[Federal Register Volume 77, Number 36 (Thursday, February 23, 2012)]
[Pages 10754-10755]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-4164]



Food and Drug Administration

[Docket No. FDA-2010-N-0327]

International Conference on Harmonisation; Final Recommendation 
for the Revision of the Permitted Daily Exposure for the Solvent Cumene 
According to the Maintenance Procedures for the Guidance Q3C 
Impurities: Residual Solvents; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.


SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a final recommendation for the revision of the 
permitted daily exposure (PDE) for the solvent cumene according to the 
maintenance procedures for the guidance for industry entitled ``Q3C 
Impurities: Residual Solvents.'' The recommendation was prepared under 
the auspices of the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH).

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

ADDRESSES: Submit written requests for single copies of the 
recommendation to the Division of Drug Information (HFD-240), Center 
for Drug Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002, 
or the Office of Communication, Outreach and Development (HFM-40), 
Center for Biologics Evaluation and Research (CBER), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one 
self-addressed adhesive label to assist the office in processing your 
requests. The draft recommendation may also be obtained by mail by 
calling CBER at 1-800-835-4709 or 301-827-1800. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the draft recommendation.
    Submit electronic comments on the recommendation to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.


Regarding the Q3C Guidance

    David Jacobson-Kram, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 6488, 
Silver Spring, MD 20993, 301-796-0175.

Regarding the ICH

    Michelle Limoli, Office of International Programs, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 32, rm. 3506, Silver 
Spring, MD 20993-0002, 301-796-4600.


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: The European Union, Japan, 
and the United States. The six 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; the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research, FDA; and 
the Pharmaceutical Research and Manufacturers of America. 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, Health Canada, and the European Free Trade Area.
    In 1999, ICH instituted a Q3C maintenance agreement and formed a 
maintenance Expert Working Group (Q3C EWG). The agreement provided for 
the reconsideration 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 PDEs. 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.

II. Revised PDE for Cumene

    In the Federal Register of July 20, 2010 (75 FR 42098), FDA 
published a notice announcing the availability of a draft 
recommendation for the revision of the PDE for cumene according to the 
ICH maintenance procedures. The notice gave interested persons an 
opportunity to submit comments by September 20, 2010.
    After consideration of the comments received and revisions to the 
guidance, a final draft of the recommendation was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
Agencies in February 2011.
    The final recommendation addresses the safety classification of 
cumene. When the Q3C guidance was published in 1997 (62 FR 67377, 
December 24, 1997), cumene was listed as a class 3

[[Page 10755]]

solvent (i.e., a solvent with low toxicity). The Q3C EWG reviewed new 
toxicity data derived from a carcinogenicity study performed by the 
National Toxicology Program. The new data suggest a positive systemic 
carcinogenic effect, and this observation raises the toxicity 
associated with this solvent. The final recommendation is that cumene 
be placed into class 2. A PDE of 0.7 milligrams per day and a 
concentration limit of 70 parts per million are being declared for this 
solvent. The analysis and recommendation are available for review on 
the Internet (see section V of this document on electronic access). The 
final recommendation is also available from the Division of Drug 
Information (see ADDRESSES). The Agency will revise the tables in the 
guidance ``Q3C--Tables and List'' to reflect the ICH final 
recommendation for cumene.
    The final recommendation for the solvent cumene is being issued 
consistent with FDA's good guidance practices regulation (21 CFR 
10.115). The revised PDE for the solvent cumene contained in the 
revised guidance ``Q3C--Tables and List'' represents the Agency's 
current thinking on this topic. It does not create or confer any rights 
for or on any person and does not operate to bind FDA or the public. An 
alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations.

III. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. The recommendation and received comments may be seen in 
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

IV. Electronic Access

    Persons with access to the Internet may obtain the Q3C guidance 
documents at http://www.regulations.gov, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
    Information on the Q3C maintenance process as well as proposals, 
data analysis, and draft and final recommendations for revisions to the 
tables and list are available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm125820.htm.

    Dated: February 16, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-4164 Filed 2-22-12; 8:45 am]