-
Guidance for Industry
Changes to an
Approved
NDA or ANDA
已批准申请的新药变更指南
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
(CDER)
April 2004
CMC
Revision 1
I.
INTRODUCTION AND BACKGROUND
This
guidance
provides
recommendations
to
holders
of
new
drug
applications
(NDAs)
and
abbreviated
new
drug
applications
(ANDAs)
who
intend
to
make
post
approval
changes
in
accordance with section
506A of the Federal Food, Drug, and Cosmetic Act
(the Act) and §
314.70
(21
CFR 314.70). The guidance covers recommended
reporting categories for postapproval changes
for
drugs
other
than
specified
biotechnology
and
specified
synthetic
biological
products.
It
supersedes
the
guidance
of
the
same
title
published
November
1999.
Recommendations
are
provided
for
postapproval
changes
in
(1)
components
and
composition,
(2)
manufacturing
sites
,
(3) manufacturing
process, (4) specifications, (5) container closure
system, and (6) labeling, as well as
(7) miscellaneous changes and (8) multiple related
changes.
本
指南给
打算将<
/p>
已批准变更的新药上市申请和
新药报审简表申请的持有者提供建议
，使其按照联邦食品、药
品、化妆品法案的
506A
部分和
§
314.70
(21 CFR 314.70)
。
该指南包括建议对药品除了
其他指定的生物技
术和特定的合成生物制品的已批准变更进行报告类别。
它取代了发表于
1999
年
1
1
月同一标题的指导原则。
为以下已批准的变更提供建议（
1
）成分和组成
（
2
）厂址
（
3
）生产工艺
（
4
）质量标准
< br>
（
5
）包装
（
6
）
标签<
/p>
（
7
）其它变
更
（
8
）复
杂相关变更
Recommendations
on
reporting
categories
for
changes
relating
to
specified
biotechnology
and
specified synthetic
biological products regulated by CDER are found in
the guidance for industry
建议由
药品评价和研究中心规定
对有关指定生物技术和特定的合成生物制品的变更进行报告类
别，出现在
企业的指南中
。
Paperwork Reduction Act Public Burden
Statement
: This guidance contains
information collection
provisions
that
are
subject
to
review
by
the
Office
of
Management
and
Budget
(OMB)
under
the
Paperwork Reduction Act of 1995 (PRA)
(44 U.S.C. 3501-3520).
The
collection(s) of information in
this
guidance were approved under OMB Control No.
0910-0538 (until August 31, 2005).
文书工作
减
少法案：本指南包含资料的收集贮藏受到
管理和预算办公室（
OMB
）的审查，根据
1995
年的文书工作减
少方案
(44
U.S.C.
3501-3520)
。在此指南下，收集的资料依据管理和预算办公室控制的第
0910-0538
获
得批准（直到
2005
年
8
月
31
日）。
On November
21, 1997, the President signed the Food and Drug
Administration
Modernization Act of
1997 (the Modernization Act).
Section
116 of the Modernization
Act amended
the the Act by adding section 506A, which provides
requirements for
making and reporting
manufacturing changes to an approved application
and for
distributing a drug product
made with such changes. The FDA has revised its
regulations on supplements and other
changes to an approved application (21 CFR
314.70) to conform to section 506A of
the Act.
3
1997
年
11
月
21
日，
总统签署了美国食品和药物管理局<
/p>
1997
现代化法案（现代化法案）。
第
116
条现
代化法修正法案，增加了第
506A
条，要求对已批准申请的任何变更以及销售变更后产品
的行为必须报告。
对一个获批准的申请
(21 CFR 314
.70)
，
FDA
已经在补充和变更内
容上修订规章，以符合法案第
506A
条。
This
guidance does not provide recommendations on the
specific information that
should be
developed by an applicant to assess the effect of
the change on the identity,
strength
(e.g., assay, content uniformity), quality (e.g.,
physical, chemical, and
biological
properties), purity (e.g., impurities and
degradation products), or potency
(e.g., biological activity,
bioavailability, bioequivalence) of a drug product
as these
factors may relate to the
safety or effectiveness of the drug product. An
applicant
should consider all relevant
CDER guidance documents for recommendations on the
information that should be submitted to
support a given change.
4
作为可能关系到药品安全性和有效性的以下因素，药品的特征、剂量（例如含量测定、含
量均一性）、
质量（例如，物理、化学和生物学特性）
、纯度（例如，杂质和降解产物）
，或药效（例
如，生物活性、生物利用度、生物等效性），申请人评估以上因
素变更效果的具体信息，本指南不提供建议。
申请者应该考虑所有相关的
药品评价和研究中心的指导文件，建议资料应该提交以支持某一特
定的变更。<
/p>
CDER has published
guidances, including the SUPAC (scale-up and
postapproval
changes) guidances, that
provide recommendations on reporting categories.
To the
extent that the recommendations
on
reporting categories
in
this guidance are found to
be
inconsistent with guidances published before this
guidance was finalized, the
recommended
reporting categories in such previously published
guidances are
superseded by this
guidance. This guidance does not provide extensive
recommendations on reporting categories
for components and composition changes
(see section V). Therefore, recommended
reporting categories for components and
composition changes provided in
previously published guidances, such as the SUPAC
guidances, still apply. Section 506A of
the Act and §
314.70(c) provide for two
types of
changes-beingeffected
supplements (see section II), while previously
there was only
one type.
It is important for applicants to use
this guidance to determine which type of
changes-being-effected supplement is
recommended. CDER intends to update the
previously published guidances to make
them consistent with this guidance.
CDER
已公布指南，包括
SUPAC
（扩大和批准后的变更）指南，对报告类别提供了建议。
发现在本指
南中报告类别的建议范围和以前已定案公布的指南不一致，推荐本指南的报告
类别取代先
前公布的。对成分和组成变更（查看第
V
条）的报告类别，本指
南不提供广泛
建议。因此，推荐先前公布的指南提供的成分和组成变更的报告类别，例如
SUPAC
指南，
目前还适用。法案的
第
506A
和
§
314.70(c)
提供了“有待生效的补充文件”的两种类型（查
看第
II
），然而先前的只有一种类型。对于申请者，
运用本指南来决定用哪个
“有待生效
的补充文件”是很重要的。
CDER
打算更新先前公布的指南使
其和本指南一致。
If
guidance for either recommended reporting
categories or information that should be
submitted to support a particular
change is not available, the appropriate CDER
chemistry or microbiology review staff
can be consulted for advice.
如果本指南中推荐的报
告类别或者支持具体变更所提交的资料没有效，可以向合适的
CDER
< br>化学或微生物检查人员征询意见。
FDA's
guidance documents, in general, 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.
Insofar as this guidance
adjusts
reporting categories pursuant to section 506A of
the Federal Food, Drug, and
Cosmetic
Act and 21 CFR 314.70, it does have binding
effect.
If you have any
questions about the effect of any
portion of this guidance, contact the Office of
Pharmaceutical Science, Center for Drug
Evaluation and Research (HFD-003), Food
and Drug Association, 5600 Fishers
Lane, Rockville, MD 20857.
FDA
的指导文件，大体上没有建立
依法强制执行的责任。相反
，指南叙述该机构目前正在考虑的话题且仅
作为建议，除非特定的法令要求被引用。词的
使用在机构的指南应该意味着一些建议或推荐，但不是要求。
在本指导的范围内调整报告
类别，依据联邦食品、药品和化妆品法第
506A
和
21 CFR 314.70
，它确实
有约束力
。如果你有关于本指导任一部份作用的任何问题，联络医药科学办公室、药物评价和研究中心
（
HFD-003
）
、美国食品和药物管理局、
5600
渔民巷，
美国马里兰州罗克维尔市
20857
。
II. REPORTING
CATEGORIES
报告类别
Section 506A of the Act and
§
314.70 provide for four reporting
categories that are
distinguished in
the following paragraphs.
法案的第
506A
和
§
314.70
提供了在以下各段落中有区分的
4
个报告类
别。
A
major
change
is a change that has a
substantial potential to have an adverse effect
on the identity, strength, quality,
purity, or potency of a drug product as these
factors
may relate to the safety or
effectiveness of the drug product. A major change
requires
the submission of a supplement
and approval by FDA prior to distribution of the
drug
product made using the change.
This type of supplement is called, and should be
clearly
labeled, a
Prior
Approval Supplement
(§
314.70(b)). An applicant may ask FDA to
expedite its review of a prior approval
supplement for public health reasons (e.g., drug
shortage) or if a delay in making the
change described in it would impose an
extraordinary hardship on the
applicant. This type of supplement is called, and
should
be clearly labeled, a
Prior Approval Supplement - Expedited
Review Requested
(§
314.70(b)(4)).
FDA is most
likely to grant requests for expedited review
based on
extraordinary hardship for
manufacturing changes made necessary by
catastrophic
events (e.g., fire) or by
events that could not be reasonably foreseen and
for which the
applicant could not plan.
5
大变更指对药品特征、剂量、质量、纯度或药效有重大潜在不
良影响、与药品的安全性和
有效性相关的变更。大变更后生产的产品需要提交补充申请，
经
FDA
批准后方可销售。这
类补充申
请应有明显标识，称作“批准前变更申请”（
314.70
）。
申请人可以以公众健康
为由（如药品短缺）要求
FDA
加速批准前变更的审核，如果变更延迟会给申请人造成极大
的困难，
可以要求加速审批。
这类变更称为
“要求加
速审批的批准前变更”
（
314.70(b)(4)
）
。
由于灾难性事故或不可预见的事故造成生产变
更，
并对申报人造成极大的困难的情况，
FDA
最有可能加速审批。
A
moderate change
is a change
that has a moderate potential to have an adverse
effect on the identity, strength,
quality, purity, or potency of the drug product as
these
factors may relate to the safety
or effectiveness of the drug product. There are
two types
of moderate change. One type
of moderate change requires the submission of a
supplement to FDA at least 30 days
before the distribution of the drug product made
using the change. This type of
supplement is called, and should be clearly
labeled, a
Supplement - Changes Being
Effected in 30 Days
(§
314.70(c)(3)). The drug product
made
using a moderate change cannot be distributed if
FDA informs the applicant within
30
days of receipt of the supplement that a prior
approval supplement is required (§
314.70(c)(5)(i)). For each change, the
supplement must contain information determined
by FDA to be appropriate and must
include the information developed by the applicant
in assessing the effects of the change
(§
314.70(a)(2) and (c)(4)). If FDA
informs the
applicant within 30 days of
receipt of the supplement that information is
missing,
distribution must be delayed
until the supplement has been amended to provide
the
missing information (§
314.70(c)(5)(ii)).
中等变更指对药品特征、剂量、质量、纯度或
药效有中等程度的潜在不良影响、可能与药
品的安全性和有效性相关的变更。有两种中等
变更，一种要求变更后生产的产品销售前至
少
30
天提交补充申请，这类补充申请应有明显标识，称作“
30
< br>天后变更生效的补充文件”
（
314.70(c)(3)
）。如果
FDA
收到补充申请的
30
天内要求提交“批准前变更申请”
（
314.70(c)(5)(i)
），则变更后生产的产品不能销售
。任何一种变更都必须包括
FDA
接受的
信息，必须包括变更影响评估的信息（
314.70(a)(2)
和
(c)(4)
）。如果
FDA<
/p>
在接收到补充申请
后的
30
天内通知申请人信息不全，则必须延迟销售直到补充申请加入缺失的信息
（<
/p>
314.70(c)(5)(ii)
）。
FDA may identify certain
moderate changes for which distribution can occur
when FDA
receives the supplement
(§
314.70(c)(6)). This type of
supplement is called, and should
be
clearly labeled, a
Supplement - Changes
Being Effected
. If, after review, FDA
disapproves a changes-being-effected-
in-30-days supplement or
changes-being-
effected supplement, FDA may order the
manufacturer to cease
distribution of
the drug products made using the disapproved
change (§
314.70(c)(7)).
FDA<
/p>
可能规定某些中等变更
FDA
接收到补充
申请时产品可以销售，这类补充申请应有明显
标识，称作“已完成变更的补充申请”。如
果评审结束后，
FDA
不批准“
30<
/p>
天后生效的变
更补充文件”或“已生效的变更补充文件”，
FDA
可以要求生产厂家停止销售变更后生产
的产品
(§
314.70(c)(7
))
。
A
minor change
is a change
that has minimal potential to have an adverse
effect on
the identity, strength,
quality, purity, or potency of the drug product as
these factors
may relate to the safety
or effectiveness of the drug product. The
applicant must
describe minor changes
in its next
Annual Report
(§
314.70(d)).
小变更指对药品特征、剂量、
质量、纯度或药效有最小的潜在不良影响、可能与药品的安
全性和有效性相关的变更。申
请人必须在下一次年度报告中描述小变更
(§
314.70(d))
。
Under
§
314.70(e),
an
applicant
can
submit
one
or
more
protocols
(i.e.,
comparability
protocols)
describing
tests,
studies,
and
acceptance
criteria
to
be
achieved
to
demonstrate
the
absence
of
an
adverse
effect
from
specified
types
of
changes.
A
comparability
protocol
can
be
used
to
reduce
the
reporting
category
for
specified
changes. A
proposed comparability protocol that was not
approved as part of the original
application must be submitted as a
prior approval supplement (314.70(e)). On February
25, 2003, FDA issued a draft guidance
on comparability protocols entitled Comparability
protocols - Chemistry, Manufacturing,
and Controls Information.
根据
314.70(e)
，申请人可以提交
1
个或多个方案（如相比性方案），描述检测、研究、可
接受标准，以证明特定的变更不
会有不良影响。相比性方案可减少特定变更的报告范围。
提交的相比性方案在原始申报资
料中没有包括，必须作为“批准前变更申请”提交。见
Comparability
protocols - Chemistry, Manufacturing, and Controls
Information
。
III. GENERAL REQUIREMENTS
常规要求
Other
than
for
editorial
changes
in
previously
submitted
information
(e.g.,
correction
of
spelling
or
typographical errors, reformatting of
batch records), an applicant must notify FDA about
each change
in each condition
established in an approved application beyond the
variations already provided for
in the
application (§
314.70(a)(1)).
除编辑上的改动，在以往提交的资料（如更正拼写或打字错误
，重新格式化的一批纪录），申请人必须通
知
FDA
了解在每个确立的情况、获批准的申请的各个改变，超出了变更在申请中应用
(§
314.70(a)(1))
。
A supplement or annual report must
include a list of all changes contained in the
supplement or annual report. On the
list, FDA recommends that the applicant describe
each change in enough detail to allow
FDA to quickly determine whether the appropriate
reporting category has been used. For
supplements, this list must be provided in the
cover letter (§
314.70(a)(6)). In annual reports, the list should
be included in the
summary section
(§
314.81(b)(2)(i)).
The applicant must describe each change
fully in
the supplement or annual
report (§
314.70(a)(1)).
增补或年报必须包括一列所有变更，载于增补或年报。在目录上，
F
DA
建议申请者对每个
变更叙述详尽，使
FDA
迅速决定是否合适的报告范围已被使用。对于增刊，此目录必须在
信封面上
(§
314.70(a)(6))
。在年报里，目录应包括在简节中
(§
31
4.81(b)(2)(i))
。申请者必
须说明每个变更都在
增刊和年报里。
An
applicant making a change to an approved
application under section 506A of the
Act must also conform to other
applicable laws and regulations, including current
good
manufacturing practice (CGMP)
requirements of the Act (21 U.S.C. 351(a)(2)(B))
and
applicable regulations in Title 21
of the
Code of Federal
Regulations
(e.g., 21 CFR
parts 210, 211, 314). For example,
manufacturers must comply with relevant CGMP
validation and recordkeeping
requirements and ensure that relevant records are
readily
available for examination by
authorized FDA personnel during an inspection.
申请者依据法案的第
506A
部分对已批准的申请作出变更，必须同时符合其它适用的法律和
规章，
包括现行的药品生产管理规范
（
CGM
P
）
要求的法案
(21 U.S.C.
351(a)(2)(B))
和美国
联邦行政法规
(e.g., 21 CFR parts 210, 211, 314)
的
21
部中适用的规章。例如，生产厂家必
须服从相关
CGMP
验证和保留记录的要求，确保有关的记
录在检查期间随时可供获授权的
FDA
工作人员检查。
A
changes-being-effected
supplement
providing
for
labeling
changes
under
§
314.70(c)(6)(iii) must include 12
copies of the final printed labeling (§
314.70(c)(1)). In
accordance with
§
314.70(a)(4), an applicant also must
promptly revise all promotional
labeling
and
drug
advertising
to
make
it
consistent
with
any
labeling
change
implemented in
accordance with §
314.70(b) or (c).
“已生效的变更补充”提供了标签变更，依据
§
314.70(c)(6)(iii)
必须包括<
/p>
12
份最后打印的
标签
< br>(§
314.70(c)(1))
。按照
§
314.70(a)(4),
申请者
还必须及时修改所有宣传标
识和药品广告，使之
符合任何标签变更，应按照
§
314.70(b) or
(c)
实施。
Except for supplements providing only
for a change in labeling, an applicant must
include in each supplement and
amendment to a supplement a statement certifying
that a field copy has been provided in
accordance with 21 CFR 314.440(a)(4)
(§
314.70(a)(5)).
除了在标签中只补充一个变更，申请者必须包括有每个补充和修改的资料来补充说明，
证明副本已按照
21 CFR 314.440(a)(4)
(§
314.70(a)(5))
提供。
IV. ASSESSING THE EFFECT OF
MANUFACTURING CHANGES
对生产变更的评估
A.
Assessment of the Effects of the Change
评估变更效果
The holder
of an approved application under section 505 of
the Act
must assess the
effects of the change before
distributing a drug product made with a
manufacturing change
(§
314.70(a)(2)).
For each
change, the supplement or annual
report
must contain information determined by FDA to be
appropriate and must include
the
information developed by the applicant in
assessing the effects of the change
(section 506A(b), (c)(1), (d)(2)(A),
and (d)(3)(A) of the Act). The type of information
that
must be included in a supplemental
application or an annual report is specified in
§
7
6
6<
/p>
314.70(b)(3), (c)(4), and (d)(3).
按照法案第
505
条，
在发
行有生产变更的药品前
(§
314.70(a)(2))
，
已批准申请的持有人必须
评估变更效果。
对每个变更，增刊或年报必须包含由
FDA
确定的合适的资料和
申请者在评
估变更效果所取得的资料
(section
506A(b), (c)(1), (d)(2)(A), and (d)(3)(A) of the A
ct)
。该
类型的资料必须包括在补充申请或年报里，特别是在
§
314.70(b)(3), (c)(4), and
(d)(3)
中。
1. Conformance to
Specifications
An assessment
of the effects of a change on the identity,
strength, quality,
purity, and potency
of the drug product should include a determination
that the
drug substance intermediates,
drug substance, in-process materials, and/or
drug product affected by the change
conform to the approved specifications.
A
specification
is a quality standard (i.e., tests, analytical
procedures, and
acceptance criteria)
provided in an approved application to confirm the
quality
of drug substances, drug
products, intermediates, raw materials, reagents,
components, in-process materials,
container closure systems, and other
materials used in the production of a
drug substance or drug product.
Acceptance criteria
are
numerical limits, ranges, or other criteria for
the tests
described (§
314.3(b)). Conformance to a specification means
that the material,
when tested
according to the analytical procedures listed in
the specification,
will meet the listed
acceptance criteria.
对药品的特征、剂量、质量、纯度和药效变更效果进行评估，应该包括原料药中间体、原料药、中控 物
料和
/
或被符合已批准质量标准变更
影响的制剂。规格是一个（例如，试验、分析步骤、可接受标准）
在已批准的申请里提供
证实原料药、成品、中间体、原材料、反应物、成分、中控物料、包装，和原料
药或制剂
生产过程中使用的其它物质的质量标准。
可接受标准是
个描述测
试的数值界限，
范围，
或其他的
标准<
/p>
(§
314.3(b))
。
符合质量标准的意思是，当物料根据质量标准中所列出的分析步骤检验，将
符合所列出
的可接受标准。
8
2. Additional
Testing
附加试验
In
addition to confirming that the material affected
by manufacturing changes
continues to
meet its specification, we recommend that the
applicant perform
additional testing,
when appropriate, to assess whether the identity,
strength, quality,
purity, or potency
of the drug product as these factors may relate to
the safety or
effectiveness of the drug
product have been or will be affected. The
assessment
should include, as
appropriate, evaluation of any changes in the
chemical, physical,
microbiological,
biological, bioavailability, and/or stability
profiles. This additional
assessment
could involve testing of the postchange drug
product itself or, if
appropriate, the
material directly affected by the change. The type
of additional testing
that an applicant
should perform would depend on the type of
manufacturing change,
the type of drug
substance and/or drug product, and the effect of
the change on the
quality of the drug
product. For example:
除了证实被生产变更影响的物料仍然符合它的质量标准，我们建议申请者实行附加试验，
适当的时候评估可能关系到药品安全性和有效性的特征、剂量、质量、纯度或药效是否已
经或将被影响
。评估应该适当包括化学的、物
理的、微生物的、生物的、生物利用度和
/
或稳定性的任何变化
。
这个附加评估包含变更后药品自身的试验或受变更直接影响的物料。
< br>申请者实行该类型的附加试验，取决于该类型的生产变更、该类型药用物质和
/<
/p>
或成品，和
在高质量药品的变更效果。例如：
Evaluation of changes in the impurity
or degradant profile could first involve
profiling using appropriate
chromatographic techniques and then, depending on
the
observed changes in the impurity
profile, toxicology tests to qualify a new
impurity or
degradant or to qualify an
impurity that is above a previously qualified
level.
对于变
更对杂质或降解物档案的评估，
首先必须包括使用合适的色谱技术进行分析，
然后根据观测到的杂质归档变更状况，对新的杂质或是降解物进行毒理试验确认，或是在< p>
确认杂质在一个先前确认的水平之上。
Evaluation of the hardness
or friability of a tablet after certain changes.
在一些变更后必须考虑对片剂的硬度或脆度进行评估。
Assessment of the effect of
a change on bioequivalence when required under 21
CFR part 320 could include, for
example, multipoint and/or multimedia dissolution
profiling and/or an in vivo
bioequivalence study.
根据
21CFR320
条款的要求，评估变更对
于生物等效性的影响。例如，进行多因素和
/
或多
介质溶解性试验，或是体外生物等效性研究。
Evaluation of extractables
from new packaging components or moisture
permeability of a new container closure
system.
对新包装组分通透性或新的容器密封系
统的水
份渗透性进行评估测试。
An
applicant should refer to all relevant CDER
guidance documents for
recommendations
on the information that should be submitted to
support a given
change. If guidance for
information that should be submitted to support a
particular
change is not available,
applicants can consult the appropriate CDER
chemistry or
microbiology review staff
for advice.
申请者应该参考所有相关的
CDER
指导文件，建议为支持给定的变更提交资料。如果在本
指南中，为支持一个特定的变更所提交的资料没有效，申请者可以向合适的
CDER
化学或
微生物检查人员征询意见。
B. Equivalence
等价
9
When testing is performed, the
applicant should usually assess the extent to
which the
manufacturing change has
affected the identity, strength, quality, purity,
and potency of
the drug product.
Typically this is accomplished by comparing test
results from pre- and
postchange
material and determining if the test results are
equivalent. Simply stated: Is
the drug
product made after the change equivalent to the
drug product made before the
change?
实行检测后，申请者应该经常评估哪个生产变更范围会影响到
药品的特征、剂量、质量、
纯度和药效。通常这是通过比较变更前和变更后物料的检验结
果来完成的，确定检验结果
是否等价。简单说明：药品是在药品变更前后等价的情况下生
产的吗？
An exception to this general approach
is that when bioequivalence is redocumented for
certain
ANDA
postapproval
changes,
FDA
recommends
that
the
comparator
be
the
reference
listed
drug.
Equivalence
comparisons
frequently
have
a
criterion
for
comparison
with
calculation
of
confidence
intervals
relative
to
a
predetermined
equivalence
interval.
这方面的例
外情况是，如果要对某个已批准的
ADDA
进行变更，要求重新
进行生物等效性
研究，
FDA
建议
该参考对照物必须是参考的药物。在相对一个预定的等价区间里，等价比
较经常有一个标
准作为比较置信区间的计算结果。
For this, as well as for other reasons,
equivalent does not necessarily mean identical.
Equivalence
may
also
relate
to
maintenance
of
a
quality
characteristic
(e.g.,
stability)
rather than a single performance of a
test.
对此，和其它原因一样，等价并不是意味着相等
。等价还可能关系到质量特征的维持（例
如，稳定性）而不是简单的一项测试行为。
C. Adverse Effect
不良作用
Some
manufacturing changes have an adverse effect on
the identity, strength, quality,
purity, or potency of the drug product.
In many cases, the applicant chooses not to
implement these manufacturing changes,
but sometimes the applicant wishes to do so.
If an assessment indicates
that a change has adversely affected the identity,
strength,
quality, purity, or potency
of the drug product
,
FDA
recommends that
the change be
submitted in a prior approval
supplement regardless of the recommended
reporting category for the
change
.
For example, a process change
recommended
for a changes-being-
effected-in-30days supplement could cause the
formation of a new
degradant that
requires qualification and/or
identification.
The applicant's
degradation
qualification procedures
may indicate that there are no safety concerns
relating to the
new degradant. Even so,
we recommend that the applicant submit this change
in a prior
approval supplement with
appropriate information to support the continued
safety and
effectiveness of the drug
product.
During the review
of the prior approval supplement,
the
FDA will assess the impact of any adverse effect
on the drug product as this change
10
may relate to the safety
or effectiveness of the drug product.
一些生产变更对药品的特征、剂量、质量、纯度或药效有不良作用。在许多情况下，申请
者选择不去实行这些生产变更，但有时申请者希望那样做。如果评估表明变更对药品的特
征、剂量、质量、纯度或药效有不良影响，
FDA
建议这种变更将提交在批准前变更申请里
而不管变更报告范围的建议。例如，
一个工序的变更，能引起新降解产物的生成，要求其
合格和
/<
/p>
或能识别，建议
30
天后进行变更补充申
请。申请者的降解合格操作可能表明没有关
于新降解产物的安全隐患。即使如此，我们建
议申请者在批准前变更申请中提交此变更，
以适当的资料支持药品持续的安全性和有效性
。
Applicants are
encouraged to consult with the appropriate CDER
chemistry or microbiology
review staff
if there are any questions on whether a change in
a characteristic would be viewed
by
CDER as adversely affecting the identity,
strength, quality, purity, or potency of the drug
product.
不论药品的特征
是否改变，
CDER
人员将当作影响药品特性、浓度、质量、纯
度或药效的
不利方面来检查，如果有任何问题，鼓励申请者咨询合适的
< br>CDER
化学或微生物检查人员。
V. COMPONENTS AND COMPOSITION
成分和组成
Changes in
the qualitative or quantitative formulation,
including inactive ingredients, as
provided
in
the
approved
application,
are
considered
major
changes
requiring
a
prior
approval
supplement,
unless
exempted
by
regulation
or
guidance
(§
314.70(b)(2)(i)).
The
deletion or reduction of an ingredient intended to
affect only the color of the drug
product may be reported in an annual
report (§
314.70(d)(2)(ii)). Guidance
on changes
in
components
and
composition
that
may
be
submitted
in
a
changes-being-effected
supplement or annual report is not
included in this document because of the
complexity
of
the
recommendations,
but
may
be
covered
in
one
or
more
guidance
documents
describing
postapproval changes (e.g., SUPAC documents).
处方质量或数量改变，包括费活性成分，认为是大变更，要求提交“批准前变更申请”，
除非有法规或指南豁免
(§
314.70(b
)(2)(i))
。
只是影响药品颜色的某种成分的取消或减少
可以
在年度报告中报告
(§
314.7
0(d)(2)(ii))
。
本指南不包括在“有待生效的变更
补充文件”
或年度
报告中提交的变更。
11
VI. MANUFACTURING
SITES
厂址
A. General Considerations
CDER must be notified when a
manufacturer changes to a manufacturing site that
is
different from those specified in
the approved application (314.70(a)).
Sites can
include those used
by an applicant to (1) manufacture or process drug
products,
in-process
materials, drug substances, or drug substance
intermediates, (2) package
12
drug products, (3) label
drug products, and (4) test components, drug
product containers,
closures, packaging
materials, in-process materials, or drug products.
Sites include
those owned by the applicant or
contract sites used by an applicant. Testing sites
include those performing physical,
chemical, biological, and microbiological testing
to
monitor, accept, or reject
materials, as well as those performing stability
testing. Sites
used to label drug
products are considered those that perform
labeling of the drug
product's primary
or secondary packaging components. Sites
performing operations that
place
identifying information on the dosage form itself
(e.g., ink imprint on a filled
capsule)
are considered to be facilities that manufacture
or process the drug product.
FDA
recommends that the supplement or annual report
identify whether the proposed
manufacturing site is an alternative to
or replacement for the site or sites provided for
in
the approved application.
当变更生产地址时，如果变更的地点不包括在批准的申请中，必须通知
CDER
(314.70(a))
。
生产地址变更的包
括申请人用于制造或处理制剂药品、
中控物料、
原料药、
原料药中间体，
包装药品、贴标签，检测成分、药品容器、密封材料、
包材、中控物料或药品的场所的地
址变更厂址包括申请人所有的或合同场所。检测厂址包
括物理、化学、生物学、微生物检
测场所，用于物料控制、接收、拒收，以及稳定性检测
。贴标签场所指对产品内包装和外
包装贴标签的场所。
FDA<
/p>
建议在增补或年度报告中必须说明提交的生产地址是否时原来已
批
准的地址的替代选择，还是完全替代地址。
FDA
recommends that a move to a different
manufacturing site, when it is a type of site
routinely subject to FDA inspection, be
submitted as a prior approval supplement if the
site does not have a
satisfactory CGMP inspection
for the
type of operation
being moved (see sections VI.B.1 and
2).
搬迁后的另一个生产厂址如果只需进行常规检查，尚未通过
GMP
检查，
FDA
建议提交“批
准前的变更申请”。
For labeling, secondary packaging, and
testing site changes, the potential for adverse
effect on the identity, strength,
quality, purity, or potency of a drug product as
these
factors may relate to the safety
or effectiveness of the drug product is considered
to be
independent of the type of drug
product dosage form or specific type of operation
being
performed.
Therefore, the recommended reporting
category for any one of these
manufacturing site changes will be the
same for all types of drug products and
operations. For manufacturing sites
used to (1) manufacture or process drug products,
in-process materials, drug substances,
or drug substance intermediates or (2) perform
primary packaging operations, the
potential for adverse effect depends on factors
such
as the type of drug substance or
drug product and operation being performed.
Therefore, recommended
reporting categories may differ depending on the
type of drug
product and operations.
对于贴标签、外包装和检测地点的变更，对关系到药品安全性或有效性的特性、剂量、质
量、纯度或药效有不良作用的潜在因素，被认为独立于药品剂型或正在执行的具体操作。
13
14
因此，建议这些生产场所任一变更
的报告范围要和所有类型的制剂和操作一样。对于生产
场所用于（
1
）生产药品、中控物料、原料药、原料药中间体（
2
）实行内包装的操作，潜
在的不良反应，取决于该类型的原料药或药品
和正在执行的操作。因此。建议报告类别可
以不同于依赖该类制剂和操作。
Except for the
situations described in sections VI.B.4, VI.C.1.b,
and VI.D.5,
construction activities at
a manufacturing site or moving production
operations within
a building or between
buildings at the same manufacturing site do not
have to be
reported to CDER.
除了描述
VI.B.4,
VI.C.1.b, and VI.D.5
的情况，在生产场所或活动的生产操作里、
在相同生
产场所、一个建筑物或两个建筑物之间的建筑活动不需要报告给
CDER
。
We recommend that a move to a
manufacturing site that involves other changes
(e.g., process, equipment) be evaluated
as a multiple related change (see section
XII) to determine the appropriate
reporting category.
我们建议生产场
所的移动牵涉到被看作是复杂的相关其他变更（例如，工序、设备），再
决定合适的报告
范围。
B.
Major Changes (Prior Approval
Supplement)
大变更
The following are examples of changes
considered to have a substantial potential to have
an
adverse effect on the identity,
strength, quality, purity, or potency of a drug
product as these
factors may relate to
the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有重大的
潜在不良影响，可能与药
品的安全性和有效性相关的变更。
1
A move to a different
manufacturing site, except one used to manufacture
or
process a drug substance
intermediate, when the new manufacturing site has
never
been inspected by FDA for the
type of operation that is being moved or the move
results
in a restart at the new
manufacturing site of a type of operation that has
been
discontinued for more than two
years.
进行该项操作的新厂址从未接受过
FDA
现场检查，
或该厂址的该项操作已中止
2
年以上，
生
产原
料药中间体的厂址除外。
2
A move to a different manufacturing
site, except one used to manufacture or
process a drug substance intermediate,
when the new manufacturing site does not have
a satisfactory CGMP inspection for the
type of operation being moved.
进行该项操作的新厂址
GMP
检查不合格，生产原料药
中间体的厂址除外。
3
A move to a different manufacturing
site for (1) the manufacture, processing, or
primary packaging of drug products when
the primary packaging components control
the dose delivered to the patient or
the formulation modifies the rate or extent of
availability of the drug, or (2) the
manufacture or processing of in-process materials
with
modified-release characteristics.
Examples of these types of drug products include
modified-release solid oral dosage
forms,
transdermal systems, liposomal
drug
products, depot drug products,
oral and nasal metered-dose inhalers (MDIs), dry
powder inhalers (DPIs), and nasal spray
pumps.
新厂址（
1
）进行生产
、加工、内包装，内包装控制患者的给药剂量或处方改变了药物吸收
的速度或程度，（<
/p>
2
）生产或加工具有缓释特性的中控物料，包括控释口服固体制剂
，透皮
吸收制剂，脂质体制剂、缓释制剂、
MDIs
、
DPIs
和鼻喷雾泵。
4
Transfer of
the manufacture of an aseptically processed
sterile drug substance or
aseptically
processed sterile drug product to (1) a newly
constructed or refurbished
aseptic
processing facility or area or (2) an existing
aseptic processing facility or area
that does not manufacture similar
(including container types and sizes) approved
drug
products. An example would be
transferring the manufacture of a lyophilized drug
product to an existing aseptic process
area where no approved lyophilized drug
products are manufactured or where the
approved lyophilized drug products being
manufactured have different container
types and/or sizes than the container of the drug
product being transferred. See section
VI.C.1.b for recommendations for other
manufacturing site changes relating to
aseptically processed sterile drug substance or
aseptically processed sterile drug
product.
无菌原料药或无菌制剂转移到（
1
）新建的或改造的无菌厂房或厂区（
2
）现有的
无菌加工
厂房或厂区，但是不未生产过类似的产品（包括包装类型和规格）。例如冻干粉
剂转移到
现有的未生产冻干粉剂的无菌生产区，或生产的产品的包装类型和规格与批准的
产品不相
符。其他无菌工艺相关的原料药或制剂的生产厂址变更见
sectionVI.C.1.b
5.
Transfer of the manufacture of a
finished drug product sterilized by terminal
processes to a newly constructed
facility at a different manufacturing site. Once
this
change has been approved,
subsequent site changes to the facility for
similar drug
product types and
processes may be submitted as a changes-being-
effected-in-30-days
supplement (see
section VI.C.1.a).
使用终端灭菌工艺生
产的制剂产品转移至不同厂址的新建厂房。一旦此变更被批准，后来
的相似药品类型和工
艺的场所变更可以作为“
30
天后进行的变更补充申请”提交。
C.
Moderate Changes (Supplement - Changes
Being Effected)
中等变更
（即将进
行的变更的补充申请）
The
following are examples of changes considered to
have a moderate potential to have
an
adverse effect on the identity, strength, quality,
purity, or potency of a drug product
as
these factors may relate to the safety or
effectiveness of the drug product. If the new
site does not have a satisfactory CGMP
inspection for the type of operation being
moved (see sections VI.B.1 and 2), then
FDA recommends that the changes listed
below (excluding changes relating to
drug substance intermediate manufacturing sites)
15
be submitted in a prior
approval supplement.
下面的例子是
对药品特征、剂量、质量、纯度或药效有中等的潜在不良影响，可能与药品
的安全性和有
效性相关的变更。如果对正在被移动的该类型操作
(see sections
VI.B.1 and
2)
，其新地点没有令人满意的
CGMP
检查，
FDA
建议变更清单（包括有关原料药中间体的
变更）提交在“批准前变更补充申请”。
1.
Supplement - Changes Being Effected in
30 Days
补充文件
-30<
/p>
后变更生效
a.
A move to a different manufacturing
site for the manufacture or processing of any
drug product, in-process material, or
drug substance that is not otherwise provided for
in
this guidance.
本指南未提及的生产或加工制剂、中控物料、原料药的新厂址
b.
For
aseptically processed sterile drug substance or
aseptically processed sterile
drug
product, a move to an aseptic processing facility
or area at the same or different
manufacturing site except as provided
for in section VI.B.4.
无菌原料药或制剂搬迁至相同或不同
厂址的无菌加工厂房或加工区域，
section
VI.B.4
除外
c.
A move to a different
manufacturing site for the primary packaging of
(1) any drug
product that is not
otherwise listed as a major change and (2)
modified-release solid oral
dosage form
drug products.
内包装搬迁至不同的厂址（
1
）不属于大变更的范畴（
2
）控制口服
固体制剂
d.
A move to a different manufacturing
site for testing if (1) the test procedures
approved in the application or
procedures that have been implemented via an
annual
report are used, (2) all
postapproval commitments made by the applicant
relating to the
test procedures have
been fulfilled (e.g., providing methods validation
samples), and (3)
the new testing
facility has the capability to perform the
intended testing.
搬迁至不同的检测厂址（
1
）使用申请中或年度报告中批准的检测规程（
2
）所有检测规程
相关的批准后承诺都已完成（如提供方法验证样品），（<
/p>
3
）新的检测场所有足够的检测能
力。<
/p>
2.
Supplement - Changes Being Effected
补充文件
-
变更已生效
A move to a different manufacturing
site for the manufacture or processing of the
final
intermediate.
搬迁至不同的厂址生产或加工最终中间体
D.
Minor Changes
(Annual Report)
小变更（年度报告）
The following are examples of changes
considered to have a minimal potential to have
an adverse effect on the identity,
strength, quality, purity, or potency of a drug
product
as these factors may relate to
the safety or effectiveness of the drug product.
If the new
site does not have a
satisfactory CGMP inspection for the type of
operation being
moved, then FDA
recommends that the changes listed below
(excluding changes
relating to drug
substance intermediate manufacturing sites) be
submitted in a prior
approval
supplement (see sections VI.B.1 and 2).
下面的例子是对药品特征、剂量、质量、纯度或药效有最小的潜在不良影响、可能与药品
的安全性和有效性相关的变更。如果新厂址针对搬迁的操作没有通过
GMP
检查，
FDA
建议
以下的
情况提交“批准前的补充申请”，不包括原料药中间体的生产厂址。
1
A move to a
different manufacturing site for secondary
packaging.
不同的外包装厂址
2
A move to a different manufacturing
site for labeling.
不同的贴标签厂址
3
A move to a different
manufacturing site for the manufacture or
processing of
drug substance
intermediates other than the final intermediate.
不同的原料药中间体生产加工厂址，不包括最终中间体
4
A change in the contract
sterilization site for packaging components when
the
process is not materially different
from that provided for in the approved application
包材的合同灭菌场所与申请中批准的不同
5
A transfer of the
manufacture of a finished product sterilized by
terminal
processes to a newly
constructed building or existing building at the
same
manufacturing site.
采用终
端灭菌工艺生产的制剂产品转移至新建厂房或同一厂址的现有厂房
6
A move to a different
manufacturing site for the ink imprinting of solid
oral dosage
form drug products.
口服固体制剂喷墨厂址改变
VII.
MANUFACTURING PROCESS
生产工艺
A.
General Considerations
The potential for adverse effects on
the identity, strength, quality, purity, or
potency of
a drug product as these
factors may relate to the safety or effectiveness
of the drug
product depends on the type
of manufacturing process and the changes being
instituted for the drug substance or
drug product. In some cases, there may be a
substantial potential for adverse
effect regardless of direct testing of the drug
substance or drug product for
conformance with the approved specification. When
there is a substantial potential for
adverse effects, a change must be submitted in a
prior approval supplement (section
506A(c) of the Act).
可能对药品的
安全性和有效性有关的特征、剂量、质量、纯度或药效的潜在不良影响，对
于原料药或制
剂，取决于该类型生产工艺和正在开始的改变。在某些情况下，可能有重大
的潜在不良影
响不管原料药或制剂的直接检测和已批准的质量标准一致。当有重大潜在不
良影响时，变
更必须提交在“批准前变更补充申请”
(section
506A(c) of the Act)
。
B.
Major Changes (Prior Approval
Supplement)
大变更
The following are examples of changes
considered to have a substantial potential to
have an adverse effect on the identity,
strength, quality, purity, or potency of a drug
product as these factors may relate to
the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有重大的
潜在不良影响，可能与药
品的安全性和有效性相关的变更
1
Changes that may affect
the controlled (or modified) release, metering or
other
characteristics (e.g., particle
size) of the dose delivered to the patient,
including the
addition or deletion of a
code imprint by embossing, debossing, or engraving
on a
modified-release solid oral dosage
form.
可能改变控释、定量给药或其他给药特性的变更，包括加入或取消刻字
2.
Changes that
may affect drug product sterility assurance
including, where
appropriate, process
changes for sterile drug substances and sterile
packaging
components. These include:
可能影响产品无菌保证的变更，包括无菌原料药和无菌包材的工艺变更，包括
Changes in
the sterilization method (e.g., gas, dry heat,
irradiation). These
include changes
from sterile filtered or aseptic processing to
terminal sterilization, or
vice versa.
无菌方法变更（如汽、干热、放射），包括无菌过滤或无菌工艺改为终端灭菌
Addition, deletion, or substitution of
sterilization steps or procedures for handling
sterile materials in an aseptic
processing operation.
无菌步骤或规程的增加、减少或替代
Replacing sterilizers that
operate by one set of principles with sterilizers
that
operate by another principle
(e.g., substituting a gravity displacement steam
process
with a process using
superheated water spray).
灭菌原理改变
Addition to an aseptic
processing line of new equipment made of different
materials (e.g., stainless steel versus
glass, changes between plastics) that will come in
contact with sterilized bulk solution
or sterile drug components, or deletion of
equipment
from an aseptic processing
line.
加入不同材料制造的
新设备的无菌工艺线，与无菌溶液或药品成分直接接触，或从
无菌生产线上取消设备
Replacing a Class 100 aseptic fill area
with a barrier system or isolator for aseptic
filling. Once this change has been
approved, subsequent process changes for similar
product types in the same barrier
system or isolator may be submitted as a
changes-being-effected-in-30-days
supplement.
用隔离
系统或无菌灌装代替
100
级无菌灌装区，后续工艺变更可提交
“
30
天后进行
的变更的补充申请”。
Replacement or addition of
lyophilization equipment of a different size that
uses
different operating parameters or
lengthens the overall process time.
不同规格、不同冻干参数、或延长工艺总时间的冻干设备的替
换或添加
Changes from bioburden-based terminal
sterilization to the use of an overkill
process, and vice versa.
使用生物灭菌柜的终端灭菌方法改为使用过度杀伤工艺，反之
亦然
Changes to aseptic processing methods,
including scale, that extend the total
processing, including bulk storage
time, by more than 50 percent beyond the validated
limits in the approved application.
改为无菌工艺方法，包括工艺能力
放大，包括贮存时间超过申报资料的验证限度
50
％以上
Changes in sterilizer load
configurations that are outside the range of
previously
validated loads.
灭菌器负荷超过预先验证的限度
Changes in materials or
pore size rating of filters used in aseptic
processing.
无菌工艺中物料或过滤器的孔径规格改变
3.
The following changes for
a natural product
下述产品变更
Changes in the virus or
adventitious agent removal or inactivation
methods.
病毒或外源性物质或去活方法的改变
This applies to any material where such
procedures are necessary, including
drug substance, drug product, reagents,
and excipients.
适用于任何物料，包括原料药、制剂、试剂、辅料
For drug
substance and drug product, changes in the source
material (e.g.,
microorganism, plant)
or cell line.
对于原料药和制剂，来源（如微生物、培养）或细胞链改变
For drug
substance and drug product, establishment of a new
master cell bank or
seed.
对于原料药和制剂，建立新的细胞库或种子
4.
Any
fundamental change in the manufacturing process or
technology from that
currently used by
the applicant. For example:
现行生产工艺或技术的基本变更，例如：
a.
Drug product
制剂
Dry to wet
granulation or vice versa.
干法改为湿法或反之
Change
from one type of drying process to another (e.g.,
oven tray, fluid
bed, microwave).
由一种干燥工艺改为另一种（如烘箱、流化床、微波炉）
b.
Drug substance
原料药
Filtration to
centrifugation or vice versa.
过滤改为离心或反之
Change
in the route of synthesis of a drug substance
原料药合成途径改变
5.
The following changes for
drug substance
原料药下述变更
Any process change made after the final
intermediate processing step in drug
substance manufacture.
原料药生产过程中，最终中间体以后的工艺步骤的任何变更
Changes in the synthesis or manufacture
of the drug substance that may affect its
impurity profile and/or the physical,
chemical, or biological properties.
可能影
响原料药杂质和
/
或物理、化学或生物学特性的合成或生产的变
更
Addition of an ink code
imprint or change to or in the ink used for an
existing
imprint code for a solid oral
dosage form drug product when the ink as changed
is not currently used on
CDER-approved drug
products
.
17
6.
加入或改变喷墨，如果当前使用的喷墨已不用于
CDER
批准的产品
7.
Establishing a new procedure for
reprocessing a batch of drug substance or drug
product that fails to meet the approved
specification.
C.
制定不合格原料药或制剂的新的再加工规程
Moderate Changes (Supplement - Changes
Being Effected)
中等变更
The following are examples of changes
considered to have a moderate potential to have
an adverse effect on the identity,
strength, quality, purity, or potency of a drug
product
as these factors may relate to
the safety or effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有中等的
潜在不良影响，可能与药品
的安全性和有效性相关的变更
1.
Supplement -
Changes Being Effected in 30 Days
30
天后进行的变更补充申请
a.
For drug products, any change in the
process, process parameters, and/or
equipment except as otherwise provided
for in this guidance.
本指南未提及的制剂产品的所有工艺、工艺参数和
/
或设备变更
b.
For drug substances, any
change in process and/or process parameters
except as otherwise provided for in
this guidance.
本指南未提及的原料药的工艺和
/
或工艺参数变更
c.
For natural protein drug substances and
natural protein drug products:
蛋白质原料药和制剂
Any change in
the process, process parameters, and/or equipment
except as
otherwise provided for in
this guidance (e.g., section VII.B.5, VII.D.7).
本指南未提及的任何工艺、工艺参
数和
/
或设备变更
An increase or
decrease in production scale during finishing
steps that involves
different
equipment.
涉及不同设备的生产结束步骤的增加或减少
Replacement of
equipment with equipment of different design that
does not affect
the process methodology
or process operating parameters.
不同设计的设备变更，不影响工艺方法和工艺参数
d.
For sterile drug products, drug
substances, and components, as
appropriate:
对于无菌制剂、原料药、成分
Changes in dry heat
depyrogenation processes for glass container
systems for
drug substances and drug
products that are produced by terminal
sterilization processes
or aseptic
processing.
终端灭
菌或无菌工艺生产的原料药或制剂的玻璃容器的干热除热原工艺的变更
Changes to
filtration parameters for aseptic processing
(including flow rate,
pressure, time,
or volume, but not filter materials or pore size
rating) when additional
validation
studies for the new parameters should be
performed.
无菌工艺
（包括流速、压力、时间、体积、不包括过滤器材料或孔径）过滤参数的
变更，新参数需
进行额外验证
Filtration process changes that provide
for a change from single to dual sterilizing
filters in series, or for repeated
filtration of a bulk.
过滤工艺变更，从单一过滤器变为双重过滤器或重复过滤
Changes from
one qualified sterilization chamber to another for
in-process or
terminal sterilization
that result in changes to validated operating
parameters (time,
temperature, F0, and
others).
一个验证过的
灭菌柜改为另一个中控或终端灭菌，
导致验证参数改变
（时间、
温度、
F0
、其他）
< br>
Changes in
scale of manufacturing for terminally sterilized
drug products that
increase the bulk
solution storage time by more than 50 percent
beyond the validated
limits in the
approved application when bioburden limits are
unchanged.
终端灭菌产品的生产规模改变，导致
原液贮存时间增加
50
％以上，在生物负荷限度
不变的情况下超过申报资料中的验证限度
e.
For drug substances, redefinition of an
intermediate, excluding the final
intermediate, as a starting material.
2.
对于原料药、中间体再定义、不包括最终中间体，作为起始物料
Supplement - Changes Being Effected
已进行的变更补充申请
a.
A
change in methods or controls that provides
increased assurance that
the drug
substance or drug product will have the
characteristics of identity, strength,
quality, purity, or potency that it
purports or is represented to possess.
方法或控制变更，提高原料药或制剂成分、剂量、质量、纯度
、药效的保证
b.
For sterile drug
products, elimination of in-process filtration
performed as
part of the manufacture of
a terminally sterilized drug product.
无菌制剂，取消终端灭菌生产的中控过滤步骤
D.
Minor Changes (Annual Report)
小变更（年报）
The
following are examples of changes considered to
have a minimal potential to have
an
adverse effect on the identity, strength, quality,
purity, or potency of a drug product
as
these factors may relate to the safety or
effectiveness of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效有最小的潜在不良影响，可能与药品
的安全性和有效性相关的变更。
1
For drug products, changes to equipment
of the same design and operating
principle and/or changes in scale
except as otherwise provided for in this guidance
(e.g.,
section VII.C.1.c, VII.D.7).
本指南未涉及的制剂产品设备设计和操作原理和
/
或规模变更
2
A minor change in an existing code
imprint for a dosage form.
For example,
changing from a
numeric to alphanumeric code.
制剂刻字喷墨的变更，如由数字改为文字数字
3
Addition of an ink code
imprint or a change in the ink used in an existing
code
imprint for a solid oral dosage
form drug product when the ink is currently used
on
CDER-approved drug products.
加入喷墨或改变喷墨
4
Addition or deletion of a code imprint
by embossing, debossing, or engraving on
a solid dosage form drug product other
than a modified-release dosage form.
非控制制剂的口服固体制剂加入或取消刻字代码
5
A change in the order of
addition of ingredients for solution dosage forms
or
solutions used in unit operations
(e.g., granulation solutions).
单剂量使用的液体制剂或溶液剂成分加入次序改变
1
Changes in
scale of manufacturing for terminally sterilized
drug products that
increase the bulk
solution storage time by no more than 50 percent
beyond the validated
limits in the
approved application when bioburden limits are
unchanged.
终端灭菌的制剂产品生产规模改变，延长原液贮存时间
50
％以上，在生物负荷限度
不变的情况下超过
申报资料中的验证限度
7.
For natural protein drug
products and natural protein drug substances:
对于蛋白质制品和天然蛋白质原料药
An increase or decrease in
production scale during finishing steps that does
not
involve an equipment change.
生产末期增加或降低生产规模，没有设备变更
Replacement of
equipment with equipment of the same design,
operating
principle, and capacity with
no change in production scale.
设备变更，变更前后的设备的设计、操作原理、产能、生产规
模相同
VIII.
SPECIFICATIONS
质量标准
A.
General Considerations
All changes in specifications from
those in the approved application must be
submitted
in a prior approval
supplement unless otherwise exempted by regulation
or guidance (§
314.70(b)(2)(i)).
Specifications
(i.e., tests,
analytical procedures, and acceptance criteria)
are the quality standards provided in
an approved application to confirm the quality of
drug substances, drug products,
intermediates, raw materials, reagents,
components,
in-process materials,
container closure systems, and other materials
used in the
production of a drug
substance or drug product. For the purpose of
defining
specifications,
acceptance criteria
are
numerical limits, ranges, or other criteria for
the
tests described. Examples of a
test, an analytical procedure, and an acceptance
criterion are, respectively, an assay,
a specific, fully described high pressure liquid
chromatography (HPLC) procedure, and a
range of 98.0
–
102.0 percent.
The
recommendations in this section also
apply to specifications associated with sterility
assurance that are included in NDA and
ANDA submissions.
18
从那些已批准申请的质量标准里的所有变更必须提交在
“批准前变更补充申请”
，
除非另
有被规章或指导原则豁免的<
/p>
(§
314.70(b)(2)(i))
。规程（例如，检测、分析步骤、可接受标
准）是在已批准的申请里提供证实原料药、
制剂、中间体、原材料、反应物、成分、中控
物料、
包装，
和原料药或制剂生产过程中使用的其它物质的质量标准。
质量标准和
可接受
标准的目的是明确数值界限，范围，或为检验所描述的其他标准。实例检验，一个
分析规
程和一个可接受标准为各自检测、完全特定的高效液相步骤、范围
98.0%-102.0%
。本
条中的建议也适用于和
无菌保证有联系的质量标准，包括在
NDA
和
< br>ANDA
。
A
regulatory
analytical
procedure is the procedure in the approved
application that is
designated for use
in evaluating a defined characteristic of the drug
substance or drug
product. Section
501(b) of the Act recognizes the analytical
procedures in the
U.S.
Pharmacopeia/National
Formulary
(USP/NF) as the regulatory
analytical procedures
for compendial
items. Tests and associated acceptance criteria
and regulatory
analytical procedures in
addition to those specified in the USP/NF may be
required for
approving compendial items
(section 505 of the Act).
获
批准的法定分析规程是能被指定用于评估原料药或制剂的确定性质的规程。
美国药典
/
国家
处方集的法定分析规程是根据
法案的第
501(b)
确定的分析规程
。对正在批准的简明条款除了那些在
USP/NF
中详细说明的，还有检测和有联系的可接受标准，法定分析规程，可能都被要求在其中。
(section
505 of the Act)
The applicant may include
in its application
alternatives
to the approved
regulatory
analytical procedures for
testing the drug substance and drug product.
However, for
purposes of determining
compliance with the Act, regulatory analytical
procedures
are used.
申请人可以在其申请书中包括其可实施的用于检验原料药和制剂的不同于法定分析规程的
替代方法。不过，为了和法案相一致，使用法定分析规程来判断决定。
In sections B through D
below, the use of the term
analytical
procedure
without a
qualifier such as
regulatory
or
alternative
refers to an
analytical procedure used to test
materials other than the drug substance
or drug product.
在
B
部分到以下
D
，
没有限定分析规程的使用范围，
例如法定或可替代的指的是被用于检测
物料而不是原料药或制剂的分析规程。
B.
Major Changes
(Prior Approval Supplement)
大变更
The following
are examples of changes in specifications
considered to have a
substantial
potential to have an adverse effect on the
identity, strength, quality, purity,
or
potency of a drug product as these factors may
relate to the safety or effectiveness
of the drug product.
下面的例子是对药品特征、剂量、质量、纯度或药效重大的潜在不良影响，可能与药品的
安全性和有效性相关的变更。
1
Relaxing an acceptance criterion except
as otherwise provided for in this
guidance (e.g., section VIII.C.1.b,
VIII.C.1.e).
本指南未提及的可接受限度变宽
2
Deleting any part of a
specification except as otherwise provided for in
this
guidance (e.g., section VIII.D.2).
本指南未提及的质量标准项目的删除
3
Establishing a new
regulatory analytical procedure including
designation of an
alternative
analytical procedure as a regulatory procedure.
制定新的法定分析规程，包括替代规程
4
A change in a regulatory
analytical procedure that does not provide the
same or
increased assurance of the
identity, strength, quality, purity, or potency of
the material
being tested as the
regulatory analytical procedure described in the
approved
application.
对申报资料中的法定分析规程的变更，但是不能等效或更好地保证被测物的特征、
< br>剂量、质量、纯度或药效
5
A change in an analytical procedure
used for testing components, packaging
components, the final intermediate, in-
process materials after the final intermediate, or
starting materials introduced after the
final intermediate that does not provide the same
or increased assurance of the identity,
strength, quality, purity, or potency of the
material
being tested as the analytical
procedure described in the approved application
except as
otherwise noted. For example,
a change from an HPLC procedure that distinguishes
impurities to (1) an HPLC procedure
that does not, (2) another type of analytical
procedure (e.g., titrimetric) that does
not, or (3) an HPLC procedure that distinguishes
impurities but the limit of detection
and/or limit of quantitation is higher.
检测成分、包材、最终中间体、最终中间体后的中控物料、或
最终中间体之后引入
的起始物料的分析规程的变更，但是不能等效或更好地保证被测物的
特征、剂量、质量、
纯度或药效。
例如将可以分辨杂质的
HPLC
方法改为不能分辨杂质的
HPLC<
/p>
方法或另一种分
析方法（如滴定），或可以分辨杂质但是检测限和
/
或定量限更高的
HPLC
方法。
6
Relating to testing of raw materials
for viruses or adventitious agents:
原料病毒或外源物相关的检测
(1)
relaxing an acceptance criterion, (2) deleting a
test, or (3) a change in the analytical
procedure
that
does
not
provide
the
same
or
increased
assurance
of
the
identity,
strength,
quality,
purity,
or
potency
of
the
material
being
tested
as
the
analytical
procedure
described in the approved application.
放宽可接受标准，取消某项检测，对申报资料种的分析规程变更且不能提供等效或更好的
质量保证
19
C.
Moderate Changes (Supplement - Changes
Being Effected)
中等变更
The following are examples of changes
in specifications considered to have a
moderate potential to have an adverse
effect on the identity, strength, quality, purity,
or potency of a drug product as these
factors may relate to the safety or effectiveness
of the drug product.
下面的例子是对
药品特征、剂量、质量、纯度或药效有中等的潜在不良影响，可能与药品
的安全性和有效
性相关的变更。
1.
a.
Supplement - Changes Being Effected in
30 Days
增补
-
变更
30
天后生效
Any change in a regulatory analytical
procedure other than those identified as major
changes or editorial changes.
大变更以外的其他法定分析规程的变更
b.
Relaxing an
acceptance criterion or deleting a test for raw
materials used
in drug substance
manufacturing, in-process materials prior to the
final intermediate,
starting materials
introduced prior to the final drug substance
intermediate, or drug
substance
intermediates (excluding final intermediate)
except as provided for in section
VIII.B.6.
放宽质量标准
或取消某项检测，用于检验原料药的原料、中控物料、起始物料、中
间体等
c.
A change in an analytical procedure
used for testing raw materials used in
drug substance manufacturing, in-
process materials prior to the intermediate,
starting
materials introduced prior to
the final drug substance intermediate, or drug
substance
intermediates (excluding
final intermediate) that does not provide the same
or increased
assurance of the identity,
strength, quality, purity, or potency of the
material being tested
as the analytical
procedure described in the approved application
except as provided for
in section
VIII.B.6.
分析规程变
更，用于检测原料药生产中的原料、中间体前的中控物料、最终原料药
中间体前引入的起
始物料、原料药中间体（不包括最终中间体），没有提供和原先批准的
分析规程等效或更
好的保证，来确保被测物的特征、含量、质量、纯度、药效，第
VII.B.6.
的部分除外
d.
Relaxing an in-process
acceptance criterion associated with
microbiological monitoring of the
production environment, materials, and components
that are included in NDA and ANDA
submissions. For example, increasing the
microbiological alert or action limits
for critical processing environments in an aseptic
fill
facility or increasing the
acceptance limit for bioburden in bulk solution
intended for
filtration and aseptic
filling.
放宽
NDA
或
ANDA
申报
中声明的生产环境、物料、成分微生物监控的中控可接受标
准。例如，增加无菌装量厂房
关键工艺环境的微生物警戒或行动限度，或增加即将过滤或
无菌装量的原液的生物负荷的
可接受限度
e.
Relaxing an acceptance
criterion or deleting a test to comply with an
official compendium that is consistent
with FDA statutory and regulatory requirements
(§
314.70(c)(2)(iii)).
放宽可接受标准或减少某项检测，
以满足药典要求、
FDA
法规要求
2.
Supplement -
Changes Being Effected
a.
An
addition
to
a
specification
that
provides
increased
assurance
that
the
drug
substance or drug product will have the
characteristics of identity, strength, quality,
purity,
or potency that it purports or
is represented to possess. For example, adding a
new test
and associated analytical
procedure and acceptance criterion.
质量标
准中加入项目以加强质量保证，例如，新的检测项目及其相关的分析规程、可接受
标准<
/p>
b.
A
change
in
an
analytical
procedure
used
for
testing
components,
packaging
components, the final intermediate, in-
process materials after the final intermediate, or
starting
materials
introduced
after
the
final
intermediate
that
provides
the
same
or
increased
assurance of
the
identity,
strength,
quality,
purity,
or potency
of the
material
being tested as the
analytical procedure described in the approved
application.
分析规程变更，用于检测成分、包材、中间体、中控物料、
起始物料
D.
Minor Changes (Annual Report)
小变更
The following
are examples of changes in specifications
considered to have a minimal
potential
to have an adverse effect on the identity,
strength, quality, purity, or potency
of a drug product as these factors may
relate to the safety or effectiveness of the drug
product.
下面的例子是对
药品特征、剂量、质量、纯度或药效有最小的潜在不良影响，可能与药品