[Federal Register: February 12, 2002 (Volume 67, Number 29)]
[Notices]
[Page 6542-6544]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12fe02-81]
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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