[Federal Register Volume 68, Number 219 (Thursday, November 13, 2003)]
[Notices]
[Pages 64352-64353]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-28372]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2001B-0431]


International Conference on Harmonisation; Final Recommendations 
on 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 final 
recommendations to revise the permitted daily exposures (PDEs) for two 
solvents, n-methylpyrrolidone (NMP) and tetrahydrofuran (THF), 
according to the maintenance procedures for the guidance for industry 
entitled ``Q3C Impurities: Residual Solvents.'' The final 
recommendations were reached under the auspices of the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH).

DATES: Submit written or electronic comments on guidance documents at 
any time.

ADDRESSES: Submit written comments on the analyses and recommendations 
to revise the PDEs for NMP and THF 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.fda.gov/dockets/ecomments. Submit written requests for single 
copies of the documents 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 888-223-7329. 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 Q3C guidance: Robert Osterberg, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2120; or Andrew Shrake, 
Center for Biologics Evaluation and Research (HFM-345), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1148, 301-402-
4635.
    Regarding the ICH: Michelle Limoli, 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 harmonisation of regulatory requirements. FDA has 
participated in many meetings designed to enhance harmonisation and is 
committed to seeking scientifically based, harmonized technical 
procedures for pharmaceutical development. One of the goals of 
harmonisation 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 
harmonisation 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 
harmonisation 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.

[[Page 64353]]

    In the Federal Register of December 24, 1997 (62 FR 67377), FDA 
published the ICH draft guidance for industry entitled ``Q3C 
Impurities: Residual Solvents.'' The draft guidance makes 
recommendations as to what amounts of residual solvents are considered 
safe in pharmaceuticals. The draft 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 draft 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 
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.
    In the Federal Register of February 12, 2002 (67 FR 6542), FDA also 
announced the availability of draft recommendations for the revision of 
the PDE for NMP and THF according to the Q3C maintenance procedures. 
The notice gave interested persons an opportunity to submit comments by 
March 14, 2002.

II. Revised PDEs for NMP and THF

    After consideration of the comments received, the EWG's 
recommendations to revise the PDEs for NMP and THF were submitted to 
the ICH Steering Committee and agreement was reached by the three 
participating regulatory agencies in September 2002.

A. N-Methylpyrrolidone (NMP)

    The Q3C EWG received new toxicity data for the solvent NMP in late 
1999. In February 2002, FDA made available for comment the EWG's draft 
recommendation for the revision of the PDE for NMP (67 FR 6542 at 
6543). At the September 2002 ICH meeting, the Steering Committee agreed 
to the EWG's recommendation to keep NMP in Class 2. A PDE of 5.3 
milligrams per day (mg/day) and a concentration limit of 530 parts per 
million (ppm) are being declared for this solvent.

B. Tetrahydrofuran (THF)

    The Q3C EWG reviewed new toxicity data for the solvent THF. In 
February 2002, FDA made available for comment the EWG's draft 
recommendation for the revision of the PDE for THF (67 FR 6542 at 
6543). At the September 2002 ICH meeting, the Steering Committee agreed 
to the EWG's recommendation to move THF from class 3 to class 2. A PDE 
of 7.2 mg/day and a concentration limit of 720 ppm are being declared 
for this solvent.
    The analyses and recommendations for NMP and THF 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) (see 
ADDRESSES). The agency will revise the tables and list in the guidance 
``Q3C: Tables and List'' to reflect the ICH final recommendations for 
NMP and THF.
    The revised PDEs for the two solvents contained in the revised 
guidance ``Q3C: Tables and List'' 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.
    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments on the list and on 
guidance documents at any time. 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 analyses and recommendations and received 
comments may be seen in the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.

III. Internet Access to Documents and the Maintenance Procedures

    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, and 
proposals, recommendations, and agreements for revisions to the tables 
and list are made available at http://www.fda.gov/cder/audiences/iact/iachome.htm. The electronic address for the Division of Dockets 
Management is http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: November 4, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-28372 Filed 11-12-03; 8:45 am]
BILLING CODE 4160-01-S