[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