-
21 March 2014
EMA/CHMP/CVMP/QWP/441071/2011- Rev.2
Committee
for
Medicinal
Products
for
Human
Use
(CHMP)/
Committee for
Medicinal Products for Veterinary Use (CVMP)
6 months after publication
Guideline on stability testing for
applications
for
variations
to
a
marketing authorization
上市许可变更申请的稳定性试验指南
Draft Agreed by CHMP/CVMP Quality
Working Party
June 2011
草案由
CHMP/CVMP
质量工作组通过<
/p>
2011
年
6
月
Adoption by CHMP for release for
consultation
June 2011
CHMP
通过并公布征求意见
2011
年
6
月
Adoption by CVMP
for release for consultation
July 2011
CVMP
通过并公布告示意见
2011
年
7
月
End of
consultation (deadline for comments)
31
January 2012
公开征求意见结束
2012
年
1
月
31
日
Agreed
by QWP
December 2013
QWP
通过
2013
年
12
月
Adoption by CHMP
February 2014
CHMP
采纳
2014
年
2
月
Adoption by CVMP
January 2014
CVMP
采纳
2014
年
1
月
Date for coming into
effect
生效日期
公布后
6
个月
This guideline replaces
Guideline on stability testing for applications
for variations to a
marketing
authorisation previous version (CPMP/QWP/576/96
Rev 1, EMEA/CVMP/373/04).
本指南替代“上市批准后变更
申请的稳定性试验指南”前版本
(CPMP/QWP/576/96 Rev 1,
EMEA/CVMP/373/04)
Keywords
Stability,
stability
testing,
stability
data,
chemical
active
substance,
specification,
variation
稳定性，稳定性试验，稳定性数据，化
学活性物质，质量标准，变更
关键词
Table of
contents
1.
2.
3.
4.
5.
6.
6.1.
(
B.I.a.1.b
)
Executive summary
Introduction (background)
Scope
Legal
basis
General requirements
Type I variations
Type II variations
Change
in
the
manufacturer
of
a
starting
material
/
reagent
/
intermediate
used
in
the
manufacturing process of the active
substance or
change
in
the
manufacturer
(including
where
relevant
quality
control
testing
sites)
of
the
active
substance,
where
no
Ph.
Eur.
Certificate
of
Suitability
is
part
of
the
approved
dossier:
Introduction
of
a
manufacturer
of
active
substance supported
by an ASMF
Change
in
the
manufacturer
of
a
starting
material
/
reagent
/
intermediate
used
in
the
manufacturing process of the active
substance or
change
in
the
manufacturer
(including
where
relevant
quality
control
testing
sites)
of
the
active
substance,
where
no
Ph.
Eur.
Certificate
of
Suitability
is
part
of
the
approved
dossier:
The proposed manufacturer uses a
substantially
different
route
of
synthesis
or
manufacturing
conditions,
which
may
have
a
potential
to
change
important
quality
characteristics
of
the
active
substance,
such
as
qualitative
and/or
quantitative
impurity
profile
requiring
qualification,
or
physico-chemical
properties
impacting on
bioavailability
Change
in
the
manufacturer
of
a
starting
material
/
reagent
/
intermediate
used
in
the
manufacturing process of the active
substance or
change
in
the
manufacturer
(including
where
relevant
quality
control
testing
sites)
of
the
active
substance,
where
no
Ph.
Eur.
Certificate
of
Suitability
is
part
of
the
approved
dossier:
Introduction of a new manufacturer of
the active
substance that is not
supported by an ASMF and
requires
significant update to the relevant active
substance section of the dossier
Changes
in
the
manufacturing
process
of
the
active
substance:
Substantial
changes
to
the
manufacturing
process
of
the
active
substance
which
may
have
a
significant
impact
on
the
quality,
safety
or
efficacy
of
the
medicinal
product.
Changes
in
the
manufacturing
process
of
the
active substance: The change relates to
a herbal
medicinal product and there is
a change to any
of
the
following:
geographical
source,
manufacturing route
or production
Change
in
immediate
packaging
of
the
active
实施摘要
介绍（背景）
范围
法规依据
一般要求
第
1
类变更
第
2
类变更
生产商变更：非
CEP
批准文件中活性
物质生
产工艺所用起始物料、试剂、中间体生产商
变更，或活性
物质生产商变更（包括相关质
量控制检测场所）
：
引入一个由
ASMF
支持的
活性物质生产商
6.2.
(
B.I.a.1.c
)
生产商变更：非
CEP
批准文件中活性物质生
产工艺所用起始物料、试剂、中间体生产商
变更，或活性物质生产商
变更（包括相关质
量控制检测场所）：拟报生产商使用显著不
同
的合成路线或生产条件，可能会对活性物
质的质量特性有重大改变的情况，例如杂质
谱数量和
/
或定性需要进行定性，或理化特
性
对生物利用度有影响
6.3.
(
B.I.a.1.g
)
生产商变更：非
CEP
批准文件中活性物质生
产工艺所用起始物料、试剂、中间体生产商
变更，或活性物质生产商
变更（包括相关质
量控制检测场所）
：
引入新的无
ASMF
支持的
活性物质生
产商，需要对申报文件有关活性
物质部分进行重大更新时
6.4.
(
B.I.a.2.b
)
活性物质生产工艺变更：对活性物质生产工
艺有重大变更，可能会对药品质
量、安全性
或有效性有重大影响时
6.5.
(
B.I.a.2.d
)
活性物质生产工艺变更：变更是关于一种草
药制品，对以下任何一项有变更
时：
来源地、
生产路线或生产
活性物质内包装变更：无菌或非冷冻生物制
6.6.
(
B.I.c.1.b
)
substance:
Qualitative
and/or
quantitative
composition
for
sterile
and
non-
frozen
biological/immunological active
substances
6.7.
Change
in
composition
(excipients)
of
the
(
.a.3.b.2
)
finished
product:
Qualitative
or
quantitative
changes in one
or more excipients that may have
a
significant
impact
on
the
safety,
quality
or
efficacy of the medicinal product.
6.8.
Change in
coating weight of oral dosage forms
(
.a.4.b
)
or
change
in
weight
of
capsule
shells:
Gastro-resistant,
modified
or
prolonged
release
pharmaceutical
forms
where
the
coating
is
a
critical
factor for the release mechanism
6.9.
Change
in
concentration
of
a
single-dose,
total
(
.a.5.
)
use parenteral product, where the
amount of the
active substance per unit
dose (i.e. the strength)
remains the
same
6.10.
Replacement or addition of a
manufacturing site
(
.b.1.c
)
for
part
or
all
of
the
manufacturing
process
of
the
finished
product:
Site
where
any
manufacturing
operation(s)
take
place,
except
batch
release,
batch
control,
and
secondary
packaging,
for
biological/immunological
medicinal products, or for
pharmaceutical forms
manufactured
by
complex
manufacturing
processes
6.11.
Change
in
the
manufacturing
process
of
the
(.b.3.b)
finished
product, including an intermediate used
in
the
manufacture
of
the
finished
product:
Substantial changes
to a manufacturing process
that
may
have
a
significant
impact
on
the
quality,
safety
and
efficacy
of
the
medicinal
product
6.12.
Change
in
the
manufacturing
process
of
the
(
.b.3.d
)
finished product, including an
intermediate used
in
the
manufacture
of
the
finished
product:
Introduction
of
a
non-standard
terminal
sterilisation
method
6.13.
Change
in
the
manufacturing
process
of
the
(
.b.3.e
)
finished product, including an
intermediate used
in
the
manufacture
of
the
finished
product:
Introduction
or
increase
in
the
overage
that
is
used for the active
substance
6.14.
Change
in
the
batch
size
(including
batch
size
(
.b.4.d
)
ranges)
of
the
finished
product:
The
change
relates
to
all
other
pharmaceutical
forms
manufactured
by
complex
manufacturing
processes
6.15.
Change in
immediate packaging of the finished
(
.e.1.a.3
)
product:
Qualitative
and
quantitative
composition:
Sterile
medicinal
products
and
biological/immunological
medicinal products
6.16.
Change in immediate packaging of the
finished
(
.e.1a.4
)
product:
Qualitative
and
quantitative
composition:
The
change
relates
to
a
less
protective
pack
where
there
are
associated
changes
in
storage
conditions
and/or
reduction
品
/
免疫类活性物质组份和
/
或组成比例
制剂组份（辅料）变更：一种或多
种辅料性
质或数量变更，可能会对药品安全、质量或
有效性产生
重大影响的
口服剂型包衣重量或胶囊壳重量变更：
肠溶、
改释或延释剂型中包衣在释放机理中作为关
键因素时
单剂量剂型、全静脉药品的浓度变更，单剂
药品中活性物质数量（即剂量）保持不变时
使
用另一生产场所替代部分或全部制剂生
产，或增加一个生产场所：除以下操作外其
它操作：批放行、批检验、外包装、生物制
品
/
免疫制品，或由复杂生产工艺生产的药品
< br>制剂生产工艺变更，包括用于制剂生产的中
间体：生产工艺有重大变更，可能对制
剂的
质量、安全性和有效性有重大影响时
制剂生产工艺变更，包括用于制剂生产的中
间体：引入一个非标终端灭菌方法
制剂生产工艺变更，包括用于制剂生产的中
间体：引入或增加活性物质使用余量
制剂批量变更（包括批量
范围）：变更是关
于采用复杂生产工艺的所有其它药品剂型时
制剂内包装变更：组成性质或数量：无菌制
品和生物
/
免疫药品
制剂内包装
变更：组成性质或数量：变更是
关于降低包装保护性时，且同时要求存贮条
件变更和
/
或缩短货架期
in shelf life
6.17.
Change in immediate
packaging of the finished
(
.e.1.b.2
)
product: Change in type of container or
addition
of
a
new
container:
Sterile
medicinal
products
and
biological/immunological
medicinal
products
6.18.
Change in
shape or dimensions of the container
(
.e.4.b
)
or
closure
(immediate
packaging):
The
change
in
shape or dimensions concerns a fundamental
part of the packaging material, which
may have
a significant impact on the
delivery, use, safety
or stability of
the finished product
6.19.
Change
in
pack
size
of
the
finished
product:
(
.e.5.c
)
Change
in
fill
weight/fill
volume
of
sterile
multidose
(or
single-dose)
parenteral
medicinal
product,
including
biological/immunological
medicinal products
7.
Commitment batches
References
Annex I
Annex II
制剂内包装变更：包装容器类型变更，或增
< br>加一种新的包装容器：无菌产品和生物制品
/
免疫产品<
/p>
包装容器或密闭器（内包装）形状或尺寸变
更：形状或尺寸变更涉及包装材料的基本部
分，可能会对制剂的运输、使用、安全性
或
稳定性产生重大影响时
制剂包装规
格变更：无菌（或单剂量）注射
剂，
包括生物制品
/
免疫制品的充填重量
/
充
填
体积变更
承诺批次
参考文献
附录
1
附录
2
Executive
summary
实施摘要
This
guideline provides guidance on the stability data
which have to be generated in order to
support a variation to a marketing
authorisation. The guideline provides general
guidance on
stability testing for type
IA and type IB variations and addresses the data
requirements for
common type II
variations.
本指南提供为支持上市许可变更而
需要产生的稳定性数据指南。本指南对
IA
和
< br>IB
类变更的
稳定性研究提供通用指南，也说明了常规<
/p>
2
类变更的数据要求。
1. Introduction (background)
介绍（背景）
This
guideline describes the stability testing
requirements for variations to a marketing
authorisation after approval. This
guideline is an extension of the CHMP and CVMP
Guidelines
on stability testing of
existing active substances and related finished
products and the respective
ICH/VICH
Guidelines for new active substances and drug
products. It is intended to be applied in
the European Union.
本指南描述了批准后的上市许可进行变更时所要求的稳定性研究。本指南是
CH
MP
和
CVMP
“已有活性物质和有关
制剂稳定性试验指南”和对应的
ICH/VICH
“新原料药和
制剂指南”
的延伸。它适用于欧盟以内。
The guideline seeks to illustrate the
stability data required for variations to active
substances
and/or finished products. It
is not always necessary to comply with this
guideline when there are
scientifically
justifiable reasons for using alternative
approaches (e.g., quality by design concept).
However, the stability data outlined in
this guideline reflects the usual expectation of
the
regulators.
本指南力图诠释活性物质和
/
或制剂变更时所需的稳定性数据。
如果具有科学理由论证使用
其它方法的合理性（例如，质量源于设计概念），也可以不符
合本指南。但是，在本指南中
所列出的稳定性数据要求反映了法规当局的一般期望。
While the guideline provides
a general indication on the requirement for
stability testing, it allows
sufficient
flexibility to encompass the variety of different
practical situations required for specific
scientific situations and
characteristics of the material being evaluated.
由于本指南只是提供稳定性试验要求的通用指示，根据特定科
学情形所要求的不同实践情
况，以及所评估的物料的不同特性，可以进行变动。
2. Scope
范围
The purpose of
this guideline is to outline the stability data
which have to be generated in case of
variations. It is applicable to
chemical active substances and related finished
products, herbal
substances, herbal
preparations and related herbal medicinal
products. Radiopharmaceuticals,
biologicals/immunologicals and products
derived from biotechnology are not within the
scope of
this guideline.
本指南目的是列出变更所需产生的稳定性数据。指南适用于化学活性物质和有关的制
剂、
草药物质、草药制品和相关草药制剂。辐
射药品、生物制品
/
免疫制品和由生物技术衍生的
药品不在本指南范围内。
Variations
for active substances and finished products
encompass a wide range of situations. The
Guideline provides general guidance on
stability testing in case of type I (A and B)
variations.
Furthermore, it addresses
the information required for active substances
and/or finished products
in common type
II variations as listed in section 6.
活性物质和制剂的变更包括很多种情形，
本指南提供的是第
1
类（
A
和
B
）
变更中稳定性试验
的一般指南。另外，在第
6
部分列出的常规
< br>2
类变更中活性物质和
/
或制剂
所需的资料。
3. Legal basis
法规依据
This
guideline should be utilised in conjunction with
Commission Regulation (EC) No 1234/2008
as amended and the introduction and
general principles section (4) of Annex I to
Directives
2001/82 and 2001/83 as
amended.
本指南就与
(EC) No 1234/2008
及其修订内容和指令
2001/82
和
2001/83
及其修订内容附录
1
第
（
4
）部分一般原则一起使
用。
4. General requirements
一般要求
In cases of
variations which require generation of stability
data on the finished product or the
active substance, the stability studies
required, including commitment batches, should
always be
continued up to the approved
shelf-life / retest period and the authorities
should be informed
immediately if any
problems with the stability appear during storage,
e.g. if outside specification
or
potentially outside specification.
如果申请的变更需要产生制剂或活性物质的稳定性数据，
稳定性研究，
包括承诺批次，
都应
该持续至批准的货
架期
/
复验期，如果在存贮期间稳定性出现任何问题，例如，超
出质量标
准或潜在超出质量标准，必须马上报告药监当局。
The scope and design of the stability
studies for variations and changes are based on
the
knowledge and experience acquired
of the active substances and finished products.
The available
information must be taken
into account such as:
变更后稳定
性研究的范围和设计应基于活性物质和制剂所需的知识和经验，
必须考虑到诸如
以下列出的可以获得的资料：
a) For
active substances:
活性物质
?
the stability
profile including the results of stress testing,
if applicable (except herbals);
?
稳定性概况，包括强降解试验结果，适用时（草药除外）
?
the supportive
data;
?
支持性数据
?
the primary
data of long term and accelerated* testing.
?
长期和加速试验初期数据
b)
For finished products:
制剂
?
the supportive data;
?
支持性数据
the primary
data of long term and accelerated* testing.
长期和加速试验初期数据
In all variations, the applicant
assesses whether the intended change has the
potential to impact the
quality
characteristics and stability of the active
substances and/or the finished products and
consequently on their stability.
s, the applicant assesses
whether the intended change has the potential to
impact the quality
characteristics and
stability of the active substances and/or the
finished products and consequently
on
their stability.
在所有变更中，申请人
应评估所拟变更是否对质量特性和活性物质和
/
或制剂稳定性产
生潜
在影响，从而影响其稳定性
产生潜在影响，从而影响其稳定性
When stability data are required, the
choice of test conditions, defined in this
guideline refers to
如果要求提交稳
定性数据，
对测试条件的选择参见以下指南
CHMP/ICH Guideline on Stability Testing
of New Drug Substances and Products,
<
/p>
CHMP/ICH
指南：新原料药和制剂稳定性试验指南
CHMP/QWP Guideline on Stability
Testing of Existing Active Substances and Related
Finished
Products,
CHMP/QWP
指南：已有活性物
质和有关制剂稳定性试验指南
the
CVMP/VICH
Guideline
on
Stability
Testing
of
New
Veterinary
Drug
Substances
and
Medicinal Products
CVMP/VICH
指南：新兽用原料药和制剂稳定性试验指南
and the CVMP/QWP Note for Guidance on
Stability Testing of Existing Active Substances
and Related Finished Products,
respectively.
C
VMP/QWP
指南解释：已有活性物质和有关制剂稳定性试验指南解释
Where appropriate, the concept of
bracketing and matrixing as described in the
CHMP/ICH and
the CVMP/VICH Note for
Guidance on Bracketing and Matrixing Designs for
Stability Testing of
Drug Substances
and Drug Products may be applied across related
products.
适当时，在
C
HMP/ICH
和
CVMP/VICH
指南“活性物质和制剂的稳定性试验所用括号法和
矩阵法指南解释”中的括号和矩阵概念
可以应用于覆盖相关产品。
在
CHM
P/ICH
和
CVMP/VICH
指南
“活性物质和制剂的稳定性试验所用括号法和矩阵法指
南解释”中的括号和矩阵概念可以
应用于覆盖相关产品。
The results of
stability studies of the varied active
substance/finished product,
including
the requested time period as defined below, using
long term and
accelerated* testing
conditions, should be compared to studies
performed on the
unchanged active
substance/finished product. This ensures that the
change does not
negatively impact the
stability profile, i.e. that the specification
limits of the active
substance/finished
product will still be met at the end of the
proposed retest
period/shelf-life. The
comparison data of the unchanged product submitted
with the
variation may come from
previous studies.
变更后活性物质
/
制剂的稳定性试验结果，
包括
以下定义
要求的时间长度，
长稳和
加速条件，应与变更前活性物质
/
制剂所进行的研究相
比较
。这样才能保证变更不会对
稳定性概况具有负面影响，即，
在拟定的复验期
/
货架期结束时，仍能
满足
活性物质
/
制剂的质量标准限度<
/p>
。变更前
后产品比较数据可以是来自之前的研究。
In relation to herbal substances,
herbal preparations and related herbal medicinal
products the guideline on quality of
herbal medicinal products / traditional herbal
medicinal products
(EMA/CPMP/QWP/2819/00 Rev. 2), the guideline on
specifications: test procedures and
acceptance criteria for herbal substances, herbal
preparations and herbal medicinal
products / traditional herbal medicinal products
(EMA/CPMP/QWP/2820/00 Rev. 2) should
also apply. The testing of herbal
substances and herbal preparations,
testing at accelerated storage conditions or at
the
intermediate storage conditions may
be omitted if justified by the applicant and if
the
storage conditions below
25°
C are clearly labelled on the
product.
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