[Federal Register Volume 73, Number 242 (Tuesday, December 16, 2008)]
[Notices]
[Pages 76361-76362]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-29674]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-D-0629]


Draft Guidance for Industry on Genotoxic and Carcinogenic 
Impurities in Drug Substances and Products: Recommended Approaches; 
Availability

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``Genotoxic and 
Carcinogenic Impurities in Drug Substances and Products: Recommended 
Approaches.'' This draft guidance is intended to inform pharmaceutical 
manufacturers of the agency's thinking regarding genotoxic and 
carcinogenic impurities in drug substances and drug products, including 
biologic products that are regulated by the Center for Drug Evaluation 
and Research (CDER), and to provide recommendations on how to evaluate 
the safety of these impurities during clinical development and for 
marketing applications. This draft guidance, when finalized, will 
clarify FDA's additional testing and exposure threshold recommendations 
for situations in which genotoxic or carcinogenic impurities are 
present. This draft guidance addresses synthetic impurities and 
degradants in drug substances, but does not otherwise address the 
genotoxicity or carcinogenicity of actual drug substances or intended 
drug product ingredients. This draft guidance also applies to known 
starting materials or anticipated reaction products.

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 
this draft guidance before it begins work on the final version of the 
guidance, submit written or electronic comments on the draft guidance 
by February 17, 2009.

ADDRESSES:  Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. Submit written comments on the draft guidance to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
comments to http://www.regulations.gov. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the draft guidance 
document.

FOR FURTHER INFORMATION CONTACT:  David Jacobson-Kram, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 6488, Silver Spring, MD 20993-0002, 301-
796-0175.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Genotoxic and Carcinogenic Impurities in Drug Substances and 
Products: Recommended Approaches.'' This draft guidance is intended to 
inform pharmaceutical manufacturers of the agency's thinking regarding 
genotoxic and carcinogenic impurities in drug substances and drug 
products, including biologic products regulated by CDER,

[[Page 76362]]

and to provide recommendations on how to evaluate the safety of these 
impurities. Genotoxic compounds, because of their ability to induce 
genetic mutations, chromosomal breaks, and/or chromosomal 
rearrangements, have the potential for being carcinogenic to humans.
    Regulatory issues related to the presence of genotoxic or 
carcinogenic impurities have arisen with greater frequency because of 
enhanced technological capability in identifying impurities and an 
increased focus on their potential for negatively affecting human 
health. FDA guidance documents that address issues related to 
impurities and residual solvents include the following International 
Conference on Harmonisation (ICH) guidances for industry: ``Q3A(R2) 
Impurities in New Drug Substances,'' ``Q3B(R2) Impurities in New Drug 
Products,'' and ``Q3C(R3) Impurities: Guideline for Residual 
Solvents.'' However, these ICH guidances do not fully address 
situations in which genotoxic or carcinogenic impurities are present.
    This draft guidance describes acceptable approaches for initially 
evaluating the genotoxic potential of impurities as well as approaches 
for handling impurities with known genotoxic or carcinogenic potential. 
These approaches include prevention of the impurity formation, 
reduction of the impurity level to an acceptable threshold, or 
additional characterization of the genotoxic and carcinogenic risk. The 
draft guidance also discusses various factors that should be considered 
in the overall risk assessment based on the drug indication, duration 
of use, and the clinical development stage.
    FDA has developed this draft guidance because these types of 
impurities are being identified more frequently and because FDA has 
received a number of questions from industry regarding acceptable 
approaches.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the agency's current thinking on recommended 
approaches for genotoxic and carcinogenic impurities in drug substances 
and products. 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.

II. The Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). The collections of information in 21 CFR parts 312 and 314 have 
been approved under OMB Control Numbers 0910-0014 and 0910-0001, 
respectively.

III. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
    Please note that on January 15, 2008, the FDA Division of Dockets 
Management Web site transitioned to the Federal Dockets Management 
System (FDMS). FDMS is a Government-wide, electronic docket management 
system. Electronic comments or submissions will be accepted by FDA only 
through FDMS at http://www.regulations.gov.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/cder/guidance/index.htm or http://www.regulations.gov.

    Dated: December 8, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-29674 Filed 12-15-08; 8:45 am]
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