[Federal Register Volume 68, Number 28 (Tuesday, February 11, 2003)]
[Notices]
[Pages 6924-6925]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-3352]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D-0325]


International Conference on Harmonisation; Revised Guidance on 
Q3A Impurities in New Drug Substances; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a revised guidance entitled ``Q3A(R) Impurities in New 
Drug Substances.'' The revised guidance, which updates a guidance on 
the same topic published in the Federal Register of January 4, 1996 
(the 1996 guidance), was prepared under the auspices of the 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). The revised 
guidance clarifies the 1996 guidance, adds information, and provides 
consistency with more recently published ICH guidances. The revised 
guidance is intended to provide guidance to applicants for drug 
marketing registration on the content and qualification of impurities 
in new drug substances produced by chemical syntheses and not 
previously registered in a country, region, or member State.

DATES: The guidance is effective February 11, 2003. Submit written or 
electronic comments at any time.

ADDRESSES: Submit written requests for single copies of the guidance to 
the Division of Drug Information (HFD-240), Center for Drug Evaluation 
and Research, Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, or the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and 
Research (CBER), Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852, or by calling the CBER Voice Information System at 
1-800-835-4709 or 301-827-1800. Copies may be obtained from CBER's FAX 
Information System at 1-888-CBER-FAX or 301-827-3844. Submit written 
comments on the guidance to the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. Requests and comments should be identified with the docket 
number found in brackets in the heading of this document. See the 
SUPPLEMENTARY INFORAMTION section of this document for electronic 
access to the guidance.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guidance: Charles P. Hoiberg, Center for Drug 
Evaluation and Research (HFD-800), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-5918.
    Regarding the ICH: Janet Showalter, Office of International 
Programs (HFG-1), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-0864.

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

[[Page 6925]]

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, and 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's Health Products and Food Branch, 
and the European Free Trade Area.
    In accordance with FDA's good guidance practices (GGPs) regulation 
(21 CFR 10.115), this document is now being called a guidance, rather 
than a guideline.
    To facilitate the process of making ICH guidances available to the 
public, the agency has changed its procedure for publishing ICH 
guidances. As of April 2000, we no longer include the text of ICH 
guidances in the Federal Register. Instead, we publish a notice in the 
Federal Register announcing the availability of an ICH guidance. The 
ICH guidance is placed in the docket and can be obtained through 
regular agency sources (see the ADDRESSES section). Draft guidances are 
left in the original ICH format. The final guidance is reformatted to 
conform to the GGP style before publication.
    In the Federal Register of July 20, 2000 (65 FR 45085), FDA 
published a draft revised tripartite guidance entitled ``Q3A(R) 
Impurities in New Drug Substances.'' The notice gave interested persons 
an opportunity to submit comments by September 18, 2000. The draft 
revised guidance was a revision of ICH guidance on the same topic 
published in the Federal Register of January 4, 1996 (61 FR 372).
    After consideration of the comments received and revisions to the 
guidance by the Quality Expert Working Group of the ICH, a final draft 
of the guidance was submitted to the ICH Steering Committee and 
endorsed by the three participating regulatory agencies on February 6, 
2002.
    ICH Q3A(R) provides guidance on the information for drug marketing 
registration regarding the content and qualification of impurities in 
new drug substances produced by chemical syntheses and not previously 
registered within the three regions of the EC, Japan, and the United 
States. The guidance is not intended to apply to new drug substances 
used during the clinical research stage of development. The following 
types of drug substances are not covered in this guidance: Biological/
biotechnological, peptide, oligonucleotide, radiopharmaceutical, 
fermentation products and semisynthetic products derived therefrom, 
herbal products, and crude products of animal or plant origin.
    Impurities in new drug substances are addressed in the guidance 
from two different perspectives: (1) Chemistry aspects--classification 
and identification of impurities in specifications, report generation, 
listing of impurities in specifications, and a brief discussion of 
analytical procedures; and (2) safety aspects--guidance for qualifying 
those impurities that were not present, or were present at 
substantially lower levels, in batches of the new drug substance used 
in safety and clinical studies.
    The ICH Q3A guidance was revised to add information to certain 
sections and to provide clarification to other sections of the previous 
guidance. The most important sections that have been revised are:
    [sbull] The text on reporting, identification, and qualification 
thresholds.
    [sbull] The text on listing impurities in specifications to provide 
a clear distinction between ICH Q3A (listing impurities) and ICH Q6A 
(setting specifications).
    [sbull] The deletion of the exception to conventional rounding 
practice, i.e., the provision recommending no rounding up to 0.1 
percent for values between 0.05 and 0.03 percent.
    [sbull] Attachment 2--an illustration of reporting impurity results 
for identification and qualification in an application.
    [sbull] Attachment 3--a decision tree for identification and 
qualification.
    [sbull] Additions and revisions to the previous glossary include 
definitions for the terms ``unspecified impurity,'' ``identification 
threshold,'' and ``qualification threshold.''
    [sbull] References to more recently published ICH guidances 
entitled ``Q3B(R) Impurities in New Drug Products,'' ``Q3C Impurities: 
Residual Solvents,'' and ``Q6A Specifications: Test Procedures and 
Acceptance Criteria for New Drug Substances and New Drug Products: 
Chemical Substances.''
    Minor editorial changes were made to improve the clarity and 
consistency of the document.
    This guidance represents the agency's current thinking on 
impurities in new drug substances. 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. Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments on the guidance at any time. 
Two copies of any mailed comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. The 
guidance and received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/cder/guidance/index.htm, http://www.fda.gov/cber/publications.htm, or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: February 4, 2003.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 03-3352 Filed 2-10-03; 8:45 am]
BILLING CODE 4160-01-S