8月5号Q1A(R2)中英文对照

2021年1月26日发(作者：罔顾)

Q1A(R2)
中英文对照



人用药品注册技术要求国际协调会


ICH
三方指导文件


新原料药和制剂的稳定性试验

Q1A(R2)

现第四版

2003
年
2
月
6
日制定














Q1A(R2)
文件历程



新编码

原编码

历史

在第二阶段被指导委员
Q1
会批准并公开发布征求
意见

在第四阶段被指导委员
Q1A
会批准并推荐给
ICH
三
1 993
年
10
方当局征求意见。

Q1A
从命名为
Q1A
第一次修订文本得到指
Q1A(R)
导委员会批准并公开发
布征求指导意见

在第四阶段第一版被指
Q1A(R)
导委员会批准并推荐给
2000
年
11
ICH
三方当局征求意
见。


现第四版


日

期

2005
年
11
月

1992
年
9
月
16
日

Q1
月
27
日

Q1A
1999
年
10
月
7
日

Q1A(R1)
月
8
日

Q1A(R1)

第四阶段第二版直接 被
指导委员会批准，没有
公开发布征求意见。此
Q1A(R2)
文本包含了 因采纳
Q1F
（Ⅲ和Ⅳ气候带注册申
请的稳定性数据包）所
引起的改变，并推 荐给
ICH
三方当局采纳。


2003
年
2
月
6
日

Q1A(R2)


新原料药和制剂的稳定性试验
Q1A(R)
修订说明



本修订的目的为了明确由于采用了
ICH
Q1F“
在 气候带Ⅲ和Ⅳ注册申请的稳定性数据
包
”
而使
Q1A(R)
而产生的 变更。这些变更如下：

1.
在下面章节中将中间储存条件从温度
30℃
±
2
℃
/
相对湿度
60%±
5%
修 改为温度
30
℃
±
2
℃
/
相对湿度
65% ±
5%
：

2.1.7.1
原料药
-
储存条件
-
一般情况

2.2.7.1
制剂
-
储存条件
-
一般情况

2.2.7.3
在半渗透性容器中包装的制剂

3
术语
-
“
中间试验
”


2.
在下面章节中可以使用温度
30
℃
±
2
℃
/
相对< br>湿度
65%±
5%
替代温度
25
℃
±
2℃
/
相对湿度
60%±
5%
作为长期稳定性试验的条件：

2.1.7.1
原料药
-
储存条件
-
一般情况

2.2.7.1
制剂
-
储存条件
-
一般情况


3. < br>在温度
25
℃
±
2
℃
/
相对湿度
4 0%±
5%
的基础

上增加了温度
30
℃
±
2
℃
/
相对湿度
35%±
5%
作
为长期稳定性试 验条件，
并且在后面的章节中
包括了失水比率相关举例的相关情况：

2.2.7.3
在半透性容器中包装的制剂


在试验阶段中间将 中间将储存条件从温度
30
℃
±
2
℃
/
相对湿度< br>60%±
5%
调整为温度
30
℃
±
2
℃/
相对湿度
65%±
5%
是可以的，但相应
的储存条件和调整的 日期要在注册申报资料中
清楚地说明和列出。

如果适用的话建议
ICH三方在公布和执行
此修订指南三年后，
注册申请资料中完整的试验
能够包含在中间 储存条件，即温度
30
℃
±
2
℃
/
相
对湿 度
65%±
5%
下的实验资料。



S
TABILITY
T
ESTING OF
N
EW
D
RUG
S
UBSTANCES AND
P
RODUCTS
1. INTRODUCTION

1.1. Objectives of the Guideline

The following guideline is a revised
version of the ICH Q1A guideline and
defines the stability data package for a
new drug substance or drug product
that is sufficient for a registration
application within the three regions of
the EC, Japan, and the United States. It
does not seek necessarily to cover the
testing for registration in or export to
other areas of the world.

The guideline seeks to exemplify the
core stability data package for new
drug substances and products, but
leaves sufficient flexibility to
encompass the variety of different
practical situations that may be
encountered due to specific scientific
considerations and characteristics of
the materials being evaluated.
Alternative approaches can be used
when there are scientifically justifiable
reasons.


1.2. Scope of the Guideline

The guideline addresses the
information to be submitted in
registration applications for new
molecular entities and associated drug
products. This guideline does not
currently seek to cover the information
to be submitted for abbreviated or
abridged applications, variations,
clinical trial applications, etc.

Specific details of the sampling and
新原料药和制剂稳定性试验



1.
导言

1.1.
目的

下述的指导原则是
ICH Q1A
的修订版本，
并且它为新原料药和制
剂在欧洲、日本、美国
三个地区注册所需要的
稳定性资料做出规定要
求。它并不涵盖 世界其
它地区或出口到这些地
区的注册要求。

本指导原则试图去
例 证新原料药和制剂的
核心稳定性数据，但是
留有足够的弹性空间去
适应由于特殊的科学 考
虑和被评估物质特殊性
质而导致的各种不同的

testing for particular dosage forms in
their proposed container closures are
not covered in this guideline.

Further
guidance
on
new
dosage
forms
and
on
biotechnological/biological
products
can
be
found
in
ICH
guidelines
Q1C and Q5C, respectively.

1.3. General Principles

The purpose of stability testing is to
provide evidence on how the quality of
a drug substance or drug product varies
with time under the influence of a
variety of environmental factors such
as temperature, humidity, and light,
and to establish a re-test period for the
drug substance or a shelf life for the
drug product and recommended
storage conditions.

The choice of test conditions defined in this
guideline
is
based
on
an
analysis
of
the
effects
of
climatic
conditions
in
the
three
regions
of
the
EC,
Japan
and
the
United
States.
The
mean
kinetic
temperature
in
any part of the world can be derived from
climatic
data,
and
the
world
can
be
divided into four climatic zones, I-IV
. This
guideline addresses climatic zones I and II.
The
principle
has
been
established
that
stability information generated in any one
of the three regions of the EC, Japan and
the
United
States
would
be
mutually
acceptable
to
the
other
two
regions,
provided the information is consistent with
this guideline and the labeling is in accord
with national/regional requirements.




2. GUIDELINES

具体情况。在有科学依
据和理由的情况下也可
以采用替代的方案。






1.2.
范围

本指导文件所 针对
的是新分子实体及其相
关制剂注册时需提交的
信息。此指导文件并不
寻< br>求
为
简
略
或
简
化
申
请，变更申请和 临床试
验申请提供指导。

在特定的密闭系统
中的特殊剂型的抽样和
检验的详细指导不包括
在此指导文件的范围
中。

有关新剂型和生物技术

2.1. Drug Substance

2.1.1. General

Information on the stability of the drug
substance is an integral part of the
systematic approach to stability
evaluation.

/
生物制品进一步指导
请分别参考
ICH
Q1C
和
Q5C
。








2.1.2. Stress Testing
Stress testing of the drug substance can
help identify the likely degradation
products, which can in turn help
establish the degradation pathways and
the intrinsic stability of the molecule
and validate the stability indicating
power of the analytical procedures
used. The nature of the stress testing
will depend on the individual drug
substance and the type of drug product
1.3
通则

involved.

Stress testing is likely to be carried out
on a single batch of the drug substance.
It should include the effect of
temperatures (in 10°
C increments (e.g.,
50°
C, 60°
C, etc.) above that for
accelerated testing), humidity (e.g.,
75% RH or greater) where appropriate,
oxidation, and photolysis on the drug
substance. The testing should also
evaluate the susceptibility of the drug
substance to hydrolysis across a wide
range of pH values when in solution or
suspension. Photostability testing
should be an integral part of stress
testing. The standard conditions for
photostability testing are described in
ICH Q1B.

Examining degradation products under
stress conditions is useful in
establishing degradation pathways and
developing and validating suitable
analytical procedures. However, it may
not be necessary to examine specifically
稳定性试验的目的< br>是为原料药或制剂的各
种环境因素，如温度、
湿度和光照等，影响下
质量在如何 随时间变化
提供证据，从而为原料
药制定复检期或为制剂
制定有效期，和推荐的
贮存条件。

本指导文件中的试
验选择是基于对欧洲、
日本、美国这三个地区

for certain degradation products if it
has been demonstrated that they are
not formed under accelerated or long
term storage conditions.

Results
from
these
studies
will
form
an
integral
part
of
the
information
provided
to regulatory authorities.

2.1.3. Selection of Batches

Data from formal stability studies
should be provided on at least three
primary batches of the drug substance.
The batches should be manufactured to
a minimum of pilot scale by the same
synthetic route as, and using a method
of manufacture and procedure that
simulates the final process to be used
for, production batches. The overall
quality of the batches of drug substance
placed on formal stability studies
should be representative of the quality
of the material to be made on a
production scale.

Other supporting data can be provided.

2.1.4. Container Closure System

The stability studies should be
conducted on the drug substance
packaged in a container closure system
that is the same as or simulates the
packaging proposed for storage and
distribution.


2.1.5. Specification

Specification, which is a list of tests,
reference to analytical procedures, and
proposed acceptance criteria, is
addressed in ICH Q6A and Q6B. In
addition, specification for degradation
products in a drug substance is
discussed in Q3A.

的气候条件影响分析制
定的。世界任何一个地
带的平均动 力学温度都
可以从气象数据中获
得，世界被分为四个气
候带Ⅰ～Ⅳ，本指导文
件描述的是Ⅰ和Ⅱ气候
带的情况。一个通用原
则已经被确立，
即欧洲、
日本、 美国这三个地区
中的任一地区的稳定性
资料都应被其他两个地
区所互相接受，提供的< br>资料应与本指导文件相
一致，标签规格应与各
自国家
/
地区的要求相< br>一致。







Stability
studies
should
include
testing
of
those attributes of the drug substance that
are
susceptible
to
change
during
storage
2.
指导文件

and
are
likely
to
influence
quality,
safety,
and/or
efficacy.
The
testing
should
cover,
2.1
原料药

as
appropriate,
the
physical,
chemical,
biological,
and
microbiological
attributes.
Validated
stability-indicating
analytical
procedures
should
be
applied.
Whether
and
to
what
extent
replication
should
be
performed will depend on the results from
validation studies.

2.1.1
概述

原料药的稳定性资
料是系统评估稳定性的
一个主要组成部分。



2.1.2
影响因素试验

原料药的影响因素
试验能帮 助确定可能的
降解物，这些降解物能
依
次
帮
忙
确
立
降
解
路
径，确立分子的内在稳
定性和确定验证方法的
稳定性 指示能力，影响
因素试验的本质取决于
具体的原料药及所涉及
的制剂类别。

影响因素试验可以
在一个批次的原料药中

2.1.6. Testing Frequency

For long term studies, frequency of
testing should be sufficient to establish
the stability profile of the drug
substance. For drug substances with a
proposed re-test period of at least 12
months, the frequency of testing at the
long term storage condition should
normally be every 3 months over the
first year, every 6 months over the
second year, and annually thereafter
through the proposed re- test period.

At the accelerated storage condition, a
minimum of three time points,
including the initial and final time
points (e.g., 0, 3, and 6 months), from a
6-month study is recommended. Where
an expectation (based on development
experience) exists that results from
accelerated studies are likely to
approach significant change criteria,
increased testing should be conducted
either by adding samples at the final
time point or by including a fourth time
point in the study design.

When
testing
at
the
intermediate
storage
condition
is
called
for
as
a
result
of
significant
change
at
the
accelerated
storage condition, a minimum of four time
points,
including the initial and final time

points
(e.g.,
0,
6,
9,
12
months),
from
a
12-month study is recommended.

2.1.7. Storage Conditions

In general, a drug substance should be
evaluated under storage conditions
(with appropriate tolerances) that test
its thermal stability and, if applicable,
its sensitivity to moisture. The storage
conditions and the lengths of studies
chosen should be sufficient to cover
storage, shipment, and subsequent use.

The long term testing should cover a
minimum of 12 months’ duration on at
least three primary batches at the time
of submission and should be continued
for a period of time sufficient to cover
the proposed re-test period. Additional
data accumulated during the
assessment period of the registration
application should be submitted to the
authorities if requested. Data from the
accelerated storage condition and, if
appropriate, from the intermediate
storage condition can be used to
evaluate the effect of short term
excursions outside the label storage
conditions (such as might occur during
shipping).

Long
term,
accelerated,
and,
where
appropriate,
intermediate
storage
conditions for drug substances are detailed
in
the
sections
below.
The
general
case
applies
if
the
drug
substance
is
not
specifically
covered
by
a
subsequent
section. Alternative storage conditions can
be used if justified.





2.1.7.1. General case
展开研究， 它包括温度
的影响
（以
10
℃为增量
单位，
如
50
℃，
60
℃等，
高于加速试验的温度）
，
湿度的影响
（例如
75%
相对湿度或更高），适
当情况下氧化和光照的
影响。当在溶液 中或悬
浮液中时，试验也可以
通过一定范围的
pH
值
评估原料药水解 作用的
敏感性。光稳定性试验
是影响因素试验的一个
主要组成部分。光稳定
性
试
验
的
标
准
条
件
在
ICH Q1B
中描述。

在影响因素试验条
件下检查降解产物能有
帮助确立 降解路径和开
发
验
证
合
适
的
分
析
方
法。但是，对于已知的
并且经证明在加速和长

Study

Storage
condition

Minimum time
period
covered by
data at
submission

期试验条件下没有形成
的降解产物没有必要再
做特别的检查。

这些试验的结果是
向监管部门提交资料的
组成部分。







2.1.3
批的选择

在正式 稳定性研究
试验中需要至少提供
3
个申报批次原料药的研
究资料。这些批次应 该
至
少
在
中
式
规
模
下
生
产，并且与生产批次采
用一样的合成路线，一
样的生产方法和与最终
过程相似的步骤。 正式
Long
term*

25°
C±2°
C/60
12 months

%
RH
±
5%
RH
or
30°
C±2°
C/65
%
RH
±
5%
RH

Interme
30°
C±2°
C/65
6 months

diate**

%
RH
±
5%
RH

Acceler
ated

40°
C±2°
C/75
6months
%
RH
±
5%
RH

*It is up to the applicant to decide whether
long
term
stability
studies
are
performed
at 25 ±
2°
C/60% RH ±
5% RH or 30°
C ±

2°
C/65% RH ±
5% RH.
**If 30°
C ± 2°
C/65% RH ± 5% RH is the
long-term
condition,
there
is
no
intermediate condition.

If
long-term
studies
are
conducted
at
25°
C
±
2°
C/60%
RH
±
5%
RH
and
“significant
change”
occurs
at
any
time
during
6
months
’
testing
at
the
accelerated
storage
condition,
additional
testing
at
the
intermediate
storage
condition
should
be
conducted
and
evaluated
against
significant
change
criteria.
Testing
at
the
intermediate
storage
condition
should
include
all
tests,
unless
otherwise
justified.
The
initial
application
should
include
a
minimum
of
6
months’
data
from
a
12-month
study
at
the
intermediate storage condition.

“Significant
change”
for
a
drug

substance
is
defined
as
failure
to
meet
its specification.


2.1.7.2.
Drug
substances
intended
for
storage in a refrigerator
Study

Storage
condition

Minimum
time period
covered by
data at
submission

稳定性研究中原料药批
次的整体质量应该能够
代表生产批次的整体质
量。

其他支持性材料也
可以提供。




2.1.4
容器密闭系统

原料药在稳定性试
验中的包装容器应该与
拟上市储存和运输的包
装相同或相似




2.1.5
质量标准

质量标准是由一系
列的测试项目，参考的< br>分析方法和拟研究标准
组成，在
ICHQ6A
和
Long
term

Acceler
ated

5°
C±3°
C

12
months

25°
C±2°
C
6 months

/60%
RH±
5%
RH

Data
from
refrigerated
storage
should
be assessed according to the evaluation
section
of
this
guideline,
except
where
explicitly noted below.

If
significant
change
occurs
between
3
and 6 months’ testing at the accelerated
storage
condition,
the proposed
re-test
period should be based on the real time
data
available
at
the
long term
storage
condition.

If
significant
change
occurs
within
the
first
3
months’
testing
at
the
accelerated
storage
condition,
a
discussion
should
be
provided
to
address
the
effect
of
short
term
excursions
outside
the
label
storage
condition,
e.g.,
during
shipping
or
handling.
This
discussion
can
be
supported,
if
appropriate,
by
further
testing
on
a
single
batch
of
the
drug
substance
for
a
period
shorter
than
3
months but with more frequent testing
than usual. It is considered unnecessary
to
continue
to
test
a
drug
substance

through
6
months
when
a
significant
change
has
occurred
within
the
first
3
months.

2.1.7.3.
Drug
substances
intended
for
storage in a freezer
Study

Storage
condition

Minimum
time period
covered by
data at
submission

Q6B
中有详细描述。 另
外，原料药降解产物的
质量标准在
Q3A
中做
讨论。
< br>稳定性研究应该包
含对原料药一些储存时
容易变化并且影响自身
质量、安全性和 有效性
的一些特性进行测试。
在适当的情况下，这些
测试应当涵盖物理的，
化 学的，生物的和微生
物的特性。应当使用经
过验证的稳定性指示分
析方法。是否需要重 复
试验以及重复的程度取
决于验证性研究的结
果。





Long
term

- 20°
C ± 5°
C

12
months

For
drug
substances
intended
for
storage
in
a
freezer,
the
re-test
period
should
be
based
on
the
real
time
data
obtained
at
the
long
term
storage
condition.
In
the
absence
of
an
accelerated
storage
condition
for
drug
substances
intended
to
be
stored
in
a
freezer,
testing
on
a
single
batch
at
an
elevated temperature (e.g., 5°
C ± 3°
C or
25°
C
±
2°
C)
for
an
appropriate
time
period should be conducted to address
the
effect
of
short
term
excursions
outside
the
proposed
label
storage
condition,
e.g.,
during
shipping
or
handling.


2.1.7.4.
Drug
substances
intended
for
storage below -20°
C
Drug
substances
intended
for
storage
below
-20°
C
should
be
treated
on
a
case-by-case basis.

2.1.8. Stability Commitment

When available long term stability data
on
primary
batches
do
not
cover
the
proposed
re-test
period
granted
at
the
time of approval, a commitment should
be
made
to
continue
the
stability
studies post approval in order to firmly

establish the re-test period.

Where
the
submission
includes
long
term stability data on three production
batches
covering
the
proposed
re-test
period,
a
post
approval
commitment
is
considered
unnecessary.
Otherwise,
one
of
the
following
commitments
should be made:

1. If the submission includes data from
stability
studies
on
at
least
three
production
batches,
a
commitment
should
be
made
to
continue
these
studies
through
the
proposed
re-test period.

2. If the submission includes data from
stability
studies
on
fewer
than
three
production
batches,
a
commitment
should
be
made
to
continue
these
studies through
the
proposed
re- test
period
and
to
place
additional
production
batches, to a total of at least three,
on
long
term
stability
studies
through
the
proposed
re-test
period.

3.
If
the
submission
does
not
include
stability
data
on
production
batches,
a
commitment
should
be
made
to
place
the
first
three
production
batches
on
long
term
stability
studies
through
the
proposed re- test period.

The
stability
protocol
used
for
long
term
studies
for
the
stability
commitment should be the same as that
for
the
primary
batches,
unless
otherwise scientifically justified.

2.1.9. Evaluation

The purpose of the stability study is to
establish,
based
on
testing
a
minimum
of
three
batches
of
the
drug
substance
2.1.6
试验频率

长期稳定性试验的< br>测试频率应该足以能够
反映原料药的稳定性概
况，对于拟复检期至少
12
个月的原料药，
在长
期储存条件下的检测频
率应该第一年每
3
个月
一次，第二年每
6
个月
一次，拟复检期后每年
一次。
在
加
速
试
验
条
件
下，
要至少
3
个时间点，
包括起始和结束的时间
点（例如，
0,3,6
个月）< br>，
推荐
6
个月的试验周
期。对于预期（根据开
发经验）可能出 现加速
试验条件下有明显改变
的，应当增加试验，可
以在最终时间点增加样
品 或者在试验设计中增

and evaluating the stability information
(including,
as
appropriate,
results
of
the
physical,
chemical,
biological,
and
microbiological
tests),
a
re-test
period
applicable
to
all
future
batches
of
the
drug
substance
manufactured
under
similar
circumstances.
The
degree
of
variability
of
individual
batches
affects
the confidence that a future production
batch
will
remain
within
specification
throughout the assigned re-test period.

The data may show so little degradation
and
so
little
variability
that
it
is
apparent
from
looking
at
the
data
that
the
requested
re- test
period
will
be
granted.
Under
these
circumstances,
it
is
normally
unnecessary
to
go
through
the
formal
statistical
analysis;
providing
a
justification
for
the
omission should be sufficient.

An approach for analyzing the data on a
quantitative
attribute
that
is
expected
to change with time is to determine the
time
at
which
the
95%
one-sided
confidence
limit
for
the
mean
curve
intersects
the
acceptance
criterion.
If
analysis
shows
that
the
batch-to-batch
variability
is
small,
it
is
advantageous
to
combine
the
data
into
one
overall
estimate.
This
can
be
done
by
first
applying
appropriate
statistical
tests
(e.g., p values for level of significance of
rejection
of
more
than
0.25)
to
the
slopes
of
the
regression
lines
and
zero
time
intercepts
for
the
individual
batches.
If
it
is
inappropriate
to
combine data from several batches, the
overall
re-test
period
should
be
based
on
the
minimum
time
a
batch
can
be
expected
to
remain
within
acceptance
criteria.
The
nature
of
any
degradation
relationship
will
determine
whether
the
data
should
be
transformed
for
加第四个时间点。

当在加速条 件下试
验下出现明显改变时可
以采用中间储存条件试
验，至少建立
4
个时间
点，包括起始和最终点
（例如：
0,6,9,12
月）
，推荐
12
个月的试验周
期。






2.1.7
储存条件

通常情况下，应该
在原料药的储 存条件下
（有适当的容差）评估
其热稳定性，如果适用
的话，还要评估其对水
分的敏感性。储存条件
和试验周期的周期应当

linear
regression
analysis.
Usually
the
relationship
can
be
represented
by
a
linear,
quadratic,
or
cubic
function
on
an
arithmetic
or
logarithmic
scale.
Statistical methods should be employed
to test the goodness of fit of the data on
all
batches
and
combined
batches
(where
appropriate)
to
the
assumed
degradation line or curve.

Limited
extrapolation
of
the
real
time
data
from
the
long
term
storage
condition beyond the observed range to
extend
the
re- test
period
can
be
undertaken
at
approval
time,
if
justified.
This
justification
should
be
based
on
what
is
known
about
the
mechanism
of
degradation,
the
results
of testing under accelerated conditions,
the goodness of fit of any mathematical
model,
batch
size,
existence
of
supporting stability data, etc. However,
this
extrapolation
assumes
that
the
same
degradation
relationship
will
continue to apply beyond the observed
data.

Any
evaluation
should
cover
not
only
the
assay,
but
also
the
levels
of
degradation
products
and
other
appropriate attributes.

2.1.10. Statements/Labeling

A
storage
statement
should
be
established
for
the
labeling
in
accordance
with
relevant
national/regional
requirements.
The
statement
should
be
based
on
the
stability
evaluation
of
the
drug
substance.
Where
applicable,
specific
instructions
should
be
provided,
particularly
for
drug
substances
that
cannot tolerate freezing. Terms such as
“ambient
conditions”
or
“room
temperature” should be avoided
.

能够涵盖日常储存，运
输和后来使用的使用。

在提交申报资料时
需 要包含至少
12
个月
3
个申报批次的长期稳定
性数据，并且应当继续
进行试验以满足能够覆
盖整个拟复验期。
另外，
如果要求的话，注册评
审期间积累的稳定性数
据也需要提供给当局。
加速条件下试验的数
据，如果适用的话 ，包
括中间储存条件下的数
据可以用来评估短期偏
离标示储存条件的情况
（比 如可能在运输途中
发生）






A re-test period should be derived from
the
stability
information,
and
a
retest
date
should
be
displayed
on
the
container label if appropriate.



2.2. Drug Product

2.2.1. General

The
design
of
the
formal
stability
studies
for
the
drug
product
should
be
based
on
knowledge
of
the
behavior
and
properties
of
the
drug
substance
and
from
stability
studies
on
the
drug
substance
and
on
experience
gained
from
clinical
formulation
studies.
The
likely
changes
on
storage
and
the
rationale for the selection of attributes
to
be
tested
in
the
formal
stability
studies should be stated.


2.2.2. Photostability Testing

Photostability
testing
should
be
conducted
on
at
least
one
primary
batch
of
the
drug
product
if
appropriate.
The
standard
conditions
for photostability testing are described
in ICH Q1B.


2.2.3. Selection of Batches

Data
from
stability
studies
should
be
provided
on
at
least
three
primary
batches
of
the
drug
product.
The
primary batches should be of the same
formulation
and
packaged
in
the
same
container
closure
system
as
proposed
for
marketing.
The
manufacturing
process
used
for
primary
batches
should
simulate
that
to
be
applied
to
production batches and should provide
product
of
the
same
quality
and
meeting
the
same
specification
as
that







2.1.7.1
一般情况

申报
研究
储存条
项目

件

时至
少完
成的
时间

25°
C ±

2°
C/60
% RH
±
5%
长期

RH
或

30°
C ±

2°
C/65
% RH
±
5%
12
个
月


intended
for
marketing.
Two
of
the
three
batches
should
be
at
least
pilot
scale
batches
and
the
third
one
can
be
smaller,
if
justified.
Where
possible,
batches
of
the
drug
product
should
be
manufactured
by
using
different
batches of the drug substance.
Stability
studies
should
be
performed
on
each
individual
strength
and
container
size
of
the
drug
product
unless
bracketing
or
matrixing
is
applied.

Other supporting data can be provided
.

2.2.4. Container Closure System

RH
30°
C ±

中间
储存

2°
C/65
% RH
±
5%
RH

40°
C ±

2°
C/75
±
5%
加速

% RH
RH

6
个
月

6
个
月

Stability testing should be conducted on
the
dosage
form
packaged
in
the
container
closure
system
proposed
for
marketing
(including,
as
appropriate,
any secondary packaging and container
label). Any available studies carried out
on
the
drug
product
outside
its
immediate
container
or
in
other
packaging
materials
can
form
a
useful
part
of
the
stress
testing
of
the
dosage
form
or
can
be
considered
as
25 ±
2°
C/60% RH ±

supporting information, respectively.
5%
RH
还是
30°
C
±

2°
C/65%
RH
±

5%

由申请者决定稳定
性研究采用
RH
。

2.2.5. Specification

Specification,
which
is
a
list
of
tests,
reference to analytical procedures, and
proposed acceptance criteria, including
the
concept
of
different
acceptance
criteria
for
release
and
shelf
life
specifications,
is
addressed
in
ICH
Q6A
and
Q6B.
In
addition,
specification
for
degradation products in a drug product
is addressed in Q3B.

如果选用
30°
C
±

2°
C/65%
RH
±

5%
RH
作为长期储存条件，
就不需要中间储存
条件。

如果在
25°
C ±
2°
C/60% RH ±
5% RH
条件下进行长期稳定性试验，并且在
6
个
月的加速试验条件中任一时间点 出现了
，
应当在中间储存条件试验中
Stability
studies
should
include
testing
“明显改变”
of
those
attributes
of
the
drug
product
增加试验来对比评估这些明显改变的项
that
are
susceptible
to
change
during
storage
and
are
likely
to
influence
目。在中间储存条件下应当包含全部的测

quality,
safety,
and/or
efficacy.
The
testing
should
cover,
as
appropriate,
the
physical,
chemical,
biological,
and
microbiological attributes, preservative
content (e.g., antioxidant, antimicrobial
preservative),
and
functionality
tests
(e.g.,
for
a
dose
delivery
system).
Analytical
procedures
should
be
fully
validated
and
stability
indicating.
Whether and to what extent replication
should be performed will depend on the
results of validation studies.

Shelf
life
acceptance
criteria
should
be
derived
from
consideration
of
all
available
stability
information.
It
may
be
appropriate
to
have
justifiable
differences
between
the
shelf
life
and
release
acceptance
criteria
based
on
the stability evaluation and the changes
observed
on
storage.
Any
differences
between
the
release
and
shelf
life
acceptance
criteria
for
antimicrobial
preservative
content
should
be
supported by a validated correlation of
chemical
content
and
preservative
effectiveness
demonstrated
during
drug development on the product in its
final
formulation
(except
for
preservative
concentration)
intended
for
marketing.
A
single
primary
stability
batch
of
the
drug
product
should
be
tested
for
antimicrobial
preservative
effectiveness
(in
addition
to
preservative
content)
at
the
proposed
shelf
life
for
verification
purposes,
regardless
of
whether
there
is a difference between the release and
shelf
life
acceptance
criteria
for
preservative content.

2.2.6. Testing Frequency

For
long
term
studies,
frequency
of
testing should be sufficient to establish
试，除非经过另外的论证。 最初的申请文
件应当至少包含
12
个月周期的中间储存条
件试验中
6
个月的试验数据。

“明显改变”是指一个原料药不符合
其质量标准。



2.1.7.2
拟冷藏储存的原料药

申报
研
究
储
时至
少完
成的
时间

长
期

5°
C ±

12
个
3°
C
25°
C
加
速

±
2°
C/60
% RH
±
5%
RH 冷藏储存条件下的
数据应该根据本指南评
估
部
分
的
要< br>求
进
行
评
6
个
月

月

项目

存条件


the stability profile of the drug product.
For products with a proposed shelf life
of
at
least
12
months,
the
frequency
of
testing
at
the
long
term
storage
condition
should
normally
be
every
3
months
over
the
first
year,
every
6
months
over
the
second
year,
and
annually
thereafter
through
the
proposed shelf life.

At
the
accelerated
storage
condition,
a
minimum
of
three
time
points,
including
the
initial
and
final
time
points (e.g., 0, 3, and 6 months), from a
6-month study is recommended. Where
an
expectation
(based
on
development
experience)
exists
that
results
from
accelerated
testing
are
likely
to
approach
significant
change
criteria,
increased
testing
should
be
conducted
either
by
adding
samples
at
the
final
time point or by including a fourth time
point in the study design.
When
testing
at
the
intermediate
storage
condition
is
called
for
as
a
result
of
significant
change
at
the
accelerated
storage
condition,
a
minimum of four time points, including
the initial and final time points (e.g., 0,
6, 9, 12 months), from a 12-month study
is recommended.

Reduced
designs,
i.e.,
matrixing
or
bracketing, where the testing frequency
is
reduced
or
certain
factor
combinations
are
not
tested
at
all,
can
be applied, if justified.

2.2.7. Storage Conditions

In
general,
a
drug
product
should
be
evaluated
under
storage
conditions
(with
appropriate
tolerances)
that
test
its
thermal
stability
and,
if
applicable,
its
sensitivity
to
moisture
or
potential
for solvent loss. The storage conditions
估，除了下面明确提到
的情况：

如果在加速试验条
件下第
3
到
6
个月间发
生变化，那拟复检期应
该根 据长期储存条件下
的真实时间数据。

如果在加速试验条
件试验下的前
3
个月发
生变化，那么需要讨论
短期偏离标示储运条件
的影响，例如运输和 搬
运过程中。如果适用的
话，这个讨论可以通过
对单批原料药进行短于
3个月但是比平常更多
检测频率的进一步试验
来完成。当原料药试验
在前
3
个月发生明显改
变时，通常认为不需要
继续进行
6
个月的试
验。


and
the
lengths
of
studies
chosen
should
be
sufficient
to
cover
storage,
shipment, and subsequent use.

Stability
testing
of
the
drug
product
after
constitution
or
dilution,
if
applicable,
should
be
conducted
to
provide information for the labeling on
the preparation, storage condition, and
in-use
period
of
the
constituted
or
diluted
product.
This
testing
should
be
performed on the constituted or diluted
product
through
the
proposed
in-use
period
on
primary
batches
as
part
of
the
formal
stability
studies
at
initial
and
final
time
points
and,
if
full
shelf
life long term data will not be available
before submission, at 12 months or the
last
time
point
for
which
data
will
be
available.
In
general,
this
testing
need
not
be
repeated
on
commitment
batches.

The
long
term
testing
should
cover
a
minimum of 12 months’ duration on at
least three primary batches at the time
of submission and should be continued
for
a
period
of
time
sufficient
to
cover
the proposed shelf life. Additional data
accumulated
during
the
assessment
period
of
the
registration
application
should
be
submitted
to
the
authorities
if requested. Data from the accelerated
storage
condition
and,
if
appropriate,
from
the
intermediate
storage
condition
can
be
used
to
evaluate
the
effect
of
short
term
excursions
outside
the
label
storage
conditions
(such
as
might occur during shipping).
Long
term,
accelerated,
and,
where
appropriate,
intermediate
storage
conditions
for
drug
products
are
detailed
in
the
sections
below.
The
general
case
applies
if
the
drug
product
is
not
specifically
covered
by
a
subsequent
section. Alternative storage conditions can








2.1.7.3
拟
冷
冻
储
存
的
原料药

申报时
研
究
储存条
至少完
项目

件

长
期

成的时
间

- 20°
C ± 5°
C

12
个月

对已拟冷冻 的原料
药，其复检期应当基于
长期试验条件下的真实
时间数据。拟冷冻的原
料 药不存在加速试验，
但是应当对单批原料药

be used, if justified.

2.2.7.1. General case
Study

Storage
condition

Minimum
time period
covered by
data at
submission

在适当时间周期内适当
提高温度
（例如，
5°
C ±
3°
C
或
25°
C ±
2°
C)
以针对短期偏离标示储运条
件下的影响。








2.1.7.4
拟在
-20°
C
以下储存的原料药

Long
term*

25°
C±2°
C/60
12
%
RH
±
5%
months

RHor
30°
C
±
2°
C/65%
RH
± 5% RH

30°
C±2°
C/65
6
%
RH
±
5%
months

RH

40°
C±2°
C/75
6
%
RH
±
5%
months

RH

Intermed
iate**

Accelerat
ed

拟在
-20°
C
以下储存的原料药要具体
情况具体分析。

*It
is
up
to
the
applicant
to
decide
whether long term stability studies are
performed
at
25
±
2°
C/60%
RH
±
5%
RH or 30°
C ± 2°
C/65% RH ± 5% RH.

**If 30°
C ± 2°
C/65% RH ± 5% RH is the
long- term
condition,
there
is
no
intermediate condition.
If
long-term
studies
are
conducted
at
25°
C
±
2°
C/60%
RH
±
5%
RH
and
“significant
change”
occurs
at
any
time
during
6
months’
testing
at
the
accelerated
storage
condition,
additional
testing
at
the
intermediate
storage
condition
should
be
conducted
and
evaluated
against
significant
change
criteria.
The
initial
application
should include a minimum of 6 months’
data
from
a
12-month
study
at
the
intermediate storage condition.

In
general,
“significant
change”
for
a
drug product is defined as:


2.1.8
稳定性承诺

当一个原料药在获
得批准后其申报批次的
长期稳定性数据还不能
涵盖其拟复检期时，应
当做出一个在批准后继
续进行稳 定性研究以确
立复检期的承诺。

当申请资料包含
3
个生产批次并且涵盖拟

1. A 5% change in assay from its initial
value;
or
failure
to
meet
the
acceptance
criteria
for
potency
when
using
biological
or
immunological procedures;

2. Any degradation product’s exceeding
its acceptance criterion;

3.
Failure
to
meet
the
acceptance
criteria
for
appearance,
physical
attributes,
and
functionality
test
(e.g.,
color,
phase
separation,
resuspendibility,
caking,
hardness,
dose
delivery
per
actuation);
however, some changes in physical
attributes
(e.g.,
softening
of
suppositories,
melting
of
creams)
may be expected under accelerated
conditions;

and,
as
appropriate
for
the
dosage
form:

4.
Failure
to
meet
the
acceptance
criterion for pH; or

5.
Failure
to
meet
the
acceptance
criteria
for
dissolution
for
12
dosage
units.

2.2.7.2.
Drug
products
packaged
in
impermeable containers

Sensitivity
to
moisture
or
potential
for
solvent
loss
is
not
a
concern
for
drug
products
packaged
in
impermeable
containers
that
provide
a
permanent
barrier
to
passage
of
moisture
or
solvent.
Thus,
stability
studies
for
products
stored
in
impermeable
containers can be conducted under any
controlled
or
ambient
humidity
condition.



复检期的长期稳定性数
据，就没有必要进行上
述承诺。否则，应当做
出以下任何一种承诺：

1.
如
果
申
请
资料
中包含至少
3
个生产批
次稳定性研究数据，应
当做出一个在复 检期间
继续进行稳定性研究的
承诺。

2.
如果申请资料
中包含了少于
3
个生产
批次的稳定性研究数
据，应承诺在拟复检期
间 继续进行研究，并加
入额外的批次使总批次
达到至少
3
批，
并且拟复
检期间进行长期稳定性
研究。

3.
如果在申请资
料中没有包含生产批次
的稳定性研究数据，应

2.2.7.3.
Drug
products
packaged
in
semi-permeable containers

Aqueous-based
products
packaged
in
semi-permeable
containers
should
be
evaluated
for
potential
water
loss
in
addition
to
physical,
chemical,
biological, and microbiological stability.
This
evaluation
can
be
carried
out
under
conditions
of
low
relative
humidity,
as
discussed
below.
Ultimately,
it
should
be
demonstrated
that
aqueous-based
drug
products
stored
in
semi- permeable
containers
can
withstand
low
relative
humidity
environments.

Other
comparable
approaches
can
be
developed
and
reported
for
non-aqueous, solvent-based products.
Study

Storage
condition

Minimum
time period
covered by
data at
submission

当做出一个对前三批生
产批次在拟复检期能进
行长期稳定性研究的承
诺。

承诺的长期稳定性
研究的方案应该与申报
批次的方案一致，除非
经过科学的论 证。









2.1.9
评估

稳定性研究的目的
是基于至少
3
个批次的
稳定性试验和稳定性评
估信息（包括，如果适
用的话，物理，化学，
Long
25°
C ±
term*

2°
C/40% RH ±
5% RH or 30°
C
± 2°
C/35% RH
± 5% RH

12
months

Inter
30°
C
±
6
medi
2°
C/65%
RH
±
months

ate**

5% RH

Accel
erate
d


40°
C
±
2°
C/not
6
more
than
months

(NMT) 25% RH



*It
is
up
to
the
applicant
to
decide
whether long term stability studies are
performed
at
25
±
2°
C/40%
RH
±
5%
RH or 30°
C ± 2°
C/35% RH ± 5% RH.


**If 30°
C ± 2°
C/35% RH ± 5% RH is the
long-term
condition,
there
is
no
intermediate condition.

For
long-term
studies
conducted
at
25°
C ± 2°
C/40% RH ± 5% RH, additional
testing
at
the
intermediate
storage
condition
should
be
performed
as
described
under
the
general
case
to
evaluate the temperature effect at 30°
C
if
significant
change
other
than
water
loss occurs during the 6 months’ testing
at
the
accelerated
storage
condition.
A
significant change in water loss alone at
the
accelerated
storage
condition
does
not
necessitate
testing
at
the
intermediate
storage
condition.
However,
data
should
be
provided
to
demonstrate that the drug product will
not
have
significant
water
loss
throughout
the
proposed
shelf
life
if
stored
at
25°
C
and
the
reference
relative humidity of 40% RH.

A 5% loss in water from its initial value
is considered a significant change for a
product
packaged
in
a semi-permeable
container
after
an
equivalent
of
3
months’
storage
at

40°
C/NMT
25%
RH.
However, for small containers (1 mL or
less) or unit-dose products, a water loss
of 5% or more after an equivalent of 3
months’
storage
at
40°C/NMT
25%
RH
may be appropriate, if justified.
An alternative approach to studying at the
reference
relative
humidity
as
recommended in the table above (for either
long
term
or
accelerated
testing)
is
performing
the
stability
studies
under
higher
relative
humidity
and
deriving
the
water
loss
at
the
reference
relative
humidity through calculation. This can be
achieved
by
experimentally
determining
the
permeation
coefficient
for
the
container
closure
system
or,
as
shown
in
the
example
below,
using
the
calculated
生物，微生物测试的结
果）来建立一个对以 后
在相似环境下生产的更
多批次的原料药适用的
复检期。各个批次间差
异的程 度会影响到后续
生产批次是否在复检期
内符合质量标准要求的
置信水平。
（< br>confidence
翻译成
置
信
水
平
参
考
其
他
版
本）

对于一些在试验期
间降解很少和变化 很小
的数据，直观上就能通
过这些数据看出其要求
的
复
检
期
是
可
以
接
受
的。在这样的情况下，
通常没有必要进 行正式
的统计学分析，只需要
为这种省略做出一个论
证就可以了。

对于预期会随时间

ratio
of
water
loss
rates
between
the
two
humidity
conditions
at
the
same
temperature.
The
permeation
coefficient
for
a
container
closure
system
can
be
experimentally
determined
by
using
the
worst case
scenario (e.g., the most diluted
of
a
series
of
concentrations)
for
the
proposed drug product.
Example of an approach for determining
water loss:

For
a
product
in
a
given
container
closure
system,
container
size,
and
fill,
an
appropriate
approach
for
deriving
the
water
loss
rate
at
the
reference
relative
humidity
is
to
multiply
the
water
loss
rate
measured
at
an
alternative
relative
humidity
at
the
same temperature by a water loss rate
ratio shown in the table below. A linear
water
loss
rate
at
the
alternative
relative
humidity
over
the
storage
period should be demonstrated.

For
example,
at
a
given
temperature,
e.g., 40°
C, the calculated water loss rate
during
storage
at
NMT
25%
RH
is
the
water
loss
rate
measured
at
75%
RH
multiplied
by
3.0,
the
corresponding
water loss rate ratio.
Alternative
Reference
Ratio of water
relative
relative
loss rates at a
given
humidity

humidity

temperature

发生变化的某种能够定
量的特性来说，其分析< br>方法是确定在
95%
的
单侧置信度的平均曲线
与验收标准相交的时间< br>点（此句参考其他版翻
译）
。如果分析显示批
间差异很小，将全部数
据 进行组合成一个整体
进
行
评
估
是
更
好
的< br>方
法。可以首先对各个批
次的回归直线的斜率和
0
点截距进行合适的统
计检验（例如将
p
值大
于
0.25
作为非显著性差
异的标准）。如果不适
合将各个批次的信息总
结，则整体的复检期应
当基于能够保持在 验收
标准中的最短时间的一
个批次。

降解关系的特性决
60% RH

60% RH

65%RH
75%RH

25% RH

40% RH

35%RH
25%RH

1.9

1.5

1.9
3.0

Valid
water
loss
rate
ratios
at
relative
humidity
conditions
other
than
those
shown in the table above can also be used.








2.2.7.4.
Drug
products
intended
for
storage
in a refrigerator
Study

Storage
condition

Minimum
time period
covered by
data at
submission

定了是否对数据进行线
性回归分析。通常情况下，这个关系可以通过
一个一次，二次或三次
的
算
术
或
对
数
函
数
表
现。应当对全部批次和
单个批次的降解直线或< br>曲线的拟合程度进行统
计，如果适用的话。

在适当的情况下，
如果经 过论证，基于长
期稳定性试验的真实时
间数据可以在观察时间
范围之外被有限的外推< br>来延长复检期。这个论
证需要基于对降解机制
了解的程度，在加速试
验条件下的 结果，数学
模型的拟合程度，批量
大小，现有的稳定性支
持数据等。但是，这个
外推法是假设降解关系
Long
term

Accelerat
ed

5°
C ± 3°
C

12
months

6 months

25°
C±2°
C/6
0%
RH
±
5% RH

If
the
drug
product
is
packaged
in
a
semi-permeable container, appropriate
information
should
be
provided
to
assess the extent of water loss.

Data
from
refrigerated
storage
should
be assessed according to the evaluation
section
of
this
guideline,
except
where
explicitly noted below.

If
significant
change
occurs
between
3
and 6 months’ testi
ng at the accelerated
storage
condition,
the
proposed
shelf
life
should
be
based
on
the
real
time
data
available
from
the
long
term
storage condition.

If
significant
change
occurs
within
the
first
3
months’
testing
at
the
accelerated
storage
condition,
a
discussion
should
be
provided
to
address
the
effect
of
short
term
excursions
outside
the
label
storage
condition,
e.g.,
during
shipment
and

handling.
This
discussion
can
be
supported,
if
appropriate,
by
further
testing
on
a
single
batch
of
the
drug
product
for
a
period
shorter
than
3
months but with more frequent testing
than usual. It is considered unnecessary
to continue to test a product through 6
months
when
a
significant
change
has
occurred within the first 3 months.
在观察期之外继续保持
之前的情况。

任何评价都不能仅仅包含含量测定，还需
要包含降解产物的水平
和其他相关的特性。











2.1.1.10
说明书
（或译
为标识）
/
标签

根据所在国家与地
区的相关要求制定标签
上的储存说明。这个说
明应当基于原 料药的稳


2.2.7.5.
Drug
products
intended
for
storage
in a freezer
Study

Storage
condition

Minimum
time
period
covered
by
data
at
submission

Long
term

- 20°
C ± 5°
C

12 months

For drug products intended for storage
in
a
freezer,
the
shelf
life
should
be
based on the real time data obtained at
the
long
term
storage
condition.
In
the
absence
of
an
accelerated
storage
condition for drug products intended to
be
stored
in
a
freezer,
testing
on
a
single batch at an elevated temperature
(e.g.,
5°
C
±
3°
C
or
25°
C
±
2°
C)
for
an
appropriate
time
period
should
be
conducted to address the effect of short
term
excursions
outside
the
proposed
label storage condition.


2.2.7.6.
Drug
products
intended
for
storage below -20°
C

Drug
products
intended
for
storage
below
-20°
C
should
be
treated
on
a
case-by-case basis.

2.2.8. Stability Commitment

When available long term stability data

on
primary
batches
do
not
cover
the
proposed
shelf
life
granted
at
the
time
of
approval,
a
commitment
should
be
made
to
continue
the
stability
studies
post
approval
in
order
to
firmly
establish the shelf life.

Where
the
submission
includes
long
term
stability
data
from
three
production
batches
covering
the
proposed
shelf
life,
a
post
approval
commitment
is
considered
unnecessary.
Otherwise,
one
of
the
following
commitments
should
be
made:

1. If the submission includes data from
stability
studies
on
at
least
three
production
batches,
a
commitment
should
be
made
to
continue
the
long
term
studies
through
the
proposed
shelf
life
and
the
accelerated studies for 6 months.

定性评 估。在适当的情
况下，应当提供明确的
说明指导，尤其对于一
些不能冷冻的药品。诸< br>如像
“环境条件”
和
“室
温”这样的词应当避免
使用。

复检期应当来源于
稳定性信息，如果合适
的话，复检日期应当在
包装容器 的标签中标识
出。


2. If the submission includes data from
stability
studies
on
fewer
than
three
production
batches,
a
commitment
should
be
made
to
continue
the
long
term
studies

through the proposed shelf life and

the
accelerated
studies
for
6
months,
and
to
place
additional
2.2
制剂

production
batches,
to
a
total
of
at
least
three,
on
long
term
stability
studies through the proposed shelf
life and on accelerated studies for 6
months.

3.
If
the
submission
does
not
include
stability
data
on
production
batches,
a
commitment
should
be
made
to
place
the
first
three
production
batches
on
long
term
stability
studies
through
the
proposed
shelf
life
and
on
accelerated
studies for 6 months.
The
stability
protocol
used
for
studies
on
commitment
batches
should
be
the
2.2.1
通则

制剂的正式稳定性研究
设计应 当基于对原料药
性能和特性的了解和原
料
药
的
稳
定
性
研
究
数
据，和临床处方研究经
验。正式稳定性研究中

same
as
that
for
the
primary
batches,
unless otherwise scientifically justified.

Where intermediate testing is called for
by
a
significant
change
at
the
accelerated
storage
condition
for
the
primary
batches,
testing
on
the
commitment
batches
can
be
conducted
at
either
the
intermediate
or
the
accelerated
storage
condition.
However, if significant change occurs at
the
accelerated
storage
condition
on
the commitment batches, testing at the
intermediate
storage
condition
should
also be conducted.

2.2.9. Evaluation

A
systematic
approach
should
be
adopted
in
the
presentation
and
evaluation
of
the
stability
information,
which
should
include,
as
appropriate,
results
from
the
physical,
chemical,
biological,
and
microbiological
tests,
including
particular
attributes
of
the
dosage
form
(for
example,
dissolution
rate for solid oral dosage forms).

The purpose of the stability study is to
establish,
based
on
testing
a
minimum
of
three
batches
of
the
drug
product,
a
shelf life and label storage instructions
applicable
to
all
future
batches
of
the
drug
product
manufactured
and
packaged
under
similar
circumstances.
The
degree
of
variability
of
individual
batches
affects
the
confidence
that
a
future
production
batch
will
remain
within specification throughout its shelf
life.

Where
the
data
show
so
little
degradation and so little variability that
it
is
apparent
from
looking
at
the
data
that
the
requested
shelf
life
will
be
granted,
it
is
normally
unnecessary
to
go
through
the
formal
statistical
存储的改变和检测项目
的
选
择
依
据
应
当
被
说
明。




2.2.2
光稳定性试验

如果适用的话，光
稳定性试验应当至少在
一个申报批 次中进行。
光稳定性试验的标准条
件在
ICH
Q1B
中被详
细描述。



2.2.3
批次选择

稳定性研究应当提
供至少
3
个申报批次的
数据。申报批次应当与
拟上市批次采用一样的
配方和一样的包装容器
系统。申报批次 的生产

analysis;
providing
a
justification
for
the omission should be sufficient.

An approach for analyzing data of a
quantitative attribute that is expected
to change with time is to determine the
time at which the 95 one-sided
confidence limit for the mean curve
intersects the acceptance criterion. If
analysis shows that the batch-to-batch
variability is small, it is advantageous
to combine the data into one overall
estimate. This can be done by first
applying appropriate statistical tests
(e.g., p values for level of significance of
rejection of more than 0.25) to the
slopes of the regression lines and zero
time intercepts for the individual
batches. If it is inappropriate to
combine data from several batches, the
overall shelf life should be based on the
minimum time a batch can be expected
to remain within acceptance criteria.

The
nature
of
the
degradation
relationship
will
determine
whether
the
data
should
be
transformed
for
linear
regression
analysis.
Usually
the
relationship
can
be
represented
by
a
linear,
quadratic,
or
cubic
function
on
an
arithmetic
or
logarithmic
scale.
Statistical methods should be employed
to test the goodness of fit on all batches
and
combined
batches
(where
appropriate)
to
the
assumed
degradation line or curve.

Limited
extrapolation
of
the
real
time
data
from
the
long
term
storage
condition beyond the observed range to
extend the shelf life can be undertaken
at
approval
time,
if
justified.
This
justification should be based on what is
known
about
the
mechanisms
of
degradation,
the
results
of
testing
under
accelerated
conditions,
the
过程应当与生 产批次相
似，并且产品质量和达
到的质量标准应该与拟
上市的产品一样。三批
中至少要有两批是在中
式规模下生产，第三批
经过论证可以适当小一
点。如果可能的话 ，不
同批次的制剂应该采用
不同批次的原料药。

除非采用括号法或
矩阵方案设计，每一种
单规格和容器尺寸的制
剂都应该进行稳定性研
究。

其他支持性数据也
可以提交。







goodness
of
fit
of
any
mathematical
model,
batch
size,
existence
of
supporting stability data, etc. However,
this
extrapolation
assumes
that
the
same
degradation
relationship
will
continue to apply beyond the observed
data.

Any
evaluation
should
consider
not
only the assay but also the degradation
products
and
other
appropriate
attributes.
Where
appropriate,
attention
should
be
paid
to
reviewing
the
adequacy
of
the
mass
balance
and
different
stability
and
degradation
performance.

2.2.10. Statements/Labeling

A
storage
statement
should
be
established
for
the
labeling
in
accordance
with
relevant
national/regional
requirements.
The
statement
should
be
based
on
the
stability evaluation of the drug product.
Where
applicable,
specific
instruction
should
be
provided,
particularly
for
drug
products
that
cannot
tolerate
freezing.
Terms
such
as
“ambient
conditions”
or
“room
temperature”
should be avoided.

There
should
be
a
direct
link
between
the
label
storage
statement
and
the
demonstrated
stability
of
the
drug
product.
An
expiration
date
should
be
displayed on the container label.



3. GLOSSARY

The
following
definitions
are
provided
to
facilitate
interpretation
of
the
guideline.

Accelerated testing

2.2.4
容器密闭系统

制剂的稳定性试验
应当在拟上市的包装 容
器中进行（包括，如果
适用的话，任何二级包
装和容器标签）
。
对 于除
去直接接触的包装或者
采用其他包装材料的制
剂所做的研究资料可以
分别 作为制剂影响因素
试验的一部分或作为支
持性数据。



2.2.5
质量标准

质量标准，包含一
系列的测试项目，参考< br>的试验方法，和拟验收
标准，包含放行标准和
货架期标准两个概念，
这
两
个
概
念
在
ICH
Q6A
和
Q6B
中专门介

Studies designed to increase the rate of
chemical
degradation
or
physical
change
of
a
drug
substance
or
drug
product
by
using
exaggerated
storage
conditions
as
part
of
the
formal
stability
studies.
Data
from
these
studies,
in
addition
to
long
term
stability
studies,
can
be
used
to
assess
longer
term
chemical
effects
at
non- accelerated
conditions
and
to
evaluate
the
effect
of
short
term
excursions
outside
the
label
storage
conditions
such
as
might
occur
during
shipping.
Results
from
accelerated
testing
studies
are
not
always
predictive of physical changes.

Bracketing

The design of a stability schedule such
that only samples on the extremes of
certain design factors, e.g., strength,
package size, are tested at all time
points as in a full design. The design
assumes that the stability of any
intermediate levels is represented by
the stability of the extremes tested.
Where a range of strengths is to be
tested, bracketing is applicable if the
strengths are identical or very closely
related in composition (e.g., for a tablet
range made with different compression
weights of a similar basic granulation,
or a capsule range made by filling
different plug fill weights of the same
basic composition into different size
capsule shells). Bracketing can be
applied to different container sizes or
different fills in the same container
closure system.

Climatic zones

The
four
zones
in
the
world
that
are
distinguished
by
their
characteristic
prevalent
annual
climatic
conditions.
This is based on the concept described
绍。另外，制剂降解产
物的质量标准在
Q3B
中专门介绍。

稳定性研究应该包
含对原料药一些储存时
容易变化并且影响自身
质量、安全性和有效 性
的一些特性进行测试。
在适当的情况下，这些
测试应当涵盖物理的，
化学的 ，生物的和微生
物的特性，保护剂含量
（例如，抗氧剂，抗菌
防腐及）
，和功能性测试
（如，药物递送系统）
。
应当使用经过验证的稳
定性指示分 析方法。是
否需要重复试验以及重
复的程度取决于验证研
究的结果。

货架期标准应当源
于所有稳定性研究数据

by W.
Grimm (
Drugs Made in Germany
,
28:196-202, 1985 and 29:39-47, 1986).

Commitment batches

Production batches of a drug substance
or
drug
product
for
which
the
stability
studies are initiated or completed post
approval
through
a
commitment
made
in the registration application.

Container closure system

The sum of packaging components that
together contain and protect the dosage
form.
This
includes
primary
packaging
components
and
secondary
packaging
components,
if
the
latter
are
intended
to
provide
additional
protection
to
the
drug
product.
A
packaging
system
is
equivalent
to
a
container
closure
system.

Dosage form

A
pharmaceutical
product
type
(e.g.,
tablet,
capsule,
solution,
cream)
that
contains
a
drug
substance
generally,
but not necessarily, in association with
excipients.

Drug product

The dosage form in the final immediate
packaging intended for marketing.

Drug substance

The
unformulated
drug
substance
that
may
subsequently
be
formulated
with
excipients to produce the dosage form.

Excipient

Anything other than the drug substance
in the dosage form.

Expiration date

The
date
placed
on
the
container
label
of
a
drug
product
designating
the
time
prior to which a batch of the product is
expected
to
remain
within
the
approved
shelf
life
specification
if
的考虑。可以根据稳定
性评估和储存过 程中观
察到的变化对货架期标
准和放行标准之间的差
别做出论证。放行标准
和 货架期标准之间的抗
菌防腐剂含量的任何差
别都需要进行到化学含
量与抗菌防腐功效的 相
关性的验证支持，这种
相关性是在最终拟上市
配方
（除了防腐剂浓度）的研发过程中得到论证
的。不论在放行标准和
货架期标准之间是否存
在保护剂含量 的差异，
一个单独的申报批次的
制剂应当用来研究验证
在有效期内的抗菌防腐
功效。




stored
under
defined
conditions,
and
after which it must not be used.
Formal stability studies

Long
term
and
accelerated
(and
intermediate)
studies
undertaken
on
primary
and/or
commitment
batches
according
to
a
prescribed
stability
protocol
to
establish
or
confirm
the
re-test
period
of
a
drug
substance
or
the shelf life of a drug product.

Impermeable containers

Containers
that
provide
a
permanent
barrier
to
the
passage
of
gases
or
solvents,
e.g.,
sealed
aluminum
tubes
for
semi-solids,
sealed
glass
ampoules
for solutions.

Intermediate testing

Studies conducted at 30°
C/65% RH and
designed
to
moderately
increase
the
rate
of
chemical
degradation
or
physical
changes
for
a
drug
substance
or
drug
product
intended
to
be
stored
long term at 25°
C.

Long term testing

Stability
studies
under
the
recommended storage condition for the
re- test period or shelf life proposed (or
approved) for labeling.

Mass balance

The
process
of
adding
together
the
assay
value
and
levels
of
degradation
products
to
see
how
closely
these
add
up to 100% of the initial value, with due
consideration
of
the
margin
of
analytical error.

Matrixing

The
design
of
a
stability
schedule
such
that
a
selected
subset
of
the
total
number
of
possible
samples
for
all
factor
combinations
is
tested
at
a
specified
time
point.
At
a
subsequent






2.2.6
试验频率

长期稳定性试验的
试 验频率应该足以能够
反
映
制
剂
的
稳
定
性< br>概
况，对于拟有效期至少
12
个月的制剂，
在长期
储存条件下 的检测频率
应该第一年每
3
个月一
次，第二年每
6
个月一< br>次，拟有效期后每年一
次。

在
加
速
试
验< br>条
件
下，
要至少
3
个时间点，
包括起始和结束的时间
点（例如，
0,3,6
个月）
，
推荐
6
个月的试验 周

time
point,
another
subset
of
samples
for
all
factor
combinations
is
tested.
The design assumes that the stability of
each
subset
of
samples
tested
represents the stability of all samples at
a
given
time
point.
The
differences
in
the samples for the same drug product
should
be
identified
as,
for
example,
covering
different
batches,
different
strengths,
different
sizes
of
the
same
container closure system, and, possibly
in
some
cases,
different
container
closure systems.

Mean kinetic temperature

A
single
derived
temperature
that,
if
maintained
over
a
defined
period
of
time,
affords
the
same
thermal
challenge
to
a
drug
substance
or
drug
product as would be experienced over a
range
of
both
higher
and
lower
temperatures for an equivalent defined
period.
The
mean
kinetic
temperature
is
higher
than
the
arithmetic
mean
temperature and takes into account the
Arrhenius equation.

When
establishing
the
mean
kinetic
temperature
for
a
defined
period,
the
formula
of
J.
D.
Haynes
(
J.
Pharm.
Sci
.,
60:927-929, 1971) can be used.

New molecular entity

An active pharmaceutical substance not
previously
contained
in
any
drug
product registered with the national or
regional
authority
concerned.
A
new
salt,
ester,
or
non-covalent-bond
derivative
of
an
approved
drug
substance
is
considered
a
new
molecular
entity
for
the
purpose
of
stability testing under this guidance.
Pilot scale batch

A
batch
of
a
drug
substance
or
drug
product
manufactured
by
a
procedure
期。对于预期（根据开
发经验）可 能出现加速
试验条件下有明显改变
的，应当增加试验，可
以在最终时间点增加样
品或者在试验设计中增
加第四个时间点。

当在加速条件下试
验下出现明显 改变时可
以采用中间储存条件试
验，至少建立
4
个时间
点，包括起始 和最终点
（例如：
0,6,9,12
月）
，
推荐
12
个月的试验周
期。

简化后的设计，例
如，在经过论证后，可
以采 用矩阵法或括号法
减少检测频率或不进行
某些综合因素的测试。




fully
representative
of
and
simulating
that
to
be
applied
to
a
full
production
scale batch. For solid oral dosage forms,
a pilot scale is generally, at a minimum,
one-tenth that of a full production scale
or
100,000
tablets
or
capsules,
whichever is the larger.

Primary batch

A
batch
of
a
drug
substance
or
drug
product used in a formal stability study,
from which stability data are submitted
in
a
registration
application
for
the
purpose of establishing a re-test period
or
shelf
life,
respectively.
A
primary
batch
of
a
drug
substance
should
be
at
least
a
pilot
scale
batch.
For
a
drug
product,
two
of
the
three
batches
should be at least pilot scale batch, and
the
third
batch
can
be
smaller
if
it
is
representative
with
regard
to
the
critical
manufacturing
steps.
However,
a
primary
batch
may
be
a
production
batch.

Production batch

A
batch
of
a
drug
substance
or
drug
product
manufactured
at
production
scale by using production equipment in
a production facility as specified in the
application.

Re-test date

The
date
after
which
samples
of
the
drug
substance
should
be
examined
to
ensure
that
the
material
is
still
in
compliance
with
the
specification
and
thus suitable for use in the manufacture
of a given drug product.

Re-test period

The
period
of
time
during
which
the
drug
substance
is
expected
to
remain
within
its
specification
and,
therefore,
can
be
used
in
the
manufacture
of
a
given
drug
product,
provided
that
the





2.2.7
储存条件

在通常情况下，制
剂应当在储存条件下（包含适当的容差）评
估其热稳定性，如果适
用的话，和对水分的敏
感性以及潜在 的溶剂损
失。储存条件和研究周
期的选择应当能够涵盖
整个储存，运输和后续
的使用。

对于需要溶解配制
或稀释后才能使用的制
剂，如果适用的话，应< br>当在标签中提供包括准
备条件，储存条件，配
制或稀释后使用期限。

drug
substance
has
been
stored
under
the
defined
conditions.
After
this
period,
a
batch
of
drug
substance
destined for use in the manufacture of a
drug
product
should
be
re-tested
for
compliance
with
the
specification
and
then used immediately. A batch of drug
substance
can
be
re-tested
multiple
times
and
a
different
portion
of
the
batch used after each re-test, as long as
it
continues
to
comply
with
the
specification.
For
most
biotechnological/biological
substances
known
to
be
labile,
it
is
more
appropriate to establish a shelf life than
a re-test period. The same may be true
for certain antibiotics.

Semi- permeable containers

Containers
that
allow
the
passage
of
solvent, usually water, while preventing
solute
loss.
The
mechanism
for
solvent
transport occurs by absorption into one
container surface, diffusion through the
bulk
of
the
container
material,
and
desorption
from
the
other
surface.
Transport
is
driven
by
a
partial- pressure
gradient.
Examples
of
semi-permeable
containers
include
plastic bags and semi-rigid, low-density
polyethylene
(LDPE)
pouches
for
large
volume
parenterals
(LVPs),
and
LDPE
ampoules, bottles, and vials.

Shelf life (also referred to as expiration
dating period)

The
time
period
during
which
a
drug
product
is
expected
to
remain
within
the
approved
shelf
life
specification,
provided
that
it
is
stored
under
the
conditions
defined
on
the
container
label.
Specification
–
Release

The
combination
of
physical,
chemical,
biological,
and
microbiological
tests
这项试验应该采用 一个
申报批次在拟使用期内
对配制或稀释后制剂进
行稳定性检测，作为正
式稳 定性试验起始和最
终时间点研究的一部
分，并且，如果整个有
效期长期稳定性试验数< br>据在提交申请时还不能
获得，则至少提交
12
个
月或最后时间点的稳定
性数据。通常情况下，
这些试验不需要在商业
批中再次重复。

长期 稳定性试验在
提交申请时应当至少包
含
3
个申报批次最少
12
个月的数据，并且应当
继续进行试验以包括整
个拟有效期。如果有要
求，注册申报期 间积累
的稳定性数据也需要向