FDA可在年度报告中提出的变更指南 中英文对照

2021年1月25日发(作者：jgd)
201006 FDA
行业指南

可在年报中报告的
CMC
已批准生产变更草案
（中英文）

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Guidance for Industry

行业指南

CMC
Postapproval
Manufacturing
Changes
Reportable
in
Annual
Reports

可在年报中报告的
CMC
已批准生产变更

DRAFT GUIDANCE

指南草案

This guidance document is being distributed for comment purposes
only.

本指南文件仅供征求意见。

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the Federal Register of the
notice
announcing
the
availability
of
the
draft
guidance.
Submit
comments
to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments
should
be
identified
with
the
docket
number
listed
in
the
notice
of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Jon E.
Clark at 301-796-2400.

关于本草案的问题请联系
CDER Jon E. Clark at 301-796-2400

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

June 2010

CMC



Guidance for Industry

行业指南

CMC
Postapproval
Manufacturing
Changes
Reportable
in
Annual
Reports

可在年报中报告的
CMC
已批准生产变更

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201 Center for Drug
Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave.

Silver Spring, MD 20993-0002

Phone: 301-796-3400; Fax: 301-847-8714

druginfo@

/Drugs/GuidanceComplianceReg ulatoryInformation/Guidan
ces/

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

June 2010



TABLE OF CONTENTS
I. INTRODUCTION.
介
绍
............... .................................................. ..
.........................................1
II. BACKGROUND.
背
景
................. ..................................................
...........................................1
III. DISCUSSION..
讨
论
............... .................................................. ..
............................................ ...2
IV. CONTENTS OF ANNUAL REPORT NOTIFICATIO N.
年报通知的内
容
.........................4
APPENDIX A: CMC POSTAPROVAL MANUFACTURING CHANGES REPORTABLE IN
ANNUAL REPORTS.......... ............................................
附件
A
：可在年报中报告的
CMC
已批准生产变更




Guidance for Industry[1]
行业指南

CMC
Postapproval
Manufacturing
Changes
Reportable
in
Annual
Reports

可在年报中报告的
CMC
已批准生产变更


This
draft
guidance,
when
finalized,
will
represent
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 number listed on the title
page of this guidance.
本指南草案，
如果最终定稿，
代表的是
FDA
目前对这一专题的态度。
它并未
建立或赋予任何个人任何权利，
并不与
FDA
或公众有任何绑定。
你可以使用任何
一种替代方法，
只要所用的方法满足成文 的法规要求。
如果你想要讨论一个替代
方法，
请与
FDA
负责实施本 指南的相关人员联系。
如果你无法无法识别要联系的
人，可以拨打本指南首页所列的相应的电话 号。



I. INTRODUCTION
介绍

This guidance provides recommendations to holders of new drug
applications (NDAs) and abbreviated new drug applications (ANDAs)
regarding the types of changes that may be reported in annual reports.
Specifically, the guidance describes chemistry, manufacturing, and
controls
(CMC)
postapproval
manufacturing
changes
that
we
have
determined
will
likely
present
minimal
potential
to
have
adverse
effects
on
product
quality and, therefore, may be reported by applicants in an annual
report.[2][3]
本指南给
NDA
和
ANDA
持有人提供建议，说明哪些变更可以在年报中进行报
告。指南专门针对的是化学、生产和控制（
CMC
）批准后生产变更，哪些可能对
产品质量产生潜在不良影响很小，因此可以在年度报告中 进行报告。

Appendix A lists the CMC postapproval manufacturing changes
previously submitted under manufacturing supplements that we have
determined to be generally of low risk to product quality (product
identity, strength, quality, purity, and potency as they relate to the
safety or effectiveness of the product).
附 件
A
列出了
CMC
已批准生产变更，
我们认为一般来说对产品质量< br>（与产品
安全性或有效性相关的属性，
如产品鉴别、
剂量、
质量、纯度和效价）
影响较低，
但之前要求在生产增补中提交的变更。

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 v
iewed 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.
FDA
的指南文件，包括本文件，并未设立法律强制责任。它只是描述了 当局
目前对某一主题的想法，如果未引用特定的法律法规要求的话，应仅作为推荐。
“应当should”一词在指南中表示建议或推荐的做法，并非强制。

II. BACKGROUND
背景

An applicant must notify FDA of a change to an approved application
in
accordance
with
all
statutory
and
regulatory
requirements
—
including
section
506A
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(21
U.S.C.
356a)
(the Act), which was added by section 116 of the Food and Drug
Modernization
Act,[4] and
21
CFR
314.70.
Section
506A
of
the
Act
provides
requirements for making and reporting manufacturing changes to an
approved application and for distributing a drug product made with such
changes. Under 21 CFR 314.70, all postapproval CMC changes beyond the
established variations in an approved NDA and ANDA are categorized into
one of three reporting categories: major, moderate, or minor.
对于已根据相关的法规要求—包括联邦食品药品和化妆品法案（
21 U.S.C.
356a
）
第
506A
条
（该条款经由食品和药品现代化法案和21CFR
第
314.70
条增加）
获得批准的申请，申请人必须将相关 变更通知
FDA
。法案的第
506A
条说明了对
已批准的申请生产变 更报告要求，和对药品的销售变更报告要求。根据
21CFR314.70
，
所有超出 已批准的
NDA
和
ANDA
中已有变更范围的预批准
CMC
变更
均属于三个报告类别之一：重大、中等、轻微。

If a change is considered to be major, an applicant must submit and
receive FDA approval of a supplement before the product made with the
manufacturing change is distributed. If a change is considered to be
moderate, an applicant must submit a supplement at least 30 days before
the product is distributed
or, in some
cases, submit a
supplement at the
time
of
distribution.
If
a
change
is
considered
to
be
minor,
an
applicant
may
proceed
with
the
change,
but
must
notify
FDA
of
the
change
in
an
annual
report.
For
any
change,
applicants
must
assess
the
effects
of
the
change
as they relate to product safety and efficacy and demonstrate those
effects
through
appropriate
studies
to
determine
whether
it
would
be
more
appropriate
to
submit
a
supplement.
For
additional
background
information
regarding
the
reporting
categories
for
NDAs
and
ANDAs,
see
FDA’s
guidance
for industry on Changes to an Approved NDA or ANDA (April 2004).[5]
如果变更被作为是 重大变更，则申请人必须提交变更至
FDA
，并在收到
FDA
批准后才能将变 更后工艺生产的产品用于销售。
如果变更被作为是中等，
申请人
必须在产品销售前30
天提交变更申请，或在某些情况下，在销售同时提交变更
申请。
如果变更被作 为是轻微的，
则申请人可以直接进行变更，
但必须在变更当
年的年报中通知
F DA
。对于任何变更，申请人均必须评价变更对产品安全性和有
效性的影响，通过适当的研究证 明该变更是否需要提交变更申请。更多与
NDA
和
ANDA
报告分类相关的背 景资料，
请参见
FDA
指南“已批准的
NDA
和
ANDA< br>的变
更”（
2004
年
4
月）（注释
5
）。

In our September 2004 final report, Pharmaceutical Current Good
Manufacturing Practices (CGMPs) for the 21st Century
–
A Risk-Based
Approach
(Pharmaceutical
Product
Quality
Initiative),
FDA
stated
that
to
keep pace with the many advances in quality management practices in
manufacturing and to enable the Agency to more effectively allocate our
limited regulatory resources, we would implement a cooperative,
risk-based
approach
for
regulating
pharmaceutical
manufacturing.
As
part
of
this
approach,
FDA
determined
that
to
provide
the
most
effective
public
health protection, our CMC regulatory review should be based on an
understanding of product risk and how best to manage this risk.
在我们
2004
年
9
月最终报告“21
世纪药品
CGMP
—基于风险的方法”
（药品
质量创新）中，
FDA
申明继续进行质量管理规范倡议，促进当局更有效利用我 们
有限的法规资源。
我们将建立一个合作的，
基于风险的方法对药品生产进行管理。< br>作为该方法的一部分，
FDA
决定提供更有效的公共安全保护，我们的
CMC< br>法规审
核将基于对产品风险的理解，以及如何更好地管理这种风险。

In
addition
to
the
requirements
in
section
506A
of
the
Act
and
21
CFR
314.70,
applicants
are
required
to
comply
with
other
applicable
laws
and
regulations,
including
the
CGMP
for
Finished
Pharmaceutical
regulations
in 21 CFR Parts 210 and 211.
除了法案第
506A
部分和
21CFR
314.70
之外 ，
申请人还需要符合其它与申报
相关的法律法规，
包括在
21CFR
（美国联邦法规）
第
210
和
211
中关于制剂
CGMP< br>的法规。

III. DISCUSSION
讨论

The number of CMC manufacturing supplements for NDAs and ANDAs has
continued to increase over the last several years. In connection with
FDA’s Pharmaceutical Product Quality Initiative and our risk
-based
approach to CMC review,
we have evaluated the
types of changes that
have
been submitted in CMC postapproval manufacturing supplements and
determined
that
many of
the
changes
being
reported
present
very
low
risk
to the quality of the product and do not need to be submitted in
supplements.
在过去几年中，对NDA
和
ANDA
的
CMC
生产变更申请数目持续增长。与FDA
的“药品质量倡议”和我们对
CMC
基于风险的审核方法相关连，
我们对已提交的
CMC
批准后生产变更进行了评价，并认为其中许多变更对产品质量的风险极小 ，
不需要提交变更批准。

Based on this recent evaluation, we developed a list (see Appendix
A) to provide current recommendations to companies regarding which
postapproval manufacturing changes for NDAs and ANDAs may be considered
to
have
a
minimal
potential
for
an
adverse
effect
on
the
identity,
strength,
quality, purity, or potency of the drug product and, therefore, may be
classified
as
a
change
reportable
in
an
annual
report
(e.g.,
notification
of
a
change
after
implementation)
rather
than
in
a
supplement.
The
changes
are
categorized
according
to
types
of
manufacturing
changes
and
are
either
additions or revisions to the classification of changes listed in the
guidance, Changes to an Approved NDA or ANDA.
基于最近的评价，我们列出了一个清单（见附件
A
），向公司建议，对于一
些 可以认为对药品的鉴别、
剂量、
质量、
纯度或效价只有非常小的潜在负面影响
的已批准的
NDA
和
ANDA
生产变更，
可以归类为年报变更
（例如实施后通知类型）
，
而不需要提交增补。
根据生产变更的类型分类的变更，< br>以及对变更分类的增加和
修订已在指南“已批准
NDA
或
ANDA”中 列出。

Thus,
if
you
are
submitting
supplemental
applications
that
are
based
on
the
recommendations
for
CMC
changes
provided
in
Changes
to
an
Approved
NDA or ANDA, you also should refer to the list of risk-based
recommendations that are provided in Appendix A of this guidance to
determine if a particular change may now be reported in an annual
report.[6] In
addition,
the
recommendations
in
this
guidance
should
help
clarify when to submit a supplement and when a change may be reported in
an annual report.
因此，如果你正准备根据“已批准
NDA或
ANDA”中
CMC
变更建议提交增补
申请，你需要同时参考基于风险 的建议清单，该清单是本指南附件
A
，以决定某
个具体的变更现在是否可以在年报中报 告。
另外，
本指南中的建议可以帮助澄清
什么时候需要提交一个增补，什么时候变更可 以包括在年报中。

We expect NDA and ANDA holders to evaluate the specific change that
they
are
planning
to
make
in
the
context
of
their
particular
circumstances
to
determine
whether
the
proposed
change
would
present
a
minimal
potential
to
have
an
adverse
effect
on
the
identity,
strength,
quality,
purity,
or
potency of the drug product. Based on such an analysis, an NDA or ANDA
holder may decide that a change described in Appendix A would more
appropriately
be
submitted
as
a
supplement
rather
than
in
an
annual
report.
We, therefore, consider this guidance to provide recommendations for
changes that may be appropriately submitted in an annual report rather
than to provide a mandatory requirement for reporting these changes in
annual reports pursuant to 21 CFR 314.70(a)(3).[7]
我们希望
NDA
和
ANDA
持 有人对具体的计划中的变更进行评价，根据其具体
的环境来决定提议的变更是否对药品的鉴别、
剂量、
质量、
纯度或效价只有非常
小的潜在负面影响。基于该分析，
NDA< br>或
ANDA
持有人可以决定在附件
A
中所述
的变更是否更适合 提交一个增补，
而不是在年报中报告。
在此，
我们认为本指南
仅是提供一些建 议，说明一些变更可能可以在年报中报告，而不是根据
21CFR
314.70(a)(3)
强制要求这些变更必须在年报中报告。

Applicants
should
remember
that
regardless
of
the
reporting
category
for the postapproval manufacturing change, they are required to comply
with the CGMP for Finished Pharmaceuticals regulations at 21 CFR Parts
210 and 211. Also, applicants should note FDA’s recommendations for
active pharmaceutical ingredient manufacturing that are provided in the
guidance for industry, Q7A Good Manufacturing Practice Guidance for
Active Pharmaceutical Ingredients. CGMP regulations for finished
pharmaceuticals contain specific requirements relevant to the types of
changes addressed in this guidance, and compliance with the CGMP
regulations is required regardless of how the change is reported to the
Agency. CGMP requirements include the need to qualify equipment as
suitable
for
its
intended
use,
the
need
to
assure
validated
test
methods
and ongoing state of control of manufacturing processes, and the
requirement to maintain appropriate written procedures that the quality
unit has reviewed and approved.[8]
申请人应记住，不管已批准的生产变更如何分类，这些变更都需要符合
21CFR 210和
211
中
CGMP
对制剂法规的要求。同时，申请人还要注意
FDA
对活
性原料药生产的建议已包括在行业指南“Q7A 原料药
GMP”中。CGMP
对制剂的法
规包括对本指南中所述的变更类型的特定要求，
不管变更类型 如何，
所有变更均
需要符合
CGMP
法规要求。
CGMP
要 求包括了需要确认设备是否符合其用途，需要
使用验证过的检验方法，
生产工艺应处于受控状态 ，
需要维护适当、
经过质量部
分审核和批准的书面程序。

If you have specific questions associated with whether or not the
change may be classified as requiring a supplement or is reportable in
an annual report, we recommend that you contact the appropriate CDER
review division in the Office of New Drug Quality Assessment (ONDQA),
Office
of
Generic
Drugs
(OGD),
or
New
Drug
Microbiology
Staff
(OPS-NDMS).