gov/
Triethylamine and Submissions’’ and ‘‘Instructions’’). fdsys/pkg/FR-2015-09-18/pdf/2015-
Methylisobutylketone, According to Written/Paper Submissions 23389.pdf.
the Maintenance Procedures for the Docket: For access to the docket to
Guidance Q3C Impurities: Residual Submit written/paper submissions as read background documents or the
Solvents; International Council for follows: electronic and written/paper comments
• Mail/Hand delivery/Courier (for received, go to https://
Harmonisation; Guidance for Industry;
written/paper submissions): Dockets www.regulations.gov and insert the
Availability
Management Staff (HFA–305), Food and docket number, found in brackets in the
AGENCY: Food and Drug Administration, Drug Administration, 5630 Fishers heading of this document, into the
HHS. Lane, Rm. 1061, Rockville, MD 20852. ‘‘Search’’ box and follow the prompts
ACTION: Notice of availability. • For written/paper comments
and/or go to the Dockets Management
submitted to the Dockets Management
SUMMARY: The Food and Drug Staff, 5630 Fishers Lane, Rm. 1061,
Staff, FDA will post your comment, as
Administration (FDA or Agency) is Rockville, MD 20852.
well as any attachments, except for
announcing the availability of Submit written requests for single
information submitted, marked and
recommendations for a new permitted copies of this guidance to the Division
identified, as confidential, if submitted
daily exposure (PDE) for the residual of Drug Information, Center for Drug
as detailed in ‘‘Instructions.’’
solvent triethylamine and a revised PDE Instructions: All submissions received Evaluation and Research (CDER), Food
for the residual solvent must include the Docket No. FDA– and Drug Administration, 10001 New
methylisobutylketone. The PDEs were 2015–D–3474 for ‘‘Recommendations Hampshire Ave., Hillandale Building,
developed according to the methods for for the Permitted Daily Exposures for 4th Floor, Silver Spring, MD 20993–
establishing exposure limits included in Two Solvents, Triethylamine and 0002; or the Office of Communication,
the guidance for industry entitled ‘‘Q3C Methylisobutylketone, According to the Outreach and Development, Center for
Impurities: Residual Solvents.’’ The Maintenance Procedures for the Biologics Evaluation and Research
recommendations were prepared under Guidance Q3C Impurities: Residual (CBER), Food and Drug Administration,
the auspices of the International Council Solvents; International Council for 10903 New Hampshire Ave., Bldg. 71,
for Harmonisation (ICH), formerly the Harmonisation; Guidance for Industry; Rm. 3128, Silver Spring, MD 20993–
International Conference on Availability.’’ Received comments will 0002. Send one self-addressed adhesive
Harmonisation. The document is be placed in the docket and, except for label to assist that office in processing
intended to recommend acceptable those submitted as ‘‘Confidential your requests. The guidance may also be
amounts for the listed residual solvents Submissions,’’ publicly viewable at obtained by mail by calling CBER at
in pharmaceuticals for the safety of the https://www.regulations.gov or at the 800–835–4709 or 240–402–8010. See
patient. Dockets Management Staff between 9 the SUPPLEMENTARY INFORMATION section
a.m. and 4 p.m., Monday through for electronic access to the guidance
DATES: Submit either electronic or
Friday. document.
written comments on Agency guidances
at any time. • Confidential Submissions—To FOR FURTHER INFORMATION CONTACT:
ADDRESSES: You may submit comments submit a comment with confidential Regarding the guidance: Timothy J.
as follows: information that you do not wish to be McGovern, Center for Drug Evaluation
made publicly available, submit your and Research, Food and Drug
Electronic Submissions comments only as a written/paper Administration, 10903 New Hampshire
Submit electronic comments in the submission. You should submit two Ave., Bldg. 22, Rm. 6300, Silver Spring,
following way: copies total. One copy will include the MD 20993–0002, 240–402–0477.
• Federal eRulemaking Portal: information you claim to be confidential Regarding the ICH: Amanda Roache,
https://www.regulations.gov. Follow the with a heading or cover note that states Center for Drug Evaluation and
instructions for submitting comments. ‘‘THIS DOCUMENT CONTAINS Research, Food and Drug
Comments submitted electronically, CONFIDENTIAL INFORMATION.’’ The Administration, 10903 New Hampshire
including attachments, to https:// Agency will review this copy, including Ave., Bldg. 51, Rm. 1176, Silver Spring,
www.regulations.gov will be posted to the claimed confidential information, in MD 20993–0002, 301–796–4548.
the docket unchanged. Because your its consideration of comments. The SUPPLEMENTARY INFORMATION:
comment will be made public, you are second copy, which will have the
solely responsible for ensuring that your claimed confidential information I. Background
comment does not include any redacted/blacked out, will be available In recent years, many important
confidential information that you or a for public viewing and posted on initiatives have been undertaken by
third party may not wish to be posted, https://www.regulations.gov. Submit regulatory authorities and industry
mstockstill on DSK30JT082PROD with NOTICES
such as medical information, your or both copies to the Dockets Management associations to promote international
anyone else’s Social Security number, or Staff. If you do not wish your name and harmonization of regulatory
confidential business information, such contact information to be made publicly requirements. FDA has participated in
as a manufacturing process. Please note available, you can provide this many meetings designed to enhance
that if you include your name, contact information on the cover sheet and not harmonization and is committed to
information, or other information that in the body of your comments and you seeking scientifically based harmonized
identifies you in the body of your must identify this information as technical procedures for pharmaceutical
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![34538 Federal Register / Vol. 82, No. 141 / Tuesday, July 25, 2017 / Notices
development. One of the goals of solvents and PDEs that could be added use an alternative approach if it satisfies
harmonization is to identify and then to the tables and list based on adequate the requirements of the applicable
reduce differences in technical toxicity data. In the Federal Register of statutes and regulations.
requirements for drug development February 12, 2002 (67 FR 6542), FDA
II. Electronic Access
among regulatory agencies. briefly described the process for
ICH was organized to provide an proposing future revisions to the PDE. Persons with access to the Internet
opportunity for harmonization In the same notice, the Agency may obtain the document at https://
initiatives to be developed with input announced its decision to delink the www.fda.gov/Drugs/Guidance
from both regulatory and industry tables and list from the Q3C guidance ComplianceRegulatoryInformation/
representatives. FDA also seeks input and create a stand-alone document Guidances/default.htm, https://
from consumer representatives and entitled ‘‘Q3C: Tables and List’’ to www.fda.gov/BiologicsBloodVaccines/
others. ICH is concerned with facilitate making changes recommended GuidanceCompliance
harmonization of technical by ICH, available at https:// RegulatoryInformation/Guidances/
requirements for the registration of www.fda.gov/downloads/drugs/ default.htm, or https://
pharmaceutical products for human use guidancecomplianceregulatory www.regulations.gov.
among regulators around the world. The information/guidances/ucm073395.pdf. Dated: July 18, 2017.
six founding members of the ICH are: The ‘‘Q3C: Tables and List’’ has been Anna K. Abram,
The European Commission; the updated as of January 2017 to include
European Federation of Pharmaceutical Deputy Commissioner for Policy, Planning,
the recommended PDE for triethylamine
Legislation, and Analysis.
Industries Associations; the Japanese and methylisobutylketone.
[FR Doc. 2017–15537 Filed 7–24–17; 8:45 am]
Ministry of Health, Labour, and Welfare; In the Federal Register of October 16,
the Japanese Pharmaceutical 2015 (80 FR 62537), FDA published a BILLING CODE 4164–01–P
Manufacturers Association; CDER and notice announcing the availability of
CBER, FDA; and the Pharmaceutical draft recommendations for the PDEs for
Research and Manufacturers of America. two solvents, trimethylamine and DEPARTMENT OF HEALTH AND
The Standing Members of the ICH methylisobutylketone, according to the HUMAN SERVICES
Association include Health Canada and maintenance procedures for the Food and Drug Administration
Swissmedic. Any party eligible as a guidance entitled ‘‘Q3C Impurities:
Member in accordance with the ICH Residual Solvents,’’ available at https:// [Docket No. FDA–2015–D–3235]
Articles of Association can apply for www.fda.gov/ucm/groups/fdagov-
membership in writing to the ICH public/@fdagov-drugs-gen/documents/ M4E(R2): The Common Technical
Secretariat. The ICH Secretariat, which document/ucm073394.pdf. The notice Document—Efficacy; International
coordinates the preparation of gave interested persons an opportunity Council for Harmonisation; Guidance
documentation, operates as an to submit comments by December 15, for Industry; Availability
international nonprofit organization and 2015. After consideration of the AGENCY: Food and Drug Administration,
is funded by the Members of the ICH comments received and revisions to the HHS.
Association. The ICH Assembly is the guidance, a final draft of the
ACTION: Notice of availability.
overarching body of the Association and recommendations was submitted to the
includes representatives from each of ICH Assembly and endorsed by the SUMMARY: The Food and Drug
the ICH members and observers. regulatory agencies in November 2016. Administration (FDA or Agency) is
In the Federal Register of December The guidance provides a new PDE for announcing the availability of a
24, 1997 (62 FR 67377), FDA published the solvent trimethylamine and a guidance entitled ‘‘M4E(R2): The CTD—
a notice announcing the availability of revised PDE for the solvent Efficacy.’’ The guidance was prepared
the ICH guidance for industry entitled methylisobutylketone. In addition, the under the auspices of the International
‘‘Q3C Impurities: Residual Solvents.’’ data used to derive the PDEs are Council for Harmonisation (ICH),
The guidance makes recommendations summarized. Revisions made to the formerly the International Conference
as to what amounts of residual solvents final guidance as a result of comments on Harmonisation. The guidance revises
are considered toxicologically include a modification of the PDE for the ICH guidance ‘‘M4E: The CTD—
acceptable for some residual solvents. methylisobutylketone from 22.6 Efficacy’’ (M4E guidance). The revised
Upon issuance in 1997, the text and milligrams (mg)/day to 45 mg/day based guidance standardizes the presentation
appendix 1 of the guidance contained on reconsideration of the severity of of benefit-risk information in regulatory
several tables and a list of solvents effects identified in rat studies and the submissions, providing greater
categorizing residual solvents by human relevance of effects identified in specificity on the format and structure
toxicity, classes 1 through 3, with class mouse carcinogenicity study. The
of benefit-risk information. This
1 being the most toxic. The ICH Quality recommendation to place
revision is intended to facilitate
Expert Working Group (EWG) agreed methylisobutylketone into class 2
communication among regulators and
that the PDE could be modified if remains. The ‘‘Q3C: Tables and List’’
industry.
reliable and more relevant toxicity data has been updated as of January 2017 to
were brought to the attention of the include the recommended PDE for DATES: Submit either electronic or
group and the modified PDE could triethylamine and written comments on Agency guidance’s
result in a revision of the tables and list. methylisobutylketone. at any time.
In 1999, ICH instituted a Q3C This guidance is being issued ADDRESSES: You may submit comments
mstockstill on DSK30JT082PROD with NOTICES
maintenance agreement and formed a consistent with FDA’s good guidance as follows:
maintenance EWG (Q3C EWG). The practices regulation (21 CFR 10.115).
agreement provided for the revisitation The guidance represents the current Electronic Submissions
of solvent PDEs and allowed for minor thinking of FDA on ‘‘Q3C Impurities: Submit electronic comments in the
changes to the tables and list that Residual Solvents.’’ It does not establish following way:
include the existing PDEs. The any rights for any person and is not • Federal eRulemaking Portal:
agreement also provided for new binding on FDA or the public. You can https://www.regulations.gov. Follow the
VerDate Sep<11>2014 19:30 Jul 24, 2017 Jkt 241001 PO 00000 Frm 00067 Fmt 4703 Sfmt 4703 E:\FR\FM\25JYN1.SGM 25JYN1](https://thefederalregister.org/doc/82_FR_34678/page/2.svg)
Document Created: 2018-10-24 11:22:23
Document Modified: 2018-10-24 11:22:23
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notice of availability. | |
| Dates | Submit either electronic or written comments on Agency guidances at any time. | |
| 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. | |
| FR Citation | 82 FR 34537 |
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