ICH Q8(中英文)

2021年1月25日发(作者：liyuan)
ICH Q8
（中英文）


blueski
推荐
[2009-12-20]

出处：
Julia
的
blog

作者：不详



INTERNATIONAL
CONFERENCE
ON
HARMONISATION
OF
TECHNICAL
REQUIREMENTS
FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
人用药物注册技术要求
国际协调会议

ICH Harmonised Tripartite Guideline ICH
三方协调指南

Pharmaceutical Development
药物开发

Q8
Recommended for
Adoption at Step
4 of the ICH Process on 10 November
2005 by the ICH Steering Committee ICH
指导委员会
2005
年< br>11
月
10
日
ICH
第四阶段推荐采用


This
Guideline
has
been
developed
by
the
appropriate
ICH
Expert
Working
Group
and
has
been
subject
to
consultation
by
the
regulatory
parties,
in
accordance
with
the
ICH
Process. At
Step
4
of
the
Process
the
final
draft
is
recommended
for
adoption
to
the
regulatory
bodies
of
the
European
Union,
Japan and USA.
本指南根据
ICH
规程由合适的
I CH
专家工作组起草并经向法规
部门咨询。
在规程的第
4
步，
建议欧洲共同体、
日本和美国的药政部门采用其最
终的草案。


TABLE OF CONTENTS
目录


1. INTRODUCTION
简介
... 1

1.1 Objective of the Guideline
指南目的
... 1

1.2 Scope
范围
... 1

2. PHARMACEUTICAL DEVELOPMENT
药物开发
... 1

2.1 Components of the Drug Product
制剂产品的组分
... 4

2.1.1 Drug Substance
活性成分
... 4

2.1.2 Excipients
辅料
... 4

2.2 Drug Product
制剂
... 5

2.2.1 Formulation Development
配方开发
... 5

2.2.2 Overages
超量
... 6

2.2.3 Physicochemical and Biological Properties
物化和生化性
质
... 7

2.3 Manufacturing Process Development
制造工艺开发
... 7

2.4 Container Closure System
容器系统
... 9

2.5 Microbiological Attributes
微生物属性
... 9

2.6 Compatibility
兼容性
... 10

3. GLOSSARY
术语
... 11

1. INTRODUCTION
简介

1.1 Objective of Guideline
指南目的

This guideline describes the suggested contents for the 3.2.P.2
(Pharmaceutical Development) section of a regulatory submission in the
ICH M4 Common Technical Document (CTD) format.
本指南就
CTD
格式申请
文件中第
3.2.P.2
章：药物开发需要叙述的内容给出了建议。

The Pharmaceutical Development section provides an opportunity to
present the knowledge gained through the application of scientific
approaches and quality risk management (for definition, see ICH Q9) to
the development of a product and its manufacturing process. It is first
produced for the original marketing application and can be updated to
support new knowledge gained over the lifecycle of a product. The
Pharmaceutical
Development
section
is
intended
to
provide
a
comprehensive
understanding
of
the
product
and
manufacturing
process
for
reviewers
and
inspectors. The guideline also indicates areas where the demonstration
of
greater
understanding
of
pharmaceutical
and
manufacturing
sciences
can
create a basis for flexible regulatory approaches. The degree of
regulatory
flexibility
is
predicated
on
the
level
of
relevant
scientific
knowledge
provided.
药物开发一章给申请企业提供了一个机会，
来阐述其应用
科学的方法和风险管理手段，在产品及其生产工艺的开发过程中所获得的知识。
它既可以被用于原始的 制剂上市申请，
又可以经过更新后被用于支持产品生命周
期内所获得的新知识。
本指导 文件也说明了在什么情况下，
药物和生产方面的最
大程度的理解可以形成灵活的药政管理办法的 基础。
药物开发一章旨在为审核官
和检查官就产品和生产工艺提供更详尽的理解。

1.2 Scope
范围


This guideline is intended to provide guidance on the contents of
Section
3.2.P.2
(Pharmaceutical
Development)
for
drug
products
as
defined
in the scope of
Module 3
of
the Common
Technical Document (ICH guideline
M4). The guideline does not apply to contents of submissions for drug
products
during
the
clinical
research
stages
of
drug
development.
However,
the principles in this guideline are important to consider during those
stages
as
well.
This guideline
might
also
be
appropriate
for
other
types
of products. To determine the applicability of this guideline to a
particular type of product, applicants can consult with the appropriate
regulatory
authorities.
本指导文件就
CTD
模块
3
（
ICH
标题
M4
）中所定义
的制剂的第
3.2.P.2
（药物开发）一章中的内容提供了指南。本指导文件不适用
于临床研究阶段制剂递交文件的内容。
然而，
在这些阶段对本指导文件中的原则
进行考 虑也是重要的。
本指南可能也适用于其他一些类型的产品。
申请者向合适
的药政管理当 局进行咨询来确定本指导文件是否适用于某一特定类型的产品。

2. PHARMACEUTICAL DEVELOPMENT
药物开发

The
aim
of
pharmaceutical
development
is
to
design
a
quality
product
and its manufacturing process to consistently deliver the intended
performance of the product. The information and knowledge gained from
pharmaceutical
development
studies
and
manufacturing
experience
provide
scientific
understanding
to
support
the
establishment
of
the
design
space,
specifications,
and
manufacturing
controls.
药物开发的目的在于设计符
合质量要求的产品及符合重复生产模式的制造工艺。
在药物开发和研究过程中所
获得的 信息和知识将为建立质量标准和生产控制提供科学的依据。

Information from pharmaceutical development studies can be a basis
for quality risk management. It is important to recognize that quality
cannot
be
tested
into
products;
i.e.,
quality
should
be
built
in
by
design.
Changes
in
formulation
and
manufacturing
processes
during
development
and
lifecycle management should be looked upon as opportunities to gain
additional knowledge and further support establishment of the design
space.
Similarly,
inclusion
of
relevant
knowledge
gained
from
experiments
giving unexpected results can also be useful. Design space is proposed
by the applicant and is subject to regulatory assessment and approval.
Working within the design space is not considered as a change. Movement
out of the design space is considered to be a change and would normally
initiate a regulatory post approval change process.
药物开发研 究过程中
所获得的信息是风险评估的基础。
质量是通过设计建立起来的，
而不是通过对 产
品的检测得来的，
认识这一点是很重要的。
开发过程中的配方和生产工艺的变更应当被看成是获得更多额外知识的机会，
以进一步支持设计空间的建立。
包括从
失 败实验中获得的知识也是有用的，也可以用于支持所选择的产品及其生产工
艺。

The
Pharmaceutical
Development
section
should
describe
the
knowledge
that
establishes
that
the
type
of
dosage
form
selected
and
the
formulation
proposed are suitable for the intended use. This section should include
sufficient information in each part to provide an understanding of the
development of the drug product and its manufacturing process. Summary
tables and graphs are encouraged where they add clarity and facilitate
review.
药物开发一章应 当阐述为满足申请中所规定的目的，
建立所选择的剂型
和拟定的配方的知识基础。
在本 章节中的每一个部分都应当要包括足够的资料用
以理解制剂及其生产工艺的开发。
鼓励使用表格 和图表进行概述。
At
a
minimum,
those
aspects
of
drug
substances,
excipients,
container
closure
systems,
and manufacturing processes that are critical to product quality should
be determined and control strategies justified. Critical formulation
attributes and process parameters are generally identified through an
assessment of the extent
to which their
variation can have
impact on the
quality of the drug product.
至少，应当要对关键的且能很 大程度上影响产
品质量的方面进行确定和讨论，
它们包括原料药，
赋形剂和生产工艺，
这些方面
也是需要检测和控制的。
通过评估它们的变化程度对制剂质量的影响可确定这 些
关键的配方属性和工艺参数。

In addition, the applicant can choose to conduct pharmaceutical
development studies that can lead to an enhanced knowledge of product
performance
over
a
wider
range
of
material
attributes,
processing
options
and
process
parameters.
Inclusion
of
this
additional
information
in
this
section provides an opportunity to demonstrate a higher degree of
understanding
of
material
attributes,
manufacturing
processes
and
their
controls.
This
scientific
understanding facilitates
establishment
of
an
expanded design space. In these situations, opportunities exist to
develop
more
flexible
regulatory
approaches,
for
example,
to
facilitate:
此外，申请者也可以选 择进行一些其它的药物开发研究以在更广的物料属性范
围，
操作选项范围和工艺参数范围内对产 品的性能有更深的了解。
将这些更多的
信息包括在本章节使得可以对生产工艺和过程控制有更高 的理解。
这样的科学理
解确立了设计空间。这些情况为建立更灵活的药政管理办法提供了可能， 比如，
便于：

·
risk-based regulatory decisions (reviews and
inspections);
基于风险管理的药政决议（审核和现场检查）；

·
manufacturing process improvements, within the approved
design
space
described
in
the
dossier,
without
further
regulatory
review;
生产工艺改进，
在文件所述的已批 准的设计空间范围内，
不需要进一步的药政审
核；

·
reduction of post-approval submissions;
减少预审批呈递

·
real-time quality control, leading to a reduction of
end-
product release testing. “实时”质量控制，导致最终产品的放行检测
的减少

To realise this flexibility, the applicant should demonstrate an
enhanced knowledge of product performance over a range of material
attributes, manufacturing process options and process parameters. This
understanding can be gained by application of, for example, formal
experimental
designs,
process
analytical technology
(PAT),
and/or
prior
knowledge. Appropriate use of quality risk management principles can be
helpful in prioritising the additional pharmaceutical development
studies to collect such knowledge.
为了实现这种灵活性，申请者应当要在
物性（如：粒径分布 、水分、流动性），操作选项和工艺参数等的某一范围内对
产品性能进行更高层次的论述。可以通过实行 规范的实验设计或工艺分析技术
（
PAT
）来获得这些知识。适当地应用风险管理原则 ，有助于按其优先性进行排
序额外的药物开发研究，以获得这些知识。
The design and conduct of
pharmaceutical development studies should be consistent with their
intended scientific purpose. It should be recognized that the level of
knowledge gained, and not the volume of data, provides the basis for
science-based submissions and their regulatory evaluation.
药物开发研
究的设计和实施应当要和其拟定的科学目的和产品开发阶 段相一致。
需要认识到
的是所获知识的层次，
而不是数据量，
为科学的申请文 件及其药政评审提供了基
础。

2.1 Components of the Drug Product
制剂产品的组分

2.1.1 Drug Substance
活性成分


The
physicochemical
and
biological
properties
of
the
drug
substance
that can influence the performance of the drug product and its
manufacturability,
or
were
specifically
designed
into
the
drug
substance
(e.g., solid state properties), should be identified and
discussed. Examples of physicochemical and biological properties that
might
need
to
be
examined
include
solubility,
water
content,
particle
size,
crystal properties, biological activity, and permeability. These
properties could be inter-related and might need to be considered in
combination.
应当要 对原料药的能对制剂的性质及其生产能力产生影响的，
或
是已被专门设计在原料药方面的
（如：
晶体工程学）
物化性质和生物学特性进行
说明和讨论。可能需要检查的物化属 性和生物特性有：溶解性、水分、粒径、晶
体特性、生物活性、和渗透性等。这些性质可能相互之间是有 联系的，因此可能
需要综合起来考虑。有些性质会随着时间而改变的，或是和供应商相关。


To evaluate the potential effect of drug substance physicochemical
properties
on
the
performance
of
the
drug
product,
studies
on
drug
product
might be warranted. For example, the ICH Q6A Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances describes some of the circumstances in
which drug product studies are recommended (e.g., Decision Tree #3 and
#4
(Part
2)).
This
approach
applies
equally
for
the
ICH
Q6B
Specifications:
Test Procedures and Acceptance Criteria for Biotechnology/Biological
Products. The knowledge gained from the studies investigating the
potential
effect
of
drug
substance
properties
on
drug
product
performance
can be used, as appropriate, to justify elements of the drug substance
specification (3.2.S.4.5).
为了评估原料药的物理化学性质对制剂产品性能
的潜在影响，应当 要提供制剂的研究资料。比如说，
ICH
Q6A
质量标准：新化学
原料药 及新制剂的检验方法及合格标准中建议的一些情况下需要进行制剂研究
（如决策树
#3
和
#4
（第
2
部分））。对原料药性质可能会对制剂性能产生的影
响进行研究所获得的知识，
如果合适，
可被用于论证原料药的质量标准建立的原
因（
3.2.S.4.5
）。


The compatibility of the drug substance with excipients listed in
3.2.P.1
should
be
evaluated.
For
products
that
contain
more
than
one
drug
substance,
the
compatibility
of
the
drug
substances
with
each
other
should
also
be
evaluated.
需讨论原料药与第
3.2.P.1
章中所列辅料的兼容性。对于
含有多个原料药的制剂，还应讨论各原料药间的兼容性。


2.1.2 Excipients
辅料

The
excipients
chosen,
their
concentration,
and
the
characteristics
that
can influence the drug product performance (e.g., stability,
bioavailability)
or
manufacturability
should
be
discussed
relative
to
the
respective
function
of
each
excipient.
This
should
include
all
substances
used in the manufacture of the drug product, whether they appear in the
finished product or not (e.g., processing aids). Compatibility of
excipients with other excipients, where relevant (for example,
combination of preservatives in a dual preservative system), should be
established.
The
ability
of
excipients
(e.g.,
antioxidants,
penetration
enhancers, disintegrants, release controlling agents) to provide their
intended functionality, and to perform throughout the intended drug
product shelf life, should also be demonstrated. The information on
excipient
performance
can
be
used,
as
appropriate,
to
justify
the
choice
and
quality
attributes
of
the
excipient,
and
to
support
the
justification
of the drug product specification (3.2.P.5.6).
可以影响制剂产品的性能
（例如，
稳定性和生物利用度）
或是制剂产品的工艺性的辅料选择，
辅料的浓度
和特性 必须按各自的功效逐一讨论。
在相关的情况下
（比如双防腐剂系统中的防
腐剂），还需 确定各赋形剂间的兼容性。还应阐述各种辅料（如防氧化剂、穿透
增强剂、分解质、释放控制剂）在整个 制剂保质期内实现其预期作用的能力。可
适当应用辅料性能方面的资料来论证辅料选择及其质量特性的合 理性，
以支持制
剂质量标准的合理性说明（
3.2.P.5.6
）。

Information to support the safety of excipients, when appropriate,
should be cross- referenced (3.2.P.4.6).
适当时，还应交叉引用相关资料以
支持辅料 的安全性论证（
3.2.P.4.6
）。


2.2 Drug Product
制剂

2.2.1 Formulation Development
处方开发

A summary should be provided describing the development of the
formulation, including identification of those attributes that are
critical to the quality of the drug product, taking into consideration
intended usage and route of administration. Information from formal
experimental
designs
can
be
useful
in
identifying
critical
or
interacting
variables
that
might
be
important
to
ensure
the
quality
of
the
drug
product. < br>应综述配方的开发过程，
包括那些对制剂产品质量很重要的属性，
并考虑拟定用
途和给药途径。

The
summary
should
highlight
the
evolution
of
the
formulation
design
from
initial
concept
up
to
the
final
design.
This
summary
should
also
take
into consideration the choice of drug product components (e.g., the
properties of the drug substance, excipients, container closure system,
any relevant dosing device), the manufacturing process, and, if
appropriate, knowledge gained from the development of similar drug
product(s).
该综 述应着重说明配方设计从最初概念到最终设计的发展过程。
该
综述还应当要考虑各制剂组分的选 择（如：原料药，赋形剂，包装系统和相关剂
型装置）
，
生产工艺和类似制剂产品开发 过程中所获得的经验
（如果合适的话）
。

Any
excipient
ranges
included
in
the
batch
formula
(3.2.P.3.2)
should
be justified in this section of the application; this justification can
often be based on the experience gained during development or
manufacture.
正式的实验设计所获得的资料可用于确定关键的或有相互 作用
的变量，
这些变量对于确保制剂产品的质量可能是重要的。
在申请文件的此章节< br>中应对批配方（
3.2.P.3.2
）中的辅料范围进行合理性说明。通常，该合理性说
明会建立在配方和生产工艺的开发所获得的经验这个基础上。


A summary of formulations used in clinical safety and efficacy and
in any relevant bioavailability or bioequivalence studies should be
provided. Any changes between the proposed commercial formulation and
those
formulations
used
in
pivotal
clinical
batches
and
primary
stability
batches should be clearly described and the rationale for the changes
provided.
应综述在临床安全性和有效性，
生物利用度研究或生物等效性研究中