Guidance for Industry
Changes to an Approved NDA or ANDA;
Specifications – Use of Enforcement Discretion for
Compendial Changes
(PDF
version of this document)
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 2004
CMC
Additional copies are available
from:
Office of Training and
Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
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Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Guidance for Industry
Changes to an Approved NDA or ANDA;
Specifications – Use of Enforcement Discretion for Compendial
Changes
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if the approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate telephone number listed on the title page of this
guidance.
I. INTRODUCTION
This guidance is
intended to inform new drug application (NDA) and abbreviated new
drug application (ANDA) holders of the Food and Drug
Administration's (FDA’s) plan to use enforcement discretion with
regard to section 314.70(c)(2)(iii) of the final rule entitled
Supplements and Other Changes to an Approved Application (21 CFR
314.70(c)(2)(iii)).
This subsection describes the filing requirement that a relaxation
of acceptance criteria or deletion of a test to comply with an
official compendium must be reported in a
changes-being-effected-in-30-days supplement (CBE-30). In the
exercise of its enforcement discretion,
FDA does not intend to take
enforcement action if manufacturers continue to submit such changes
in their annual reports. The use of enforcement discretion
will give the Agency time to clarify that some of these types of
postapproval changes can be submitted in an annual report, rather
than in a CBE-30. The Agency intends to clarify this issue in an
upcoming revision to the guidance for industry Changes to an
Approved NDA or ANDA; Questions and Answers.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
On April 8,
2004, FDA published in the Federal Register (69 FR 18728) the
final rule entitled Supplements and Other Changes to an Approved
Application. In the same issue of the Federal Register (69
FR 18768), FDA announced the availability of the guidance for
industry entitled Changes to an Approved NDA or ANDA (the
Changes guidance). The final rule sets forth requirements for
postapproval changes.
Under section 314.70(c)(2)(iii) of the final
rule, the relaxation of acceptance criteria or deletion of a test to
comply with an official compendium that is consistent with FDA
statutory and regulatory requirements must be submitted as a
supplement – changes-being-effected-in-30 days (CBE-30) (see section
VIII.C.1.e of the Changes guidance). Under 314.70(d)(2)(i)
of the final rule, any change in a specification made to comply with
an official compendium, except the relaxation of acceptance criteria
or deletion of a test that is consistent with FDA statutory and
regulatory requirements, is to be submitted as an Annual Report (see
section VIII.D.1 of the Changes guidance).
Since publication of the final rule, the Agency
has received communications from NDA and ANDA holders requesting
clarification of the regulation as it applies to changes such as
excipient monographs and general chapters. As written now, the
regulations could be interpreted to require a CBE for any compendial
change to relax or delete a test, resulting in an increase in the
number of supplements, something that was not intended. The Agency
plans to revise the Guidance for Industry: Changes to an
Approved NDA or ANDA; Questions and Answers to provide more
specific recommendations as to what types of changes can be
submitted in an annual report instead of a CBE-30 supplement.
In addition, the Agency is aware that
stakeholders have expressed concern that the final rule (i.e., 21
CFR 314.70), which published on April 8, 2004, and the accompanying
Changes guidance do not take into consideration the recent
FDA Pharmaceutical CGMP Initiative for the 21st Century.
Accordingly, the Agency plans to align this guidance with the
initiative in order to facilitate manufacturing changes to enhance
product quality.
FDA intends to exercise enforcement
discretion and does not intend to take action to enforce compliance
with the compendial changes requirement as stated in 21 CFR
314.70(c)(2)(iii) if manufacturers submit such changes in their
annual reports. FDA intends to develop further guidance to clarify
the requirements of 21 CFR 314.70(c)(2)(iii).
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Date created: November 19, 2004 |