[Federal Register Volume 67, Number 29 (Tuesday, February 12, 2002)]
[Notices]
[Pages 6542-6544]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-3388]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01B-0431]


International Conference on Harmonisation; Draft Recommendations 
for the Revision of the Permitted Daily Exposures for Two Solvents, N-
Methylpyrrolidone and Tetrahydrofuran, According to the Maintenance 
Procedures for the Guidance Q3C Impurities: Residual Solvents; 
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 draft recommendations for the revision of the permitted 
daily exposures (PDE) for two solvents, n-methylpyrrolidone (NMP) and 
tetrahydrofuran (THF), according to the maintenance procedures for 
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). This document also 
describes procedures for proposing future revisions to the PDE.

DATES: Submit written or electronic comments on the draft 
recommendations by March 14, 2002.

ADDRESSES: Submit written comments on the draft recommendations 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. Submit written requests for 
single copies of these draft recommendations 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, 1401 Rockville Pike, 
Rockville, MD 20852-1448, FAX 888-CBERFAX. Send two self-addressed 
adhesive labels to assist the office in processing your requests. See 
the SUPPLEMENTARY INFORMATION section for electronic access to 
documents and maintenance procedures.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guidance: Robert Osterberg, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 5600 
Fishers Lane,Rockville, MD 20857, 301-827-2120.
    Regarding the ICH: Janet J. Showalter, Office of International 
Programs (HFG-1),Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-0865.

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: 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, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    In accordance with FDA's good guidance practices (GGPs) regulation 
(65 FR 56468, September 19, 2000), this document is being called a 
guidance, rather than a guideline.

[[Page 6543]]

    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 will be 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 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 safe in pharmaceuticals. 
The guidance recommends use of less toxic solvents and describes levels 
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 Quality Expert Working Group (EWG) agreed that the PDE could 
be modified if reliable and relevant toxicity data were brought to the 
attention of the group and that the modified PDE would 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. This notice announces the availability of draft 
recommendations for the revision of the PDE for NMP and THF according 
to the Q3C maintenance procedures. It also briefly describes the 
process for proposing future revisions to the PDE.

II. Draft Recommendations to Revise the Tables and List

    In July of 2000, the ICH Steering Committee agreed that draft 
proposals and recommendations to revise the PDE for the solvents NMP 
and THF should be made available for public comment. The draft 
recommendations are the product of the Q3C EWG review of new data.

A. N-Methylpyrrolidone (NMP)

    The Q3C EWG received new toxicity data for the solvent NMP in late 
1999. The data had been provided to FDA by the NMP producers group, who 
had proposed moving NMP from class 2 to class 3. The data resulted from 
a 2-year chronic feeding study in rats performed by E.I. Dupont de 
Nemours & Co (unpublished data). The data were sent to the members of 
the Q3C EWG for their analysis. These data appeared to be the best 
available upon which to make a recommendation to the ICH Steering 
Committee regarding a change in the status of NMP. At the last ICH 
meeting, February 28 to March 2, 2000, the ICH Steering Committee was 
briefed on the results of the EWG's analysis. The recommendation was to 
keep NMP in class 2 and to reduce the PDE. The analysis and the draft 
recommendation are available for review at http://www.fda.gov/cder/audiences/iact/iachome.htm. They are also available from the Division 
of Drug Information (HFD-240); address above.

B. Tetrahydrofuran (THF)

    The Q3C EWG reviewed new toxicity data for the solvent THF. The 
data were published by the U.S. National Toxicology Program and 
consisted of data from several mutagenicity studies and two 
carcinogenicity studies in rodents via the inhalational route of 
administration. Information was sent to the members of the Q3C EWG for 
their analysis. At the last ICH meeting, February 28 to March 2, 2000, 
the ICH Steering Committee was briefed on the results of the Q3C EWG's 
analysis. The recommendation was to move THF from class 3 into class 2. 
The analysis and the draft recommendation are available for review at 
http://www.fda.gov/cder/audiences/iact/iachome.htm. They are also 
available from the Division of Drug Information (HFD-240) (address 
above).
    The agency is interested in comments on the draft recommendations 
regarding the classification of NMP and THF. Comments about the draft 
recommendations will be considered by FDA and the Q3C EWG.

III. Process for Proposing Future Revisions

    In November 2000, the ICH Steering Committee agreed to formalize 
the maintenance procedures for the guidance entitled ``Q3C Impurities: 
Residual Solvents.'' The maintenance procedures include multiple ways 
to establish a PDE for a new solvent or to revise a PDE for an already 
classified solvent. A proposal with supporting information can be 
submitted to the ICH Secretariat, to the regulatory agency via the 
public docket, or to an ICH-involved scientist in an agency or in a 
pharmaceutical company to submit to the ICH Secretariat. The 
maintenance procedures state that this information should be based on 
significant toxicity data from studies such as genotoxicity studies, 
repeat-dose studies, reproductive toxicity studies, and/or other 
relevant toxicology studies. Single-dose toxicity data alone are not 
sufficient. The toxicity data should be of good laboratory practice 
quality and sufficient to calculate a PDE for a new solvent that will 
place the new solvent into a toxicity class.
    The details of the ICH Q3C maintenance procedures are available on 
the Internet at http://www.fda.gov/cder/audiences/iact/iachome.htm.

IV. Procedural Changes to Facilitate the Maintenance Process

    To facilitate the maintenance process, FDA has decided to delink 
the tables and list from the Q3C guidance and create a stand alone 
guidance entitled ``Q3C: Tables and List.'' Creating a stand alone 
document will enable the agency to update the tables and list when ICH 
endorses a recommendation to recategorize, remove, or add solvents 
without revising the Q3C guidance. In addition, the 1997 guidance has 
been reformatted consistent with FDA's good guidance practices 
regulation (21 CFR 10.115). Both the reformatted Q3C guidance and the 
delinked tables and list are available on the agency's Web sites.
    The availability of draft and final recommendations for revisions 
of PDEs and classifications will be announced through a notice in the 
Federal Register. In addition, an FDA Web site at http://www.fda.gov/cder/audiences/iact/iachome.htm details the maintenance procedures, 
provides contact information, and allows the dissemination of the 
revised information as quickly as possible. In the future, notices in 
the Federal Register announcing proposals and draft and final 
recommendations to change the list will send the reader to the Web site 
for details.
    The Q3C EWG's draft recommendations for the two solvents will, when 
finalized, represent the agency's current thinking on this topic. They 
do not create or confer any rights for or on any person and do 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.

[[Page 6544]]

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments on the recommendations 
to change the list by March 14, 2002. Two copies of any 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 draft recommendations and received 
comments may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday.

V. Electronic Access

    Persons with access to the Internet may obtain the Q3C documents at 
http://www.fda.gov/cder/guidance/index.htm, or http://www.fda.gov/cber/guidelines.htm. 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 being made available at http://www.fda.gov/cder/audiences/iact/iachome.htm. The electronic address for 
submitting comments to Dockets Management Branch is http://www.fda.gov/dockets/ecomments.

    Dated: February 5, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-3388 Filed 2-11-02; 8:45 am]
BILLING CODE 4160-01-S