metta-thin的反义词
Q7a
（
中英文对照
）
FDA
原
料药
GMP
指南
Table of Contents
1. INTRODUCTION
1.1
Objective
1.2 Regulatory Applicability
1.3 Scope
2.
QUALITY MANAGEMENT
2.1 Principles
2.2 Responsibilities of the Quality
Unit(s)
2.3 Responsibility for
Production Activities
2.4 Internal
Audits (Self Inspection)
2.5 Product
Quality Review
3. PERSONNEL
3.1 Personnel Qualifications
3.2 Personnel Hygiene
3.3
Consultants
4. BUILDINGS
AND FACILITIES
4.1 Design and
Construction
4.2 Utilities
4.3 Water
4.4
Containment
4.5 Lighting
4.6
Sewage and Refuse
4.7 Sanitation and
Maintenance
5. PROCESS
EQUIPMENT
5.1 Design and Construction
5.2 Equipment Maintenance and Cleaning
5.3 Calibration
目录
1.
简介
1.1
目的
1.2
法规的适用性
1.3
范围
2.
质量管理
2.1
总则
2.2
质量部门的责任
2.3
生产作业的职责
2.4
内部审计（自检）
2.5
产品质量审核
3.
人员
3.
人员的资质
3.2
人员卫生
3.3
顾问
4.
建筑和设施
4.1
设计和结构
4.2
公用设施
4.3
水
4.4
限制
4.5
照明
4.6
排污和垃圾
4.7
卫生和保养
5.
工艺设备
5.1
设计和结构
5.2
设备保养和清洁
5.3
校验
EC_Q7a
5.4 Computerized Systems
6. DOCUMENTATION AND RECORDS
6.1
Documentation
System
and
Specifications
6.2 Equipment
cleaning and Use Record
6.3
Records
of
Raw
Materials,
Intermediates,
API Labeling
and Packaging
Materials
6.4
Master
Production
Instructions
(Master
Production and Control Records)
6.5
Batch
Production
Records
(Batch
Production and
Control Records)
6.6 Laboratory Control
Records
6.7 Batch Production Record
Review
7. MATERIALS
MANAGEMENT
7.1 General Controls
7.2 Receipt and Quarantine
7.3
Sampling
and
Testing
of
Incoming
Production
Materials
7.4 Storage
7.5
Re-evaluation
8.
PRODUCTION
AND
IN-PROCESS
CONTROLS
8.1 Production Operations
8.2 Time Limits
8.3 In-
process Sampling and Controls
8.4
Blending
Batches
of
Intermediates
or
APIs
8.5
Contamination Control
9.
PACKAGING
AND
IDENTIFICATION
LABELING
OF
APIs
AND
INTERMEDIATES
9.1 General
9.2 Packaging Materials
9.3
Label Issuance and Control
9.4
Packaging and Labeling Operations
10. STORAGE AND DISTRIBUTION
10.1 Warehousing Procedures
10.2 Distribution Procedures
2
5.4
计算机控制系统
6.
文件和记录
6.1
文件系统和质量标准
6.2
设备的清洁和使用记录
6.3
原料、中间体、原料药的标签和包装材
料的记录
6.4
生产工艺规程（主生产和控制记录）
6.5
批生产记录（批生产和控制记录）
6.6
实验室控制记录
6.7
批生产记录审核
7.
物料管理
7.1
控制通则
7.2
接收和待验
7.3
进厂物料的取样与测试
7.4
储存
7.5
复验
8.
生产和过程控制
8.1
生产操作
8.2
时限
8.3
工序取样和控制
8.4
中间体或原料药的混批
8.5
污染控制
9.
原料药和中间体的包装和贴签
9.1
总则
9.2
包装材料
9.3
标签发放与控制
9.4
包装和贴签操作
10.
储存和分发
10.1
入库程序
10.2
分发程序
EC_Q7a
11. LABORATORY CONTROLS
11.1 General Controls
11.2
Testing of Intermediates and APIs
11.3
Validation of Analytical Procedures
11.4 Certificates of Analysis
11.5 Stability Monitoring of APIs
11.6 Expiry and Retest Dating
11.7 Reserve/Retention Samples
12. V
ALIDATION
12.1 Validation Policy
12.2
Validation Documentation
12.3
Qualification
12.4 Approaches to
Process Validation
12.5 Process
Validation Program
12.6 Periodic Review
of Validated Systems
12.7 Cleaning
Validation
12.8 Validation of
Analytical Methods
13.
CHANGE CONTROL
14.
REJECTION
AND
RE-
USE
OF
MATERIALS
14.1 Rejection
14.2
Reprocessing
14.3 Reworking
14.4 Recovery of Materials and Solvents
14.5 Returns
15.
COMPLAINTS AND RECALLS
16.
CONTRACT
MANUFACTURERS
(INCLUDING LABORATORIES)
17.
AGENTS,
BROKERS,
TRADERS,
DISTRIBUTORS,
REPACKERS,
AND
RELABELLERS
17.1 Applicability
17.2
Traceability
of
Distributed
APIs
and
Intermediates
17.3 Quality Management
17.4
Repackaging,
Relabeling,
and
Holding
of
APIs and Intermediates
3
11.
实验室控制
11.1
控制通则
11.2
中间体和原料药的测试
11.3
分析方法的验证
11.4
分析报告单
11.5
原料药的稳定性监测
11.6
有效期和复验期
11.7
留样
12.
验证
12.1
验证方针
12.2
验证文件
12.3
确认
12.4
工艺验证的方法
12.5
工艺验证的程序
12.6
验证系统的定期审核
12.7
清洗验证
12.8
分析方法的验证
13.
变更的控制
14.
拒收和物料的再利用
14.1
拒收
14.2
返工
14.3
重新加工
14.4
物料与溶剂的回收
14.5
退货
15.
投诉与召回
16.
协议生产商（包括实验室）
17.
代理商、经纪人、贸易商、经
销商、重新
包装者和重新贴签者
17.1
适用性
17.2
已分发的原料药和中间体的可追溯性
17.3
质量管理
< br>17.4
原料药和中间体的重新包装、重新贴签
和待检<
/p>
EC_Q7a
17.5 Stability
17.6 Transfer of Information
17.7 Handling of Complaints and Recalls
17.8 Handling of Returns
18.
Specific
Guidance
for
APIs
Manufactured by Cell
Culture/Fermentation
18.1 General
18.2
Cell
Bank
Maintenance
and
Record
17.5
稳定性
17.6
信息的传达
17.7
投诉和召回的处理
17.8
退货的处理
18.
用细胞繁殖
/
发酵生产的原料药的特殊
指南
18.1
总则
18.2
细胞库的维护和记录的保存
Keeping
18.3 Cell
Culture/Fermentation
18.4 Harvesting,
Isolation and Purification
18.5 Viral
Removal/Inactivation steps
19.
APIs for Use
in Clinical Trials
19.1 General
19.2 Quality
19.3 Equipment
and Facilities
19.4 Control of Raw
Materials
19.5 Production
19.6 Validation
19.7 Changes
19.8 Laboratory Controls
19.9 Documentation
20. Glossary
18.
3
细胞繁殖
/
发酵
18.4
收取、分离和精制
18.5
病毒的去除
/
灭活步骤
19.
用于临床研究的原料药
19.1
总则
19.2
质量
19.3
设备和设施
19.4
原料的控制
19.5
生产
19.6
验证
19.7
变更
19.8
实验室控制
19.9
文件
20.
术语
4
EC_Q7a
Q7a GMP Guidance for APIs
Q7
a
原料药的
GMP
指南
1. INTRODUCTION
1.1 Objective
This document
is intended to provide guidance
regarding
good
manufacturing
practice
(GMP)
for the manufacturing
of active pharmaceutical
ingredients
(APIs) under an appropriate system
for
managing quality. It is also intended to help
ensure
that
APIs
meet
the
quality
and
purity
characteristics
that
they
purport,
or
are
represented, to possess.
In
this
guidance,
the
term
manufacturing
is
defined
to
include
all
operations
of
receipt
of
materials,
production,
packaging,
repackaging,
labeling,
relabeling,
quality
control,
release,
storage and
distribution of APIs and the related
controls.
In
this
guidance,
the
term
should
identifies
recommendations
that,
when
followed, will ensure compliance with
CGMPs.
An
alternative
approach
may
be
used
if
such
approach
satisfies
the
requirements
of
the
applicable
statues.
For
the
purposes
of
this
guidance,
the
terms
current
good
manufacturing
practices
and
good
manufacturing
practices
are equivalent.
5
1.
简介
1.1
目的
本文件旨在为在合适的质量管理体系下制造
活性药用成分（以下称原料药）提供有关优<
/p>
良药品生产管理规范（
GMP
）提供指南
。它
也着眼于帮助确保原料药符合其旨在达到或
表明拥有的质量
与纯度要求。
本指南中所指的“制
造”包括物料接收、生
产、包装、重新包装、贴签、重新贴签、质
量控制、放行、原料药的储存和分发及其相
关控制的所有操作。本指南中，
“应当”一词
表示希望采用的建议，除非证明其不适用或
< br>者可用一种已证明有同等或更高质量保证水
平的供选物来替代。本指南中的“现行
优良
生产管理规范（
cGMP
）
”和“优良生产管理
规范（
GMP
）
”是等同的。
EC_Q7a
The guidance as a whole does not cover
safety
aspects
for
the
personnel
engaged
in
manufacturing, nor aspects related to
protecting
the
environment.
These
controls
are
inherent
responsibilities
of
the
manufacturer
and
are
governed
by national laws.
This
guidance
is
not
intended
to
define
registration
and/or
filing
requirements
or
modify
pharmacopoeial
requirements.
This
guidance
does
not
affect
the
ability
of
the
responsible
regulatory
agency
to
establish
specific
registration/filing
requirements
regarding
APIs
within
the
context
of
marketing/manufacturing authorizations
or drug
applications.
All
commitments
in
registration/filing documents should be
met.
1.2 Regulatory
Applicability
Within
the
world
community,
materials
may
vary
as
to
their
legal
classification
as
an
API.
When a
material
is classified as an API in the
region or country in which it is
manufactured or
used
in
a
drug
product,
it
should
be
manufactured according to this
guidance.
1.3 Scope
This
guidance
applies
to
the
manufacture
of
APIs
for
use
in
human
drug
(medicinal)
products. It
applies to the manufacture of sterile
APIs only up to the point immediately
prior to
the
APIs
being
rendered
sterile.
The
sterilization
and
aseptic
processing
of
sterile
APIs
are
not
covered
by
this
guidance,
but
should
be
performed
in
accordance
with
GMP
guidances
for
drug
(medicinal)
products
as
defined by local authorities.
This
guidance
covers
APIs
that
are
manufactured
by
chemical
synthesis,
extraction,
cell
culture/fermentation,
recovery
from
natural
sources,
or
any
combination
of
these
processes.
Specific
guidance
for
APIs
manufactured
by
cell
culture/fermentation
is
6
本指南在总体上未涉及生产人员的安全问
题，亦不包括环保方面的内容。这方面的管
理是生产者固有的责任，也是国家法律规定
的。
本指南未规定注册
/
归档的要求、或修改药典
的要求。本指南不影响负责药政审理部门在
原料药上市
/
制造授权或药品申请方面建立
特定注册
/
归档要求的能力。
注册
/
归档的所有
承诺
必须做到。
1.2
法规的适用性
在世界范围内对原料药的法定定义是各不相
同的。当某种物料在其制造或用于药
品的地
区或国家被称为原料药，就应该按照本指南
进行生产。<
/p>
1.3
范围
本文件适用于人用药品（医疗用品）所含原
料药的生产。它适用于无菌原料药在灭菌前<
/p>
的步骤。本指南不包括无菌原料药的消毒和
灭菌工艺，但是，应当
符合地方当局所规定
的药品（医疗用品）生产的
GMP
指南。
本文件适用
于通过化学合成、提取、细胞培
养
/
发
酵，通过从自然资源回收，或通过这些
工艺的结合而得到的原料药。通过细胞培养
/
发酵生产的原料药的特殊指南则在第
18<
/p>
章论
述。
EC_Q7a
described in Section 18.
This
guidance
excludes
all
vaccines,
whole
cells,
whole
blood
and
plasma,
blood
and
plasma
derivatives
(plasma
fractionation),
and
gene
therapy
APIs.
However,
it
does
include
APIs
that
are
produced
using
blood
or
plasma
as
raw
materials.
Note
that
cell
substrates
(mammalian,
plant,
insect
or
microbial
cells,
tissue
or
animal
sources
including
transgenic
animals) and
early process steps may be subject
to
GMP but are not covered by this guidance. In
addition,
the
guidance
does
not
apply
to
medical
gases, bulk-packaged drug (medicinal)
products
(e.g.,
tablets
or
capsules
in
bulk
containers), or radiopharmaceuticals.
Section 19 contains
guidance that only applies
to
the
manufacture
of
APIs
used
in
the
production
of
drug
(medicinal)
products
specifically
for
clinical
trials
(investigational
medicinal
products).
An
API starting material
is a
raw material, an
intermediate,
or
an
API
that
is
used
in
the
production
of an API and that is incorporated as
a
significant
structural
fragment
into
the
structure
of
the
API.
An
API
starting
material
can
be
an
article
of
commerce,
a
material
purchased
from
one
or
more
suppliers
under
contract or commercial
agreement, or produced
in-house. API
starting materials normally have
defined chemical properties and
structure.
The
company
should
designate
and
document
the
rationale
for
the
point
at
which
production
of the API
begins. For synthetic processes, this
is
known
as
the
point
at
which
API
starting
materials are
entered into the process. For other
processes
(e.g.,
fermentation,
extraction,
purification),
this
rationale
should
be
established
on
a
case-by-case
basis.
Table
1
gives
guidance
on
the
point
at
which
the
API
starting material is normally
introduced into the
7
本指南不包括所有疫苗、完整细胞、全
血和血浆、全血和血浆的衍生物
（血浆成分）
和基因治疗的原
料药。但是却包括以血或血
浆为原材料生产的原料药。值得注意的是细
< br>胞培养基（哺乳动物、植物、昆虫或微生物
的细胞、组织或动物源包括转基因动物
）和
前期生产可能应遵循
GMP
规范，
但不包括在
本指南之内。另外，本指南不适用于医用气
体、散装的制剂药（例如，散装的片剂和胶
囊）和放射性药物的生产。<
/p>
第
19
章的
指南只适用于用在药品
（医疗用品）
生产中的原料药制造，特别
是临床实验用药
（研究用医疗产品）的原料药制造。
“原料药的起始物料”是指一种原料、中间
< br>体或原料药，用来生产一种原料药，或者以
主要结构单元的形式被结合进原料药结
构
中。
原料药的起始物料可能是在市场上有售、
能够通过合同或商业协议从一个或多个供应
商处购得，或由生产厂家自制。原料
药的起
始物料一般来说有特定的化学特性和结构。
生产厂商要指定并用书面文件说明原料药的
< br>生产从何处开始的理论依据。对于合成工艺
而言，就是“原料药的起始物料”进入
工艺
的那一点。对其他工艺（如：发酵，提取，
纯化等）可能需
要具体问题具体对待。表
1
给出了原料药的起始物料从哪一点引
入工艺
过程的指导原则。
EC_Q7a
process.
From this point on, appropriate GMP as
defined
从这步开始，
本指南中的有关
GMP
规范应当
in
this
guidance
should
be
applied
to
these
应用在这些中间体
和
/
或原料药的制造中。这
inter
mediate
and/or
API
manufacturing
steps.
包括对原料药质量有影响的关键工艺步骤的
This
would
include
the
validation
of
critical
验证。但是，值得注意的是厂商选择某一步
process
steps
determined
to
impact
the
quality
骤进行验证，并不一定将该步骤定为关键步
of the
API. However, it should be noted that the
骤。
fact
that
a
company
chooses
to
validate
a
process
step
does
not
necessarily
define
that
steps
as critical.
The guidance in this document would
normally
本文件的指南通常适用于表
1
中的灰色步骤。
be applied to the steps
shown in gray in Table
但
在
表
中
体
现
的
所
有
步
骤
并
不
是
将
应
用
1.
However,
all
steps
shown
may
not
be
GMP
管理的所有步骤全部体现出来了。
原料
complet
ed.
The
stringency
of
GMP
in
API
药生产中的
GMP
要求应当随着工艺的进行，
manufacturing
should
increase
as
the
process
从原料药的前几步到最后几步，
精制和包装，
proceeds
from
early
API
steps
to
final
steps,
越来越严
格。原料药的物理加工，如制粒、
purification,
and
packaging.
Physical
包衣或颗粒度的物理处理（例如制粉、微粉
processing of APIs, such as
granulation, coating
化）应当按本指南的标准进行。
or
physical
manipulation
of
particle
size
(e.g.,
milling,
micronizing)
should
be
conducted
according to this guidance.
This
GMP
guidance
does
not
apply
to
steps
本
GMP
指南不适用于引入定义了的
“原料药
prior
to
the
introduction
of
the
defined
API
的起始物料”以前的步骤。
starting material.
Table 1: Application of this Guidance
to API Manufacturing
Type of
Manufacturing
Chemical
manufacturing
Production of
the API
Starting material
Introduction of the API
starting material into
process
API derived from
animal sources
Collection of
organ,
fluid, or tissue
Cutting, mixing, and/or
initial processing
Introduction of the API
starting material into
process
API extracted from
plant sources
Collection of
plant
Cutting and initial
extraction(s)
Introduction
of the API
starting material into
process
Herbal extracts used
as API
API consisting of
comminuted or
Collection of
plants
and/or cultivation
Collection of plants
Cutting
and initial
extraction
Cutting/comminuting
Further
extraction
Physical processing, and
packaging
Physical
processing, and
packaging
Isolation and
purification
Physical processing, and
packaging
Isolation and
purification
Physical
processing, and
packaging
Production of
Intermediate(s)
Isolation
and
purification
Physical
processing, and
packaging
Application of this guidance to steps
(shown in gray) used in this type of manufacturing
8
EC_Q7a
powdered herbs
Biotechnology:
fermentation/cell
culture
“Classical”
fermentation to
produce an
API
and harvesting
Establishment of
master cell
bank and
working cell bank
Establishment of cell
bank
Maintenance of the cell
bank
Introduction of the cells
into fermentation
Isolation
and
purification
Physical
processing, and
packaging
Maintenance of working
cell
bank
Cell culture and/or
fermentation
Isolation and
purification
Physical
processing, and
packaging
Increasing GMP requirements
表
1:
本指南在原料药生产中的应用
生产类型
化学品的生产
本指南在用于各类生产的工艺步骤（灰色背景）中的应用
原料药起始物料的生
产
动物源原料药
器官、分泌物或组织
的收集
从植物源提取的原料
药
草药提取物用作原料
药
由粉碎的或粉末状草
药组成的原料药
生物技术：发酵
/
细胞
培养
“
经典
”
发酵生产原
料药
植物的收集和
/
或培养
和收获
主细胞库和工作细胞
库的建立
细胞库的建立
细胞库的维护
细胞引入发酵
分离和纯化
物理加工和包装
工作细胞库的维护
细胞培养和
/
或发酵
分离和纯化
物理加工和包装
切割
/
粉碎
物理加工和包装
植物的收集
切割和初步提取
植物的收集
原料药起始物料引入工
艺过程
切割、混合和
/
或初步加
工
切割和初步提取
原料药起始物料引入工
艺过程
原料药起始物料引入工
艺过程
进一步提取
物理加工和包装
分离和纯化
物理加工和包装
分离和纯化
物理加工和包装
中间体的生产
分离和纯化
物理加工和包装
GMP
的要求增加
2.
QUALITY MANAGEMENT
2
．质量管理
2.1 Principles
2.1
总则
2.10
Quality should be the
responsibilities of all
2.10
参与原料药生产的每一个人都应当对质
persons
involved in manufacturing.
量负责。
2.11
Each
manufacturer
should
establish,
2.11
每一个生产商都应当建立并执行一套有
document,
and
implement
an
effective
system
管理人员和有关员工积极参与的有效的质量
for
managing
quality
that
involves
the
active
管理体系，并使其文件化。
participation
of
management
and
appropriate
manufacturing
personnel.
9
EC_Q7a
2.12
The
system
for
managing
quality
should
encompass
the
organizational
structure,
procedures,
process
and
resources,
as
well
as
activities to ensure confidence that
the API will
meet its intended
specifications for quality and
purity.
All
quality-related
activities
should
be
defined and documented.
2.13
There
should
be
a
quality
unit(s)
that
is
independent of production and that
fulfills both
quality
assurance
(
QA
)
and
quality
control
(
QC)
responsibilities. The quality unit can be in
the
form
of
separate
QA
and
QC
units
or
a
single individual or
group, depending upon the
size and
structure of the organization.
2.14
The
persons
authorized
to
release
intermediates and APIs should be
specified.
2.15
All
quality-related
activities
should
be
recorded at the time they
are performed.
2.16
Any deviation from
established procedures
should
be
documented
and
explained.
Critical
deviations
should
be
investigated,
and
the
investigation
and
its
conclusions
should
be
documented.
2.17
No
materials
should
be
released
or
used
before the satisfactory
completion of evaluation
by
the
quality
unit(s)
unless
there
are
appropriate
systems
in
place
to
allow
for
such
use (e.g., release under quarantine as
described
in
Section
10
or
the
use
of
raw
materials
or
intermediates
pending
completion
of
evaluation).
2.18
Procedures
should
exist
for
notifying
responsible
management in a timely manner of
regulatory
inspections,
serious
GMP
deficiencies, product defects and
related actions
(e.g.,
quality-related
complaints,
recalls,
and
regulatory actions).
2.12
质量管理体系应当包括组织机构、
规程、
工艺和资源，以及确保
原料药会符合其预期
的质量与纯度要求所必需的活动。所有涉及
质量管理的活动都应当明确规定，并使其文
件化。
2.13
应当设立一个独立于生产部门的质量部
门，
同时履行质量保证<
/p>
(
QA
)
和质量
控制
(
QC
)
的职责。依照组织机构的大小，可以是分开
的
QA
和
QC
部门，或者只是一
个人或小组。
2.14
应当指定授权发放中间体和
原料药的人
员。
2.15
所有有关质量的活动应当在
其执行时就
记录。
2.16
任何偏离既定规程的情况都
应当有文字
记录并加以解释。对于关键性偏差应当进行
调查，并
记录调查经过及其结果。
2.17
在质量部门对物料完成满意
的评价之
前，任何物料都不应当发放或使用，除非有
合适的系统
允许此类使用
（如
10.20
条款所述
的待检情况下的使用，或是原料或中间体在
等待评价结束时的使
用）
。
2.18
应当有规程能确保公司的责
任管理部门
能及时得到有关药政检查、严重的
GMP
缺
陷、产品缺陷及其相关活动（如质量投诉，
召回
，药政活动等）的通知。
10
EC_Q7a
2.2 Responsibilities of the Quality
Unit(s)
2.20
The
quality
unit(s)
should
be
involved
in
all
quality-related matters.
2.21
The
quality
unit(s)
should
review
and
approve
all
appropriate
quality-related
documents.
2.22
The
main
responsibilities
of
the
independent
quality
unit(s)
should
not
be
delegated.
These
responsibilities
should
be
described in writing and should
include, but not
necessarily be limited
to:
1.
Releasing
or
rejecting
all
APIs.
Releasing
or
rejecting
intermediates
for
use
outside
the
control of the manufacturing company
2.
Establishing
a
system
to
release
or
reject
raw
materials,
intermediates,
packaging,
and labeling materials
3.
Reviewing
completed batch production and
laboratory
control
records
of
critical
process steps
before release of the API for
distribution
4.
Making
sure
that
critical
deviations
are
investigated and
resolved
5.
Approving
all
specifications
and
master
production
instructions
6.
Approving
all
procedures
affecting
the
quality of intermediates
or APIs
7.
Making
sure
that
internal
audits
(self-inspections) are performed
8.
Approving
intermediate
and
API
contract
manufacturers
9.
Approving
changes
that
potentially
affect
intermediate or API
quality
10.
Reviewing
and
approving
validation
protocols and reports
11.
Making sure
that quality-related complaints
are
investigated and resolved
12.
Making sure
that effective systems are used
for
maintaining
and
calibrating
critical
equipment
13.
Making
sure
that
materials
are
appropriately
tested
and
the
results
are
2.2
质量部门的责任
2.20
质量部门应当参与所有与质
量有关的事
物。
2.21
所有与质量有关的文件应当
由质量部门
审核批准。
2.22
独立的质量部门的主要职责
不应当委派
给他人。
这些责任应当以文字形式加以说明，
而且应当包括，但不限于：
1.
所有
原料药的放行与否。
用于生产商控制
范围以外的中间体的放行与
否；
2.
建立一个放行与拒收原材料、
中间体、
包
装材料和标签的系统；
3.
在供销售的原料药放行前，
审核已完成的
关键步骤的批生产记录和实验室检验记
录；
4.
确保已对重大偏差进行了调查并已解决；
5.
批准所有的规格标准和主生产指令；
6.
批准所有可能影响原料药和中间
体质量
的规程；
7.
确保进行内部审计（自检）
；
8.
批准中间体或原料药的委托生产商；
9.
批准可能影响到中间体或原料药
质量的
变更；
10.
审核并批准验证方案和报告；
11.
确保调查并解决质量问题的投诉；
12.
确保用有效的体系来维护和校
验关键设
备；
13.
确保物料都经过了适当的检验
并报告结
果；
11
EC_Q7a
reported
14.
Making
sure
that
there
is
stability
data
to
support
retest
or
expiry
dates
and
storage
conditions
on
APIs
and/or
intermediates,
where
appropriate
15.
Performing
product
quality
reviews
(as
defined in Section
2.5
)
2.3 Responsibility for Production
Activities
The
responsibility
for
production
activities
should
be
described
in
writing
and
should
include, but not
necessarily be limited to:
1.
Preparing,
reviewing,
approving,
and
distributing
the
instructions
for
the
production
of
intermediates
or
APIs
according to written
procedures
2.
Producing
APIs
and,
when
appropriate,
intermediates
according
to
pre-
approved
instructions
3.
Reviewing all
production batch records and
ensuring
that
these
are
completed
and
signed
4.
Making sure that all production
deviations
are reported and evaluated
and that critical
deviations
are
investigated
and
the
conclusions are recorded
5.
Making
sure
that
production
facilities
are
clean and, when
appropriate, disinfected
6.
Making sure that the necessary
calibrations
are performed and records
kept
7.
Making
sure
that
the
premises
and
equipment are maintained and records
kept
8.
Making
sure
that
validation
protocols
and
reports are reviewed and
approved
9.
Evaluating
proposed
changes
in
product,
process or
equipment
10.
Making
sure
that
new
and,
when
appropriate,
modified
facilities
and
equipment are qualified
2.4 Internal Audits (Self Inspection)
2.40
To
verify
compliance
with
the
principles
of GMP for APIs,
regular internal audits should
be
performed
in
accordance
with
an
approved
14.
确
保有稳定性数据支持中间体或原料药
的复验期或有效期和储存条件；
15.
开展产品质量审核（详见
2.5
节）
。
2.3
生产作业的职责
生产作业的职责应当以文字形式加以说明，
并应当包括，但不限于以下内容：
1.
<
/p>
按书面程序起草、
审核、
批准和分发中间
体或原料药的生产指令；
2.
按照
已批准的指令生产原料药或者中间
体；
3.
审核
所有的批生产记录确保其完整并有
签名；
4.
确保
所有的生产偏差都已报告、
评价，
对
关
键的偏差已做了调查，并记录结论；
5.
确保生产设施的清洁，必要时要消毒；
6.
确保进行必要的校验，并有记录；
7.
确保对厂房和设备进行保养，并有记录；
8.
确保验证方案和报告的审核与批准；
9.
对产品、工艺或设备拟作的变更
进行评
估；
10.
确保新的或已改进的生产设施
和设备经
过了确认。
2.4
内部审计（自检）
2.40
为确实符合原料药
GMP
原则，应当按
照批准的计划进行定期的内
部审计。
12
EC_Q7a
schedule.
2.41
Audit
findings
and
corrective
actions
should
be
documented
and
brought
to
the
attention
of
responsible
management
of
the
firm.
Agreed
corrective
actions
should
be
completed in a timely and effective
manner.
2.5 Product Quality
Review
2.50
Regular quality-
reviews of APIs should be
conducted
with
the
objective
of
verifying
the
consistency of the process. Such
reviews should
normally
be
conducted
and
documented
annually and
should include at least:
●
A review of critical in-process control
and critical API test results
●
A
review
of
all
batches
that
failed
to
meet
established specification(s)
●
A
review
of
all
critical
deviations
or
nonconformances
and
related
investigations
●
A review of any changes carried out to
the processes or analytical methods
●
A
review
of
results
of
the
stability
monitoring program
●
A review of all
quality-related returns,
complaints and
recalls
●
A
review
of
adequacy
of
corrective
actions
2.51
The
results
of
this
review
should
be
evaluated
and
an
assessment
made
of
whether
corrective action or any revalidation
should be
undertaken. Reasons for such
corrective action
should
be
documented.
Agreed
corrective
actions
should
be
completed
in
a
timely
and
effective manner.
3. PERSONNEL
3.1
Personnel Qualifications
3.10
There
should
be
an
adequate
number
of
personnel
qualified
by
appropriate
education,
training,
and/or
experience
to
perform
and
2.41
审计结果及整改措施应当形成文件，并
引起公司责任管理人员的重视。获准的整改
措施应当及时、有效地完成。
2.5
产品质量审核
2.50
原料药的定期质量审核应当
以证实工艺
的一致性为目的来进行。此种审核通常应当
每年进行
一次，并记录，
内容至少应当包括：
●
关键工
艺控制以及原料药关键测试
结果的审核；
●
所有不符合既定质量标准的产品批
号的审核；
●
所有关键的偏差或违规行为及有关
调查的审核；
●
任何工艺或分析方法变动的审核；
●
稳定性监测的审核；
●
所有与质量有关的退货、
投诉和召回
的审核；
●
整改措施的适当性的审核。
2.51
应当对质量审核结果进行评
估，并做出
是否需要整改或做任何再验证的评价。此类
整改措施
的理由应当文件化。获准的整改措
施应当及时、有效地完成。
3.
人员
3.1
员工的资质
3.10
应当有足够数量的员工具备
从事和监管
原料药和中间体生产的教育、培训和
/
或经历
等资格。
13
EC_Q7a
supervise the manufacture of
intermediates and
APIs.
3.11
The
responsibilities
of
all
personnel
engaged
in
the
manufacture
of
intermediates
and APIs
should be specified in writing.
3.12
Training should be
regularly conducted by
qualified
individuals
and
should
cover,
at
a
minimum,
the
particular
operations
that
the
employee
performs and GMP as it relates to the
employee
’
s
functions.
Records
of
training
should
be
maintained.
Training
should
be
periodically assessed.
3.2 Personnel Hygiene
3.20
Personnel should
practice good sanitation
and health
habits.
3.21
Personnel
should
wear
clean
clothing
suitable
for
the
manufacturing
activity
with
which
they
are
involved
and
this
clothing
should
be
changed,
when
appropriate.
Additional
protective
apparel,
such
as
head,
face, hand, and arm coverings, should
be worn,
when
necessary,
to
protect
intermediates
and
APIs from contamination.
3.22
Personnel should avoid
direct contact with
intermediates and
APIs.
3.23
Smoking,
eating,
drinking,
chewing
and
the
storage
of
food
should
be
restricted
to
certain
designated
areas
separate
from
the
manufacturing areas.
3.24
Personnel
suffering
from
an
infectious
disease
or having
open
lesions
on
the
exposed
surface
of
the
body
should
not
engage
in
activities that could
result in compromising the
quality of
APIs. Any person shown at any time
(either
by
medical
examination
or
supervisory
observation) to have an apparent
illness or open
lesions
should
be
excluded
from
activities
3.11
参与原料药和中间体生产的
所有人员的
职责应当书面规定。
3.12
应当由有资格的人员定期进
行培训，内
容至少应当包括员工所从事的特定操作和与
其职能有
关的
GMP
。培训记录应当保存，并
应
当定期对培训进行评估。
3.2
员工的卫生
3.20
员工应当养成良好的卫生和健康习惯。
3.21
员工应当穿着适合其所从事生产操作的
干净服装，必要时应当更换。其它保护性用
品如头、脸、手和臂等遮护用品必要时也应
当佩带，以免原料药和中间
体受到污染。
3.22
员工应当避免与中间体或原
料药的直接
接触。
3.23
吸烟、吃、喝、咀嚼及存放
食品仅限于
与生产区隔开的指定区域。
3.24
患传染性疾病或身体表面有开放性创伤
的员工不应当从事危及原料药质量的生产活
动。在任何时候（经医学检验或监控检查）
任何患有危及到原料药质量
的疾病或创伤的
人员都不应当参与作业，直到健康状况已恢
复，
或者有资格的医学人员确认该员工不会
危及到原料药的安全性和质量。
< br>
14
EC_Q7a
where
the
condition
could
adversely
affect
the
quality
of
the
APIs
until
the
condition
is
corrected
or
qualified
medical
personnel
determine that the
person
’
s inclusion would not
jeopardize the safety or quality of the
APIs.
3.3 Consultants
3.30
Consultants
advising
on
the
manufacture
and
control
of
intermediates
or
APIs
should
have
sufficient
education,
training,
and
experience,
or
any
combination
thereof,
to
advise
on
the
subject
for
which
they
are
retained.
3.31
Records
should
be
maintained
stating
the
name,
address,
qualifications,
and
type
of
service provided by these consultants.
4. BUILDINGS
AND FACILITIES
4.1 Design and
Construction
4.10
Buildings
and
facilities
used
in
the
manufacture
of
intermediates
and
APIs
should
be
located,
designed,
and
constructed
to
facilitate cleaning,
maintenance, and operations
as
appropriate
to
the
type
and
stage
of
manufacture. Facilities should also be
designed
to
minimize
potential
contamination.
Where
microbiological
specifications
have
been
established
for
the
intermediate
or
API,
facilities
should
also
be
designed
to
limit
exposure
to
objectionable
microbiological
contaminants, as appropriate.
4.11
Buildings
and
facilities
should
have
adequate
space
for
the
orderly
placement
of
equipment
and
materials
to
prevent
mix-ups
and contamination.
4.12
Where the equipment
itself (e.g., closed or
contained
system) provides adequate protection
of
the material, such equipment can be located
outdoors.
3.3
顾问
3.30
中间体或原料药生产和控制
的顾问应当
有足够的学历，受训和经验，能胜任所承担
的工作。
3.31
顾问的姓名、地址、资格和提供服务的
类型都应当有文字记录。
4.
建筑和设施
4.1
设计和结构
4.10
用于中间体和原料药生产的厂房和设施
的选址、设计和建造应当便于清洁，维
护和
适应一定类型和阶段的生产操作。设施的设
计应尽量减少潜
在的污染。如果中间体或原
料药的生产有微生物限度要求，那么设施设
< br>计应相应的限制有害微生物的污染。
4.11
厂房和设施应有足够空间，
以便有秩序
地放置设备和物料，防止混淆和污染。
4.12
自身能对物料提供足够保护的设备（如
关闭的或封闭的系统）
，
可以在户外放置。
15
EC_Q7a
4.13
The
flow
of
materials
and
personnel
through
the
building
or
facilities
should
be
designed
to
prevent
mix-ups
and
contamination.
4.14
There
should
be
defined
areas
or
other
control systems for
the following activities:
●
Receipt,
identification,
sampling,
and
quarantine
of
incoming
materials,
pending
release or rejection
●
Quarantine
before
release
or
rejection
of
intermediates and APIs
●
Sampling of
intermediates and APIs
●
Holding
rejected
materials
before
further
disposition
(e.g.,
return,
reprocessing
or
destruction)
●
Storage of released materials
●
Production
operations
●
Packaging and labeling operations
●
Laboratory
operations
4.15
Adequate
and
clean
washing
and
toilet
facilities
should
be
provided
for
personnel.
These
facilities
should
be
equipped
with
hot
and
cold
water,
as
appropriate,
soap
or
detergent,
air
dryers,
or
single
service
towels.
The
washing
and
toilet
facilities
should
be
separate
from,
but
easily
accessible
to,
manufacturing
areas.
Adequate
facilities
for
showering
and/or
changing
clothes
should
be
provided, when appropriate.
4.16
Laboratory
areas/operations
should
normally
be
separated
from
production
areas.
Some laboratory areas, in particular
those used
for
in-process
controls,
can
be
located
in
production areas, provided the
operations of the
production
process
do
not
adversely
affect
the
accuracy
of
the
laboratory
measurements,
and
the
laboratory
and
its
operations
do
not
adversely
affect
the
production
process,
intermediate, or
API.
4.2 Utilities
4.13
通过厂房和设施的物流和人流的设计应
当能防止混杂和污染。
4.14
以下活动应当有指定区域或其它控制系
统：
●
来料的接收、
鉴别、
取样和待验，
等待放
行或拒
收；
●
中间体和原料药放行或拒收前的待验；
●
中间体和原料药的取样
●
不合格物料处理（如退货、返工或
销毁）
前的贮存；
●
已放行物料的贮存；
●
生产操作；
●
包装及贴标签操作；
●
实验室操作。
4.15
应当为员工提供足够和清洁
的盥洗设
施。这些盥洗设施应当装有冷热水（视情况
而定）
、
肥皂或洗涤剂，
干手机和一次性毛巾。<
/p>
盥洗室应当与生产区隔离，但要便于达到。
应当根据情况提供足够
的淋浴和
/
或更衣设
施。
4.16
实验室区域
/
操作通常应当与生产区隔
离。有些实验室区域，特别是用于中间控制
的，可以位于生产区内，只要生
产工艺操作
对实验室测量的准确性没有负面影响，
而且，
实验室及其操作对生产过程，或中间体，或
原料药也没有负面影响。<
/p>
4.2
公用设施
16
EC_Q7a
4.20
All
utilities
that
could
affect
product
quality
(e.g.,
steam,
gas,
compressed
air,
heating,
ventilation,
and
air
conditioning)
should
be
qualified
and
appropriately
monitored
and
action
should
be
taken
when
limits
are
exceeded.
Drawings
for
these
utility
systems should be available.
4.21
Adequate
ventilation,
air
filtration
and
exhaust
systems
should
be
provided,
where
appropriate. These systems should be
designed
and
constructed
to
minimize
risks
of
contamination
and
cross-contamination
and
should
include
equipment
for
control
of
air
pressure, microorganisms
(if appropriate), dust,
humidity, and
temperature, as appropriate to the
stage
of
manufacture.
Particular
attention
should
be
giving
to
areas
where
APIs
are
exposed to the
environment.
4.22
If
air
is
recirculated
to
production
areas,
appropriate measures should be taken to
control
risks of contamination and
cross-contamination.
4.23
Permanently installed
pipework should be
appropriately
identified.
This
can
be
accomplished
by
identifying
individual
lines,
documentation,
computer
control
system,
or
alternative
means.
Pipework
should
be
located
to
avoid
risks
of
contamination
of
the
intermediate or ApI.
4.24
Drains
should
be
of
adequate
size
and
should
be
provided
with
an
air
break
or
a
suitable
device
to
prevent
back-
siphonage,
when appropriate.
4.3 Water
4.30
Water
used
in
the
manufacture
of
APIs
should
be
demonstrated
to
be
suitable
for
its
intended use.
4.31
Unless
otherwise
justified,
process
water
should,
at
a
minimum,
meet
World
Health
4.20
对产品质量会有影响的所有
公用设施
（如蒸汽，气体，压缩空气和加热，通风及
空调）都应
当确认合格，并进行适当监控，
在超出限度时应当采取相应措施。应当有这
些公用设施的系统图。
4.21
应当根据情况，提供足够的
通风、空气
过滤和排气系统。这些系统应当根据相应的
生产阶段
，设计和建造成将污染和交叉污染
降至最低限度，
并包括控制气
压、
微生物
（如
果适用）
、灰尘、湿度和温度的设备。特别值
得注意的是原料药暴露的区域。
4.22
如果空气再循环到生产区域，应当采取
适当的控制污染和交叉污染的风
险。
4.23
永久性安装的管道应当有适
宜的标识。
这可以通过标识每根管道、提供证明文件、
计算机控
制系统，或其它替代方法来达到。
管道的安装处应当防止污染中间体或原料
药。
4.24
排水沟应当有足够的尺寸，
而且应当根
据情况装有空断器或适当的装置，防止倒虹
吸。
4.3
水
4.30
原料药生产中使用的水应当证明适合于
其预定的用途。
4.31
除非有其它理由，工艺用水最低限度应
当符合世界卫生组织（
WHO
）的饮用水质量
17
EC_Q7a
Organization
(WHO)
guidelines
for
drinking
(portable) water
quality.
4.32
If
drinking (portable) water is insufficient
to
ensure
API
quality
and
tighter
chemical
and/or
microbiological
water
quality
specifications
are
called
for,
appropriate
specifications
for
physical/chemical
attributes,
total microbial
counts, objectionable organisms,
and/or
endotoxins should be established.
4.33
Where water used in the
process is treated
by
the
manufacturer
to
achieve
a
defined
quality,
the
treatment
process
should
be
validated and monitored with
appropriate action
limits.
4.34
Where
the
manufacturer
of
a
nonsterile
API
either
intends
or
claims
that
it
is
suitable
for use in further
processing to produce a sterile
drug
(medicinal)
product,
water
used
in
the
final
isolation
and
purification
steps
should
be
monitored
and
controlled
for
total
microbial
counts,
objectionable
organisms,
and
endotoxins.
4.4
Containment
4.40
Dedicated
production
areas,
which
can
include facilities, air handling
equipment and/or
process
equipment,
should be
employed
in
the
production of highly sensitizing
materials, such
as penicillins or
cephalosprins.
4.41
The
use
of
dedicated
production
areas
should also be considered when material
of an
infectious
nature
or
high
pharmacological
activity
or
toxicity
is
involved
(e.g.,
certain
steroids or
cytotoxic anti-cancer agents) unless
validated
inactivation
and/or
cleaning
procedures are established and
maintained.
4.42
Appropriate
measures
should
be
established
and
implemented
to
prevent
cross-contamination
from
personnel
and
指南。
4.32
如果饮用水不足以确保原料
的质量，并
要求更为严格的化学和
/
或
微生物水质规格
标准，应当指定合适的物理
/
< br>化学特性、微生
物总数、控制菌和
/
或内毒素的规格标准。
4.33
在工艺用水为达到规定质量
由制造商进
行处理时，处理工艺应当经过验证，并用合
适的处置
限度来监测。
4.34
当非无菌原料药的制造商打算或者声称
该原料药适用于进一步加工生产无
菌药品
（医疗用品）时，最终分离和精制阶段的用
水应当进行微
生物总数、致病菌和内毒素方
面的监测和控制。
4.4
限制
4.40
在高致敏性物质，如青霉素
或头孢菌素
类的生产中，应当使用专用的生产区，包括
设施、空
气处理设备和
/
或工艺设备。
4.41
当涉及具有感染性、高药理活性或毒性
的物料时（如，激素类或抗肿瘤类）
，也应当
考虑专用的生产区，除非已建立并维持一套
经验证的灭活和
/
或清洗程序。
4.42
应当建立并实施相应的措施，防止由于
在各专用区域间流动的人员和物料而造成的
交叉污染。
18
EC_Q7a
materials
moving
from
one
dedicated
area
to
another.
4.43
Any
production
activities
(including
weighing,
milling,
or
packaging)
of
highly
toxic
nonpharmaceutical
materials,
such
as
herbicides
and
pesticides,
should
not
be
conducted
using the buildings and/or equipment
being
used
for
the
production
of
APIs.
Handling
and
storage
of
these
highly
toxic
nonpharmaceutical
materials should be separate
from APIs.
4.5 Lighting
4.50
Adequate
lighting
should
be
provided
in
all areas to facilitate cleaning,
maintenance, and
proper operations.
4.6 Sewage and Refuse
4.60
Sewage,
refuse,
and
other
waste
(e.g.,
solids,
liquids,
or
gaseous
by-
products
from
manufacturing)
in
and
from
buildings
and
the
immediate surrounding area should be
disposed
of
in
a
safe,
timely,
and
sanitary
manner.
Containers
and/or
pipes
for
waste
material
should be clearly
identified.
4.7 Sanitation
and Maintenance
4.70
Buildings
used
in
the
manufacture
of
intermediates
and
APIs
should
be
properly
maintained
and
repaired
and
kept
in
a
clean
condition.
4.71
Written
procedures
should
be
established
assigning
responsibility
for
sanitation
and
describing
the
cleaning
schedules,
methods,
equipment, and materials to be used in
cleaning
buildings and facilities.
4.72
When
necessary,
written
procedures
should
be
established
for
the
use
of
suitable
rodenticides,
insecticides,
fungicides,
fumigating
agents,
and
cleaning
and
sanitizing
agents
to
prevent
the
contamination
of
4.43
剧毒的非药用物质，如除草剂、杀虫剂
的任何生产活动（包括称重、研磨或包装）
都不应当使用生产原料药所使用的厂房和
/
或
设备。这类剧毒非药用物质的处理和储存
都应当与原料药分开。
4.5
照明
4.50
所有区域都应当提供充足的
照明，以便
于清洗、保养或其它操作。
4.6
排污和垃圾
4.60
进入和流出厂房及邻近区域
的污水、垃
圾和其它废物（如生产中的固态、液态或气
态的副产
物）
，
应当安全、
及时、
卫生的处理。
废物的容器和
/
或管道应当显著地标明。
4.7
卫生和保养
4.70
生产中间体和原料药的厂房应当适当地
保养、维修并保持清洁。
4.71
应当制定书
面程序来分配卫生工作的职
责，并描述用于清洁厂房和设施的清洁的计
< br>划、方法、设备和材料。
4.72
必要时，还应当对合适的灭鼠药、杀虫
剂、杀真菌剂、烟熏剂和清洁消毒剂的使用
制定书面程序，以避免对设备、原
料、包装
/
标签、中间体和原料药的污染。
19
EC_Q7a
equipment,
raw
materials,
packaging/labeling
materials, intermediates, and APIs.
5. PROCESS
EQUIPMENT
5.1 Design and Construction
5.10
Equipment
used
in
the
manufacture
of
intermediates
and
APIs
should
be
of
appropriate
design
and
adequate
size,
and
suitably
located
for
its
intended
use,
cleaning,
sanitation
(where
appropriate),
and
maintenance.
5.11
Equipment
should
be
constructed
so
that
surfaces
that
contact
raw
materials,
intermediates,
or
APIs
do
not
alter
the
quality
of
the
intermediates
and
APIs
beyond
the
official or other established
specifications.
5.12
Production equipment
should only be used
within its
qualified operating range.
5.13
Major
equipment
(e.g.,
reactors,
storage
containers)
and
permanently
installed
processing
lines
used
during
the
production
of
an
intermediate or API should be appropriately
identified.
5.14
Any
substances
associated
with
the
operation
of
equipment,
such
as
lubricants,
heating
fluids
or
coolants,
should
not
contact
intermediates or APIs so as to alter
the quality
of APIs or intermediates
beyond the official or
other
established specifications. Any deviations
from this practice should be evaluated
to ensure
that
there
are
no
detrimental
effects
on
the
material
’
s
fitness
for
use.
Wherever
possible,
food grade lubricants and oils should
be used.
5.15
Closed or contained equipment should be
used
whenever
appropriate.
Where
open
equipment
is
used,
or
equipment
is
opened,
appropriate
precautions
should
be
taken
to
minimize the risk of contamination.
5.
工艺设备
5.1
设计和结构
5.10
中间体和原料药生产中使用的设备应当
有合理的设计和足够的尺寸，并且放置
在适
宜于其使用、清洁、消毒（根据情况而定）
和保养的地方。
5.11
设备的构造中与原料、中间体或原料药
接触的表面不会改变中间
体和原料药的质量
而使其不符合法定的或其他已规定的质量标
准
。
5.12
生产设备应该只在其确认的
操作范围内
运行。
5.13
中间体或原料药生产过程中
使用的主要
设备（如反应釜、贮存容器）和永久性安装
的工艺管
道，应当作适当的识别标志。
5.14
设备运转所需的任何物质，
如润滑剂、
加热液或冷却剂，不应当与中间体或原料药
接触，以
免影响其质量，导致无法达到法定
的或其它已规定的质量标准。任何违背该规
定的情况都应当进行评估，以确保对该物质
效果的适用性没有有害的影响。
可能的话，
应当使用食用级的润滑剂和油类。
5.15
应当尽量使用关闭的或封闭的设备。若
使用开放设备或设备被打开时，应当采取适
当的预防措施，将污染的风险降至最小。
20
EC_Q7a
5.16
A
set
of
current
drawings
should
be
maintained
for
equipment
and
critical
installations
(e.g.,
instrumentation
and
utility
systems).
5.2
Equipment Maintenance and Cleaning
5.20
Schedules
and
procedures
(including
assignment
of
responsibility)
should
be
established for the
preventative maintenance of
equipment.
5.21
Written
procedures
should
be
established
for
cleaning
equipment
release
for
use
in
the
manufacture
of
intermediates
and
APIs.
Cleaning
procedures
should
contain
sufficient
details to enable operators to clean
each type of
equipment
in
a
reproducible
and
effective
manner. These procedures should
include:
●
Assignment
of
responsibility
for
cleaning
of equipment
●
Cleaning
schedules,
including,
where
appropriate,
sanitizing schedules
●
A complete description of the methods
and
materials,
including
dilution
of
cleaning
agents used to
clean equipment
●
When
appropriate,
instructions
for
disassembling
and
reassembling
each
article
of
equipment
to
ensure
proper
cleaning
●
Instructions for the removal or
obliteration
of previous batch
identification
●
Instructions
for
the
protection
of
clean
equipment from
contamination prior to use
●
Inspection
of
equipment
for
cleanliness
immediately
before use, if practical
●
Establishing
the
maximum
time
that
may
elapse
between
the
completion
of
processing
and
equipment
cleaning,
when
appropriate
5.22
Equipment and utensils
should be cleaned,
stored,
and,
where
appropriate,
sanitized
or
sterilized
to
prevent
contamination
or
5.16
应当保存一套现在的设备和
关键装置的
图纸（如测试设备和公用系统）
。
< br>
5.2
设备保养和清洁
5.20
应当制订设备预防性保养的计划和程序
（包括职责的分配）
。
5.21
应当制订设备清洗及允许用于中间体和
原料药生产的书面程序。清洁程序
应当尽量
详细，
使操作者能对各类设备进行可重复的、
有效
的清洗。这些程序应当包括：
●
设备清洗职责分配；
●
清洗计划，必要时包括消毒计划；
●
方法和材料的详尽描述，
包括用于清洗设
备的清洗剂的稀释方法；
●
为确保
正确的清洗，
根据具体情况还应当
包括包装设备拆卸和安装的方
法；
●
拿走或抹掉上一批的标识；
●
使用前防止已清洁的设备被污染；
●
如果可行，使用前对设备进行检查；
●
根据情况，
规定生产结束和清洗之间允许
的最大时间间隔。
5.22
设备和用具应当清洁、存放，必要时还
应进行消毒或灭菌，以防止污染或夹带物质
影响中间体或原料药的质量导致其不符合法
21
EC_Q7a
carry-over
of
a
material
that
would
alter
the
quality
of
the
intermediate
or
API
beyond
the
official or other established
specifications.
5.23
Where
equipment
is
assigned
to
continuous production
or
campaign
production
of successive batches of the same
intermediate
or
API,
equipment
should
be
cleaned
at
appropriate
intervals
to
prevent
build-
up
and
carry-over of
contaminants (e.g., degradants or
objectionable levels of
microorganisms).
5.24
Nondedicated
equipment
should
be
cleaned
between
production
of
different
materials to prevent cross-
contamination.
5.25
Acceptance
criteria
for
residues
and
the
choice
of
cleaning
procedures
and
cleaning
agents should be defined and justified.
5.26
Equipment
should
be
identified
as
to
its
contents
and
its
cleanliness
status
by
appropriate means.
5.3 Calibration
5.30
Control, weighing,
measuring, monitoring,
and
testing
equipment
critical
for
ensuring
the
quality
of
intermediates
or
APIs
should
be
calibrated
according
to
written
procedures
and
an
established schedule.
5.31
Equipment
calibrations
should
be
performed using standards
traceable to certified
standards, if
they exist.
5.32
Records
of
these
calibrations
should
be
maintained.
5.33
The
current
calibration
status
of
critical
equipment should be
known and verifiable.
5.34
Instruments
that
do
not
meet
calibration
criteria should not be used.
定的或其它已规定的质量标准。
5.23
若设备指定用于同一中间体
或原料药的
连续生产，或连续批号的集中生产，应当在
适宜是时
间间隔对设备进行清洗，以防污染
物（如降解物或达到有害程度的微生物）的
累积和夹带。
5.24
非专用设备应当在生产不同
物料之间作
清洁，以防止交叉污染。
5.25
对残留物的可接受限量、清
洗程序和清
洁剂的选择应当规定并说明理由。
5.26
设备内容物及其清洁状况应当用合适的
方法标明。
5.3
校验
5.30
用于保证中间体或原料药质量的控制、
称量、测量、监测和测试设备应当按照书面<
/p>
程序和规定的计划周期进行校验。
5.31
如果有的话，应当用可追溯
到已检定的
标准的标准来进行设备校验。
5.32
校验记录应当加以保存。
5.33
应当知道并可证实关键设备
的当前校验
状态。
5.34
不应当使用不符合校验标准的仪器。
22
EC_Q7a
5.35
Deviations
from
approved
standards
of
calibration
on
critical
instruments
should
be
investigated
to
determine
if
these
could
have
had
an
effect
on
the
quality
of
the
intermediates(s)
or
API(s)
manufactured
using
this
equipment
since
the
last
successful
calibration.
5.4 Computerized Systems
5.40
GMP-related
computerized systems should
be
validated. The depth and scope of validation
depends
on
the
diversity,
complexity,
and
criticality of the
computerized application.
5.41
Appropriate
installation
and
operational
qualifications
should demonstrate the suitability
of
computer hardware and software to perform
assigned tasks.
5.42
Commercially
available
software
that
has
been
qualified
does
not
require
the
same
level
of
testing.
If
an
existing
system
was
not
validated
at time of installation, a retrospective
validation
could
be
conducted
if
appropriate
documentation is
available.
5.43
Computerized
system
should
have
sufficient
controls
to
prevent
unauthorized
access
or
changes
to
data.
There
should
be
controls
to
prevent
omissions
in
data
(e.g.,
system turned off and data not
captured). There
should
be
a
record
of
any
data
change
made,
the
previous
entry,
who
made
the
change,
and
when
the change was made.
5.44
Written procedures
should be available for
the operation
and maintenance of computerized
system.
5.45
Where
critical
data
are
being
entered
manually,
there
should
be
an
additional
check
on the accuracy of the
entry. This can be done
by a second
operator or by the system itself.
5.35
应当调查关键仪器相对于
合格校验标准
的偏差，以便确定这些偏差对自上次成功校
验以来
，用该设备生产的中间体或原料药的
质量是否有影响。
5.4
计算机控制系统
5.40
与
GMP
相关的计算机化系统应当验证。
验证的深度和广度取决于
计算机应用的差异
性、复杂性和关键性。
5.41
适当的安装确认和操作确认应当能证明
计算机硬件和软件适合于执行指定的任务。
5.42
经证明合格的商用软件不需要进行系统
水平的检验。如果现行系统在
安装时没有进
行验证，有合适的文件证明时可进行回顾性
验证。
5.43
计算机化系统应当有足够的控制，以防
止未经许可存取或改动数
据。应当有防止数
据丢失
（如系统关闭而数据未捕获）的控制。
任何数据的变更、上一次输入、谁作的变更
和什么时候变更都应
当有记录。
5.44
应当有计算机化系统操作和
维护的书面
程序。
5.45
手工输入关键性数据时，应
当另外检查
输入的准确性。这可由第二位操作人员或系
统本身来
进行。
23
EC_Q7a
5.46
Incidents
related
to
computerized
system
that could affect the quality of
intermediates or
APIs or the
reliability of records or test results
should be recorded and investigated.
5.47
Changes
to
computerized
system
should
be
made
according
to
a
change
procedure
and
should
be
formally
authorized,
documented,
and
tested.
Records
should
be
kept
of
all
changes,
including
modifications
and
enhancements made to the
hardware, software,
and any other
critical component of the system.
These
records
should
demonstrate
that
the
system is maintained in
a validated state.
5.48
If
system
breakdowns
or
failures
would
result
in
the
permanent
loss
of
records,
a
back-
up system should be provided. A means of
ensuring
data
protection
should
be
established
for all computerized system.
5.49
Data
can
be
recorded
by
a
second
means
in addition to the computer system.
6.
DOCUMENTATION AND RECORDS
6.1
Documentation
System
and
Specifications
6.10
All documents related
to the manufacture
of
intermediates
or
APIs
should
be
prepared,
reviewed,
approved,
and
distributed
according
to
written
procedures.
Such
documents
can
be
in paper or electronic form.
6.11
The
issuance,
revision,
superseding,
and
withdrawal
of
all
documents
should
be
controlled by maintaining revision
histories.
6.12
A
procedure
should
be
established
for
retaining
all
appropriate
documents
(e.g.,
development
history
reports,
scale-up
reports,
technical
transfer
reports,
process
validation
reports,
training
records,
production
records,
control
records,
and
distribution
records).
The
5.46
应当加以记录可能影响中间
体或原料药
质量、或者记录或测试结果可靠性的与计算
机化系统
有关的偶发事件，并作调查。
5.47
对计算机化系统所作的变更
应当按照变
更程序进行，并应当经过正式批准、记录成
文并作测
试。所有变更记录都应当保存，包
括对系统的硬件、软件和任何其它关键组件
的修改和升级。这些记录应当证明该系统维
持在验证过的状态。
5.48
如果计算机的故障或失效会导致记录的
永久丢失，则应当提供备份系统。
所有计算
机化的系统都应当有数据保护措施。
5.49
除计算机系统之外，数据可以用第二种
方式记录。
6.
文件和记录
6.1
文件系统和质量标准
6.10
与中间体或原料药生产有关
的所有文件
都应当按照书面程序进行拟定、审核、批准
和分发。
这些文件可以是纸张或电子形式。
6.11
所有文件的发放、修订、替
换和收回应
当通过保存修订历史来控制。
6.12
应当制订一个保存所有适用文件（如开
发历程报告、扩产报告、技术转移报告、工
艺验证报告、培训记录、生产记录、控制记
录和分发记录）的程序。应
当规定这些文件
的保存期。
24
EC_Q7a
retention periods for these documents
should be
specified.
6.13
All
production,
control,
and
distribution
records
should
be
retained
for
at
least
1
year
after the expiry date of the batch. For
APIs with
retest
dates,
records
should
be
retained
for
at
least
3
years
after
the
batch
is
completely
distributed.
6.14
When
entries
are
made
in
records,
these
should be made indelibly in spaces
provided for
such
entries,
directly
after
performing
the
activities,
and
should
identify
the
person
making
the entry. Corrections to entries should
be dated and signed and leave the
original entry
still legible.
6.15
During
the
retention
period,
originals
or
copies of records should be readily
available at
the establishment where
the activities described
in
such
records
occurred.
Records
that
can
be
promptly
retrieved
from
another
location
by
electronic or other means are
acceptable.
6.16
Specifications,
instructions,
procedures,
and
records
can
be
retained
either
as
originals
or
as
true
copies
such
as
photocopies,
microfilm,
microfiche,
or
other
accurate
reproductions
of
the
original
records.
Where
reduction
techniques
such
as
microfilming
or
electronic
records
are
used,
suitable
retrieval
equipment and a means to produce a hard
copy
should be readily available.
6.17
Specifications
should
be
established
and
documented
for
raw
materials,
intermediates
where
necessary,
APIs,
and
labeling
and
packaging materials. In addition,
specifications
may be appropriate for
certain other materials,
such as
process aids, gaskets, or other materials
used during the production of
intermediates or
APIs
that
could
critically
affect
quality.
Acceptance
criteria
should
be
established
and
6.13
所有生产、控制、销售记录都应保留至
该批的有效期后至少一年。对于有复验期的
原料药，记录应当保留至该批全部发出后三
年。
6.14
做记录时，应当在刚做操作活动后就在
所提供的空白处以不易擦掉的方式填写，并<
/p>
标明填写者。修改记录时应当注明日期、签
名并保持原来的记录仍
可识读。
6.15
在保存期间，记录的原件或
副本都应保
留在记录中描述的活动发生的地方。能以电
子或其它
方式从另一地点即时恢复的记录也
可以接受。
6.16
质量标准、指令、规程和记录保存方式
可以是原件，或者真实的副本如影印本、缩
微胶卷、缩微平片，或其它原始记录的准确
复制件。在使用压缩技术如
缩微胶卷或电子
记录时，应当有适当的制备纸张副本的恢复
设备
和方法。
6.17
应当制订原料、
中间体
（必要时）
、
原料
药和标签及包装材料的质量标准。此外，应
当为工艺助剂、垫圈
，或中间体或原料药生
产中使用的能决定性地影响质量的物料制订
质量标准。
中间控制应当制定可接受的标准，
并成文备查。<
/p>
25
EC_Q7a
documented for
in-process controls.
6.18
If
electronic
signatures
are
used
on
documents,
they
should
be
authenticated
and
secure.
6.2
Equipment cleaning and Use Record
6.20
Records of major
equipment use, cleaning,
sanitation,
and/or sterilization and maintenance
should
show
the
date,
time
(if
appropriate),
product,
and
batch
number
of
each
batch
processed in the equipment and the
person who
performed the cleaning and
maintenance.
6.21
If equipment is
dedicated to manufacturing
one
intermediate or API, individual equipment
records
are
not
necessary
if
batches
of
intermediate
or
API
follow
in
traceable
sequence. In case
where dedicated equipment is
employed,
the
records
of
cleaning,
maintenance,
and
use
can
be
part
of
the
batch
record
or maintained separately.
6.3
Records
of
Raw
Materials,
Intermediates,
API Labeling
and Packaging
Materials
6.30
Records should be
maintained including:
●
The name of the manufacturer, identity,
and
quantity of each shipment of each
batch of
raw
materials,
intermediates,
or
labeling
and
packaging
materials
for
API
’
s;
the
name of the supplier;
the supplier
’
s control
number(s), if known, or other
identification
number;
the
number
allocated
on
receipt;
and
the date of receipt
●
The
results
of
any
test
or
examination
preformed
and
the
conclusions
derived
from this
●
Records tracing the use of materials
●
Documentation
of
the
examination
and
review
of
API
labeling
and
packaging
materials
for
conformity
with
established
specifications
●
The
final
decision
regarding
rejected
raw
6.18
如果文件采用电子签名，它们应当经过
证实，并且确保其安全可靠。
6.2
设备的清洁和使用记录
6.20
主要设备的使用、
清洁、
消毒和
/
或灭菌
和保养记录应当记有日期、时间（如有必要
的话）
、
产品、
设备中加工的每批批号以及进
行清洁和保养的人。
6.21
如果设备专门用于一种中间
体或原料药
的生产，而且该中间体或原料药的批号有可
追溯性的
顺序，那就不需要有单独的设备记
录。专门设备的清洁、保养及使用记录可以
作为批记录的一部分或单独保存。
6.3
原料、中间体、原料药的标签和包装材
料的记录
6.30
需保存的记录应当包括：
●
每次到货的每批原料、
中间体、
原料药标
签和包装材料的生产商的名称，
标识和数
量；供应商的名称、供应商的管理编号，
或其它识别号码；
物料接收编号和接收日
期；
●
所进行的任何测试或检查结果，<
/p>
以及由此
得出的结论；
●
跟踪物料使用的记录；
●
检查和审核原料药的标签和包装材
料与
规定标准符合度的证明文件；
●
拒收原
料、
中间体或原料药的标签和包装
26
EC_Q7a
materials,
intermediates,
or
API
labeling
and packaging materials
6.31
Master
(approved)
labels
should
be
maintained for comparison to issued
labels.
6.4
Master
Production
Instructions
(Master
Production and Control Records)
6.40
To ensure uniformity
from batch to batch,
master
production
instructions
for
each
intermediate
and
API
should
be
prepared,
dated,
and
signed
by
one
person
and
independently checked, dated, and
signed by a
person in the quality
unit(s).
6.41
Master
production
instructions
should
include:
●
The name of the intermediate or API
being
manufactured and an identifying
document
reference code, if applicable
●
A
complete
list
of
raw
materials
and
intermediates
designated
by
names
or
codes
sufficiently
specific
to
identify
any
special quality characteristics
●
An
accurate
statement
of
the
quantity
or
ratio
of
each
raw
material
or
intermediate
to
be
used,
including
the
unit
of
measure.
Where
the
quantity
is
not
fixed,
the
calculation
for
each
batch
size
or
rate
of
production
should
be
included.
Variations
to quantities
should be included where they
are
justified
●
The
production
location
and
major
production equipment to be used
●
Detailed
production
instructions,
including
the:
-
sequences to be
followed
-
ranges
of
process
parameters
to
be
used
-
sampling
instructions
and
in-process
controls with their acceptance
criteria,
where appropriate
-
time
limits
for
completion
of
individual processing steps and/or the
total process, where appropriate
材料的最终决定。
6.31
标准标签（已批准的）应当
保留，用来
与发放的标签作比较。
6.4
生产工艺规程（主生产和控制记录）
6.40
为确保批与批的一致性，每
种中间体和
原料药的生产工艺规程应当由一人拟定、注
明日期并
签名，并由质量部门的另一人独立
进行检查、填写日期和签名。
6.41
生产工艺规程应当包括：
●
要生产的中间体或原料药的名称，
如有可
能，写明文件编号；
●
完整地
列出原料和中间体的足以区分任
何质量特性的名称或代码；
●
准确说明所用的每种原料或中间体的投
料量或投料比，
包括计量单位。
如果投料
量不是固定的，
应当写明每批的批量或产
率的计算方法。
还应当包
括经证明是合理
的量的偏差；
●
生产地点及使用的主要设备；
●
详细的生产规程，包括：
-
操作顺序，
-
工艺参数的范围，
-
取样方法，过程控制及其认可标准，
-
某些情
况下，
要说明完成某一工序和
/
或整个
工艺过程的时间，
27
EC_Q7a
expected
yield
ranges
at
appropriate
-
在某一工艺阶段或时间的预期产率。
phases of processing or time
写明注意事项、
要遵循的预防
●
Where
appropriate,
special
notations
and
●
根据情况，
precautions
to
be
followed,
or
措施，或它们的相互参照；
cross-references to these
包括标
●
The
instructions
for
storage
of
the
●
中间体或原料药的适宜贮存规定，
intermediate
or API to ensure its suitability
签、
包装材料，
某些情况下写明特殊的贮
for
use,
including
the
labeling
and
存条件、时间限制，以确保其使用。
packaging
materials
and
special
storage
conditions
with
time
limits,
where
appropriate.
6.5
Batch
Production
Records
(Batch
6.5
批生产记录（批生产和控制记录）
Production and Control Records)
6.50
Batch
production
records
should
be
6.50
应当为每种中间体和原料药准备批生产
prepared
for
each
intermediate
and
API
and
记录，内容应当包括与各批生产和控制有关
should
include complete information relating to
的完整资料。批记录发放之前，应当检查版
the
production
and
control
of
each
batch.
The
本是否正确，是否是相应生产规程的准确明
batch
production
record
should
be
checked
了的再现。如果批生产记录是按主文件的另
before
issuance
to
ensure
that
it
is
the
correct
一独立部分制定的，该文件应当包括对现行
version
and
a
legible
accurate
reproduction
of
的生产工艺规程的参考。
the appropriate master production
instruction. If
the batch production
record is produced from a
separate
part
of
the
master
document,
that
document
should
include
a
reference
to
the
current
master
production
instruction
being
used.
6.51
These
records should be numbered with a
6.51
批记录在发放时应当有一个唯一的批号
unique
batch
or
identification
number,
dated
或标识号，有日期和签名。连续生产时，在
and
signed
when
issued.
In
continuous
最终批号确定前，可以将产品代码、日
期和
production,
the
production
code
together
with
时间结合起来作为唯一的识别符。
the
date
and
time
can
serve
as
the
unique
identifier until the final number is
allocated.
6.52
Documentation
of
completion
of
each
6.52
在批生产记录
（批生产记录和控制记录）
signif
icant step in the batch production records
中提供每一重要步骤完成的证明，
应当包括：
(batch
production
and
control
records)
should
include:
●
日期，某些情况下还有时间；
●
Dates, and when
appropriate, times
（如反应釜，
干燥器
，
磨粉机等）
●
Identify of major equipment (e.g.,
reactors,
●
主要设备
driers, mills, etc.)
used
的标识；
包括原料、
中间体或
●
Specific
identification
of
each
batch,
●
每一批的识别特征，
including
weights,
measures,
and
batch
任何用于生产的
返工物料的重量、
计量单
28
-
EC_Q7a
numbers of raw
materials, intermediates, or
位、批号；
any
reprocessed
materials
used
during
manufacturing
●
Actual results
recorded for critical process
●
记录关键工艺参数的实际值；
parameters
●
取样；
●
Any sampling
performed
●
Signatures
of
the
persons
performing
and
●
每个关键步骤的操作者和直接指导者或
directly
supervising
or
checking
each
检查者的签名；
critical
step in the operation
●
过程控制和实验室的测试结果；
●
In-process and
laboratory test results
●
Actual yield at appropriate phases or
times
●
适当阶段或时间的实际产率；
●
Description
of
packaging
and
label
for
●
中间体或原料药的包装材料和标签
的描
intermediate or API
述；
●
Representative label of API or
intermediate
●
原料药或中间体的商业标签的样张；
if made commercially available
●
Any
deviation
noted,
its
evaluation,
●
发现的任何偏差，
进行的评估、
调查
（视
inv
estigation
conducted
(if
appropriate)
or
情
况而定）
，和索引到单独存放的调查报
reference
to
that
investigation
if
stored
告；
separately
●
放行测试的结果。
●
Results of
release testing
6.53
Written
procedures
should
be
established
6.53
应当建立并执行一种书面程序，对在符
and
followed
for
investigating
critical
合规格上有重大偏差或不合格的一批中间体
deviations
or
the
failure
of
a
batch
of
或原料药进行调查。调查还应当延伸到与这
intermediate or API to meet specifications.
The
批失误或偏差有关的其它批号。
investigation
should
extend
to
other
batches
that may have been
associated with the specific
failure or
deviation.
6.6
Laboratory Control Records
6.6
实验室控制记录
6.60
Laboratory control
records should include
6.60
实验室控制记录应当包括从为了确保符
complete
data derived from all tests conducted
合规定的规格和标准所做的所有测试中得到
to
ensure
compliance
with
established
的下列完整的数据，包括下列检验和测定：
specifications
and
standards,
including
examinations and assays, as
follows:
包括物料名称和
●
A
description
of
samples
received
for
●
所收到检测样品的描述，
testing,
including
the
material
name
or
来源、
批号或其它编号、
取样日期，<
/p>
某些
source,
batch
number
or
other
distinctive
情况下记录收到样品的量和时间；
code,
date
sample
was
taken,
and,
where
appropriate,
the
quantity
and
date
the
sample was
received for testing
●
A
statement
of
or
reference
to
each
test
●
每个所用检测方法的陈述或参引；
method used
标准
●
A
statement
of
the
weight
or
measure
of
●
按方法描述的所用样品重量或计量；
29
EC_Q7a
sample
used
for
each
test
as
described
by <
/p>
品、
试剂和标准溶液的配制和测试的数据
the
method;
data
on
or
cross-
reference
to
或相互参考；
the
preparation
and
testing
of
reference
standards, reagents and standard
solutions
●
A complete record of all raw data
generated
●
除了正确地标明所测试的特定物料和批
during
each
test,
in
addition
to
graphs,
号的实验室仪器的图谱、图表和光谱外，
charts
and
spectra
from
laboratory
还有一套从每次测试得到的所有原始数
instrumentation,
properly
identified
to
据的完整记录；
show the
specific material and batch tested
包括测量单
●
A
record
of
all
calculations
performed
in
●
与测试有关的所有计算记录，
connection
with
the
test,
including,
for
位、转换因子以及等量因子等；
example,
units
of
measure,
conversion
factors, and equivalency
factors
●
A statement of the test results and how
they
●
检测结果的陈述以及与规定的认可标准
compare
with
established
acceptance
的比较；
criteria
●
The signature
of the person who performed
●
每项测试的操作者的签名以及测试的日
each
test
and
the
date(s)
the
tests
were
期；
performed
表明对原记录的
●
The date and signature of a second
person
●
日期和第二个人的签名，
showing that the
original records have been
准确性、
< br>完整性和规定的标准的符合性已
reviewed
for
accuracy,
completeness,
and
复核过。
compliance
with established standards
6.61
Complete
records
should
also
be
6.61
应当保存完整的下列记录：
maintained for:
●
Any
modifications
to
an
established
●
既定的分析方法的任何修改；
analytical method
设备、
仪表和记录装置的定
●
Periodic
calibration
of
laboratory
●
实验室仪器、
instruments,
apparatus,
gauges,
and
期校验；
recording devices
●
原料药的所有稳定性测试；
●
All stability
testing performed on APIs
●
Out-of-specification (OOS)
investigations
●
不合格的调查。
6.7 Batch Production Record
Review
6.7
批生产记录审核
6.70
Written
procedures
should
be
established
6.70
应当制定并执行审核和批准批生产记录
and
followed
for
the
review
and
approval
of
和实验室控制记录，包括包装和贴签的书面
batch
production
and
laboratory
control
程序，以便放行或分发前确定中间体或原料
records,
including
packaging
and
labeling,
to
药是否符合规定标准。
determine
compliance
of
the
intermediate
or
API
with
established
specifications
before
a
batch is
released or distributed.
6.71
Batch
production
and
laboratory
control
6.71
在一批原料药放行或分发之前，关键工
30
EC_Q7a
records
of
critical
process
steps
should
be
reviewed
and
approved
by
the
quality
unit(s)
before
an
API
batch
is
released
or
distributed.
Production
and
laboratory
control
records
of
noncritical
process
steps
can
be
reviewed
by
qualified
production
personnel
or
other
units
following
procedures
approved
by
the
quality
unit(s).
6.72
All
deviation,
investigation,
and
OOS
reports
should be reviewed as part of the batch
record review before the batch is
released.
6.73
The
quality
unit(s)
can
delegate
to
the
production unit the responsibility and
authority
for
release
of
intermediates,
except
for
those
shipped
outside
the
control
of
the
manufacturing company.
7. MATERIALS
MANAGEMENT
7.1 General Controls
7.10
There
should
be
written
procedures
describing
the
receipt,
identification,
quarantine,
storage, handling, sampling, testing,
and approval or rejection of materials.
7.11
Manufacturers
of
intermediates
and/or
APIs
should
have
a
system
for
evaluating
the
suppliers of critical materials.
7.12
Materials
should
be
purchased
against
an
agreed
specification,
from
a
supplier,
or
suppliers, approved by the quality
unit(s).
7.13
If
the supplier of a critical material is not
the manufacturer of that material, the
name and
address
of
that
manufacturer
should
be
known
by the intermediate and/or API
manufacturer.
7.14
Changing
the
source
of
supply
of
critical
raw
materials
should
be
treated
according
to
Section
13
,
Change Control.
序的批生产记录和实验室控制记录应当由质
量部门审核和批准。非关键性工序的生产和
实验室控制记录可按照经质量部门批准的程
序，由有资格的生产
人员或其它部门审核。
6.72
在批放行前，所有偏差，调
查和不合格
报告都应当作为批记录的一部分进行审核。
6.73
质量部门可将发放中间体的职责和权力
委派给生产部门，运往生产商控制范围以外
的中间体除外。
7.
物料管理
7.1
控制通则
7.10
应当有书面程序阐明物料的
接收、
鉴别、
待验、贮存、搬运、取样、测试和批准或拒
收。
7.11
原料药和
< br>/
或中间体生产商应当有对关
键原料供应商的评估系统。
7.12
应当根据已确定的规格从经过质量部门
核准的一个或多个供应商
处购买物料。
7.13
如果关键物料的供应商不是
该物料的生
产商，原料药或中间体的生产商应当获知该
物料生产
商的名称和地址。
7.14
关键原料的供应商的变更应
当参照第
13
章“变更控制”进行。
31
EC_Q7a
7.2 Receipt and
Quarantine
7.20
Upon receipt
and before acceptance, each
container
or grouping of containers of materials
should
be
examined
visually
for
correct
labeling
(including
correlation
between
the
name
used
by
the
supplier
and
the
in-house
name, if these are different),
container damage,
broken
seals
and
evidence
of
tampering
or
contamination.
Materials
should
be
held
under
quarantine
until
they
have
been
sampled,
examined,
or
tested,
as
appropriate,
and
released for use.
7.21
Before incoming
materials are mixed with
existing
stocks (e.g., solvents or stocks in silos),
they
should
be
identified
as
correct,
tested,
if
appropriate, and
released. Procedures should be
available
to
prevent
discharging
incoming
materials wrongly
into the existing stock.
7.22
If
bulk
deliveries
are
made
in
nondedicated tankers, there should be
assurance
of
no
cross-contamination
from
the
tanker.
Means
of
providing
this
assurance
could
include one or more of the following:
7.2
接收和待验
7.20
一旦收到物料而尚未验收，
应当目测检
查物料每个或每组包装容器的标签是否正确
（包括如
果供应商所用名称与内部使用的名
称不一致，应当检查其相互关系）
、容器是否
损坏、密封处和开启证据有无破裂或污染。
物料
应当存放的待验区，直至它们被取样、
检查或酌情测试，并放行使用。
< br>
7.21
在进厂的物料与现有的库存（如储仓中
的溶剂或货物）混合之前，应当确认货是
否
对、必要时进行测试并放行。应当有程序来
防止把来料错放到
现有的库存中。
7.22
对于非专用槽车运送的大宗
物料，应当
确保没有来自槽车的交叉污染。可用以下的
一种或几
种方法来提供这种保证：
●
清洁证书
●
certificate of
cleaning
●
残留物的测试
●
testing for
trace impurities
●
供应商审计
●
audit of the
supplier
7.23
Large
storage
containers
and
their
7.23
大的储存容器及其随附的管路、填充和
attendant
manifolds, filling, and discharge lines
排放管都应当适当标明。
should be appropriately identified.
7.24
Each
container
or
grouping
of
containers
7.24
每个或每组物料容器（几批）的物料都
(batches)
of
materials
should
be
assigned
and
应当指定
并标上编号、批号或接收号。此号
identified
with
a
distinctive
code,
batch,
or
码应当用于记录每批的处置情况。应当有一
receipt
number. This number should be used in
个识别每批状态的系统。
recording
the
disposition
of
each
batch.
A
system should be in place to identify
the status
of each batch.
7.3
Sampling
and
Testing
of
Incoming
7.3
进厂物料的取样与测试
Production Materials
7.30
At
least
one
test
to
verify
the
identity
of
7.30
除了
7.32
中指出的物料，
对于每批物料
32
EC_Q7a
each
batch
of
material
should
be
conducted,
with
the
exception
of
the
materials
described
below.
A
supplier
’
s
certificate
of
analysis
can
be
used
in
place
of
performing
other
tests,
provided that the
manufacturer has a system in
place to
evaluate suppliers.
7.31
Supplier
approval
should
include
an
evaluation
that
provides
adequate
evidence
(e.g., past quality
history) that the manufacturer
can
consistently
provide
material
meeting
specifications.
Complete
analyses
should
be
conducted
on
at
least
three
batches
before
reducing
in-house
testing.
However,
as
a
minimum,
a
complete
analysis
should
be
performed
at
appropriate
intervals
and
compared
with
the
certificates
of
analysis.
Reliability of certificates of analysis
should be
checked at regular intervals.
7.32
Processing
aids, hazardous or highly toxic
raw
materials,
other
special
materials,
or
materials transferred to
another unit within the
company
’
s
control
do
not
need
to
be
tested
if
the
manufacturer
’
s
certificate
of
analysis
is
obtained,
showing
that
these
raw
materials
conform
to
established
specifications.
Visual
examination of containers, labels, and
recording
of
batch
numbers
should
help
in
establishing
the
identity
of
these
materials.
The
lack
of
on-site
testing
for
these
materials
should
be
justified and documented.
7.33
Samples
should
be
representative
of
the
batch
of
material
from
which
they
are
taken.
Sampling
methods
should
specify
the
number
of
containers
to
be
sampled,
which part
of
the
container
to sample, and the amount of material
to be taken from each container. The
number of
containers to sample and the
sample size should
be
based
on
a
sampling
plan
that
takes
into
consideration
the
criticality
of
the
material,
material
variability,
past
quality
history
of
the
supplier, and the quality needed for
analysis.
至少要做一个鉴别试验。在生产商对供
应商
有一套审计体系的前提下，供应商的分析报
告可以用来替代
其他项目的测试。
7.31
对供应商的核准应当包括一
次评估，提
供足够的证据（如过去的质量记录）证明该
生产商始
终都能提供符合质量标准的物料。
在减少内部测试之前至少应当对三批物料作
全检。然而，最低限度每隔一定时间应当进
行一次全检，并与分析报告进行
比较。分析
报告的可靠性应当定期进行检查。
7.32
工艺助剂、有害或剧毒的原料、其它特
殊物料、或转移到公司控制范围内的另一个
部门的物料不用测试，前提是能取得生产商
的分析报告，证明这些原料
符合规定的质量
标准。对容器、标签和批号记录进行目测检
查应
当有助于鉴别这些原料。对这些物料不
作现场测试应当说明理由，并用文件证明。
7.33
取样
应当能代表被取的那批物料。取样
方法应当规定：取样的容器数，取样部位，
每个容器的取样量。取样容器数和取样量应
当根据取样方案来决定。取样方
案的制定要
综合考虑物料的重要程度、变异性、供应商
过去的质
量情况，以及分析需用量。
33
EC_Q7a
7.34
Sampling
should
be
conducted at
defined
locations
and
by
procedures
designed
to
prevent
contamination
of
the
material
sampled
and contamination of
other materials.
7.35
Containers
from
which
samples
are
withdrawn
should
be
opened
carefully
and
subsequently reclosed. They should be
marked
to indicate that a sample has
been taken.
7.4 Storage
7.40
Materials should be
handled and stored in
a
manner
to
prevent
degradation,
contamination,
and cross-contamination.
7.41
Materials
stored
in
fiber
drums,
bags,
or
boxes should be stored off the floor
and, when
appropriate, suitably spaced
to permit cleaning
and inspection.
7.42
Materials
should
be
stored
under
conditions and for a period that have
no adverse
effect on their quality, and
should normally be
controlled so that
the oldest stock is used first.
7.43
Certain materials in
suitable containers can
be stored
outdoors, provided identifying labels
remain legible and containers are
appropriately
cleaned before opening
and use.
7.44
Rejected
materials
should
be
identified
and
controlled
under
a
quarantine
system
designed
to
prevent
their
unauthorized
use
in
manufacturing.
7.5 Re-evaluation
7.50
Materials
should
be
re-
evaluated,
as
appropriate,
to
determine
their
suitability
for
use (e.g., after
prolonged storage or exposure to
heat
or humidity).
8.
PRODUCTION
AND
IN-PROCESS
7.34
应当在规定的地点，
用规定的方法取样，
以避免取样的物料被污染，
或污染其它物料。
7.35
被取样的容器应当小心开启
，随后重新
密封。
这些容器应当做标记表明样品已抽取。
7.4
储存
7.40
物料的搬运和贮存应当防止
降解、污染
和交叉污染。
7.41
纤维板桶、袋子或盒装物料
应当离地贮
存，并根据情况留出适当空间便于清洁和检
查。
7.42
<
/p>
物料应当在对其质量没有不良影响的条
件下和时限内贮存，
而且通常应当加以控制，
做到先进先出。
7.43
某些装在适当容器中的物料可以存放在
室外，只要识别标签保持清晰，而且容器在
开启和使用前进行适当清洁。
7.44
不合格物料应当做标识，并
用隔离系统
控制，已防止未经许可而用于生产。
7.5
重新评估
7.50
应当根据情况对物料进行重
新评估以便
确定其使用的适合性（例如长期存放或暴露
于热或潮
湿的环境中）
。
8.
生产和过程控制
34
EC_Q7a
CONTROLS
8.1 Production
Operations
8.10
Raw
materials
for
intermediate
and
API
manufacturing should be
weighed or measured
under
appropriate
conditions
that
do
not
affect
their
suitability
for
use.
Weighing
and
measuring
devices
should
be
of
suitable
accuracy for the
intended use.
8.11
If a material is
subdivided for later use in
production
operations,
the
container
receiving
the material should be suitable and
should be so
identified
that
the
following
information
is
available:
●
Material name and/or item code
●
Receiving or
control number
●
Weight
or
measure
of
material
in
the
new
container
●
Re-evaluation
or retest date if appropriate
8.12
Critical
weighing,
measuring,
or
subdividing
operations
should
be
witnessed
or
subjected to an equivalent control.
Prior to use,
production
personnel
should
verify
that
the
materials are those specified in the
batch record
for the intended
intermediate or API.
8.13
Other
critical
activities
should
be
witnessed or subjected to an equivalent
control.
8.14
Actual
yields
should
be
compared
with
expected
yields
at
designated
steps
in
the
production
process.
Expected
yields
with
appropriate ranges
should be established based
on
previous
laboratory,
pilot
scale,
or
manufacturing
data.
Deviations
in
yield
associated with
critical process steps should be
investigated
to
determine
their
impact
or
potential
impact
on
the
resulting
quality
of
affected batches.
8.15
Any deviation should be
documented and
explained.
Any
critical
deviation
should
be
investigated.
8.1
生产操作
8.10
用于生产中间体和原料药的
原料应当在
适宜的条件下称重或测量，以便不影响其使
用的适合
性。称重和测量装置应当有适合于
其用途的精度。
8.11
如果某物料分出一部分留待以后的生产
操作中使用，应当用适合的容器来盛装该物
料，并应当标明下列信息：
●
物料的
名称和
/
或货号；
●
接收号或控制号；
●
新容器中物料的重量或计量；
●
如有必要，标明复验期。
8.12
关键的称重、测量或分装操
作应当有人
作证或接受相应的控制。使用前，生产人员
应当确认
该物料是要生产的中间体或原料药
的批记录中指定的。
8.13
其它关键活动应当有人作证或接受相应
的控制。
8.14
在生产过程中的指定步骤，实际收率应
当与预计的收率作比较。具有合适范围的预
计收率应当根据以前的实验室、中试规模或
生产的数据来确定。应当调
查与关键工艺步
骤有关的收率偏差，以确定其对相关批号最
终质
量的影响或潜在影响。
8.15
任何偏差都应当记录，并作
解释。任何
关键的偏差应当作调查。
35
EC_Q7a
8.16
The
processing
status
of
major
units
of
equipment
should
be
indicated
either
on
the
individual units of equipment or by
appropriate
documentation,
computer
control
systems,
or
alternative means.
8.17
Materials
to
be
reprocessed
or
reworked
should
be
appropriately
controlled
to
prevent
unauthorized use.
8.2 Time Limits
8.20
If
time
limits
are
specified
in
the
master
production
instruction
(see
6.40
),
these
time
limits
should
be
met
to
ensure
the
quality
of
intermediates
or
APIs.
Deviations
should
be
documented and evaluated. Time limits
may be
inappropriate when processing to
a target value
(e.g.,
pH
adjustment,
hydrogenation,
drying
to
predetermined
specification)
because
completion of
reactions or processing steps are
determined by in-process sampling and
testing.
8.21
Intermediates
held
for
further
processing
should
be
stored
under
appropriate
conditions
to ensure their suitability for use.
8.3 In-process Sampling and
Controls
8.30
Written
procedures
should
be
established
to
monitor
the
progress
and
control
the
performance
of
processing
steps
that
cause
variability
in
the
quality
characteristics
of
intermediates and APIs. In-process
controls and
their
acceptance
criteria
should
be
defined
based
on
the
information
gained
during
the
developmental stage or from historical
data.
8.31
The
acceptance
criteria
and
type
and
extent of testing can
depend on the nature of the
intermediate
or
API
being
manufactured,
the
reaction
or
process
step
being
conducted,
and
the
degree
to
which
the
process
introduces
variability
in
the
product
’
s
quality.
Less
stringent
in-process
controls
may
be
8.16
应当标明主要设备的生产状态，可以标
在每个设备上，或者用文
件、计算机控制系
统或其它替代的方法。
8.17
对需要进行返工或重新加工的物料应当
适当地加以控制，防止未经许可就使用。
8.2
时限
8.20
如果生产工艺规程（见
6.40
）中规定了
时限，应当遵守这些时
限，以保证中间体和
原料药的质量。所有偏差都要有记录并解释
原因。在加工到一个目标值时（例如，调节
pH
、
氢化、
干燥到预定标准）
，
时限可能就不
合适了，因为反应或加工步骤的完成是取决
于过程
中的取样和测试的。
8.21
留作进一步加工的中间体应
当在适宜的
条件下储存，以保证其适宜于使用。
8.3
工序间的取样和控制
8.30
应当制定书面程序来监测会
造成中间体
和原料药质量特性变异的工艺步骤的进程，
并控制其
生产情况。工序间控制及其接受标
准应当根据项目开发阶段或者以往的生产数
据来确定。
8.31
综合考虑所生产中间体和原
料药的特
性，反应类型，该工序对产品质量影响的程
度大小等因
素来确定可接受的标准，检测类
型和范围。前期生产的中间体控制标准可以
松一些，越接近成品，中间控制的标准越严
（如分离，纯化）
。
36
EC_Q7a
appropriate
in
early
processing
steps,
whereas
tighter
controls
may
be
appropriate
for
later
processing steps
(e.g., isolation and purification
steps).
8.32
Critical
in-process
controls
(and
critical
process
monitoring),
including
control
points
and
methods,
should
be
stated
in
writing
and
approved by the quality unit(s).
8.33
In-process
controls
can
be
performed
by
qualified
production
department
personnel
and
the
process
adjusted
without
prior
quality
unit(s)
approval
if
the
adjustments
are
made
within
pre-
established
limits
approved
by
the
quality
unit(s).
All
test
and
results
should
be
fully
documented as part of the batch record.
8.34
Written
procedures
should
describe
the
sampling
methods
for
in-
process
materials,
intermediates,
and
APIs.
Sampling
plans
and
procedures
should
be
based
on
scientifically
sound
sampling practices.
8.35
In-process
sampling
should
be
conducted
using
procedures
designed
to
prevent
contamination
of
the
sampled
material
and
other intermediates or APIs. Procedures
should
be established to ensure the
integrity of samples
after collection.
8.36
Out-of-specification
(OOS)
investigations
are not
normally needed for in-process tests that
are
performed
for
the
purpose
of
monitoring
and/or adjusting
the process.
8.4
Blending
Batches
of
Intermediates
or
APIs
8.40
For the purpose of this
document, blending
is defined as the
process of combining materials
within
the
same
specification
to
produce
a
homogeneous
intermediate
or
API.
In-
process
mixing
of
fractions
from
single
batches
(e.g.,
collecting several
centrifuge loads from a single
8.32
关键的中间控制
（和工艺监测）
，
包括控
制点和方法，应当书面规定，并经质量部门
批准。
8.33
中间控制可以由合格的生产部门的人员
来进行，而调节的工艺可以事先未经质量部
门批准，只要该调节在由质量部门批准的预
先规定的限度以内。所有测
试及结果都应当
作为批记录的一部分全部归档。
8.34
应当制定书面程序，说明中间物料、中
间体和原料药的取样方法。取样方案和程序
应当基于科学合理的取样实践。
8.35
工序间取样应当按能防止污
染所取的样
品、其它中间体或原料药的程序进行。应当
制定保证
样品收集后的完整性的程序。
8.36
生产操作中的正常监控过程
和工艺调节
过程中出现的超出标准的偏差
（
OOS
）
，
通常
< br>情况不需要调查。
8.4
中间体或原料药的混批
8.40
根据本文件的目的，混合的
定义是为了
生产出均匀的中间体或原料药而将同一质量
标准的物
料混在一起的过程。同一批号几部
分（例如，收集一个结晶批号出来的几次离
心机装的料）的工艺间的混合，或者混合从
几个批号来的部分作进一步加工
，看作是生
37
EC_Q7a
crystallization
batch)
or
combining
fractions
from
several
batches
for
further
processing
is
considered to be part of
the production process
and is not
considered to be blending.
8.41
Out-of-specification
batches should not be
blended
with
other
batches
for
the
purpose
of
meeting specifications. Each batch
incorporated
into
the
blend
should
have
been
manufactured
using
an
established
process
and
should
have
been
individually
tested
and
found
to
meet
appropriate specifications prior to
blending.
8.42
Acceptable
blending
operations
include,
but are not limited to:
●
Blending of
small batches to increase batch
size
●
Blending
of
tailings
(i.e.,
relatively
small
quantities
of
isolated
material)
from
batches of the same intermediate or API
to
form a single batch
8.43
Blending
processes
should
be
adequately
controlled
and
documented,
and
the
blended
batch
should
be
tested
for
conformance
to
established
specifications, where appropriate.
8.44
The
batch
record
of
the
blending
process
should allow
traceability back to the individual
batches that make up the blend.
8.45
Where
physical
attributes
of
the
API
are
critical
(e.g., APIs intended for use in solid oral
dosage
forms
or
suspensions),
blending
operations
should
be
validated
to
show
homogeneity of the
combined batch. Validation
should
include testing of critical attributes (e.g.,
particle
size
distribution,
bulk
density,
and
tap
density)
that
may
be
affected
by
the
blending
process.
8.46
If
the
blending
could
adversely
affect
stability,
stability
testing
of
the
final
blended
batches should be
performed.
产工艺的一部分，而不是混合。
8.41
不合格的批号不能与其他批号混合在一
起来达到符合质量标准的目的。混合的每一
个批号都应该是用规定的生产工艺
生产的，
混合前应当单独检测，并符合相应的质量标
准。
8.42
可接受的混合操作包括但不限于：
●
将小批混合，增大批量；
●
将多批同一中间体或原料药的尾料
（例
如，
分离出的相对较少的量）
混合
成为一
个批号。
8.43
混合过程应当充分控制并记录，混合后
的批号应当根据情况进行测试，以确认是否
达到质量标准。
< br>
8.44
混合过程的批记录应当允许追溯到参与
混合的每个单独批号。
< br>
8.45
如果原料药的物理性质至关重要
（例如，
用于固体口服
制剂或混悬剂的原料药）
，
混合
工艺应
当验证，
以显示混合后批号的均匀性。
验证应当包括测试可能受
混合过程影响的关
键属性（例如，粒度分布，堆密度和振实密
度
）
。
8.46
如果混合会对稳定性有不良
影响，应当
对最终混合批号进行稳定性测试。
38
EC_Q7a
8.47
The
expiry
or
retest
date
of
the
blended
batch
should
be
based
on
the
manufacturing
date of the
oldest tailings or batch in the blend.
8.5 Contamination Control
8.50
Residual materials can
be carried over into
successive batches
of the same intermediate or
API
if
there
is
adequate
control.
Examples
include
residue
adhering
to
the
wall
of
a
micronizer,
residual
layer
of
damp
crystals
remaining in a centrifuge bowl after
discharge,
and
incomplete
discharge
of
fluids
or
crystals
from
a
processing
vessel
upon
transfer
of
the
material
to
the
next
step
in
the
process.
Such
carryover
should
not
result
in
the
carryover
of
degradants or microbial
contamination that may
adversely
alter
the
established
API
impurity
profile.
8.51
Production
operations
should
be
conducted
in
a
manner
that
prevents
contamination
of
intermediates
or
APIs
by
other materials.
8.52
Precautions to avoid
contamination should
be
taken
when
APIs
are
handled
after
purification.
9.
PACKAGING
AND
IDENTIFICATION
LABELING
OF
APIs
AND
INTERMEDIATES
9.1 General
9.10
There
should
be
written
procedures
describing
the
receipt,
identification,
quarantine,
sampling,
examination,
and/or
testing, release, and
handling of packaging and
labeling
materials.
9.11
Packaging
and
labeling
materials
should
conform
to
established
specifications.
Those
that
do
not
comply
with
such
specifications
should
be
rejected
to
prevent
their
use
in
8.47
混合批号的有效期或复验期
应当以混合
中生产日期最早的尾料或批次的批号为基
准。
8.5
污染控制
8.50
在得到充分控制的前提下，
上一批号的
同一中间体或原料药的剩余物可以带入下几
个连续批
号。例如，黏附在微粉机壁上的残
留，离心出料后残留在离心机筒体内的潮湿
的结晶，将物料转至下一步工序时无法从反
应器中彻底放尽的物料。此类带
入不应当导
致因带入降解物或微生物的污染而对已经建
立的原料
药杂质概况有不良影响。
8.51
生产操作应当防止中间体或
原料药被其
它物料污染。
8.52
处理精制后的原料药应当采
取预防污染
的措施。
9.
原料药和中间体的包装和贴签
9.1
总则
9.10
应当有书面程序描述包装和
贴签用物料
的接收、
鉴别、
待验、
取样、
检查和
/
或
测试、
放行和搬运。
9.11
包装和贴签用物料应当符合
规定的质量
标准。不合格者要拒收，不得用于不适合于
其的操作
中。
39
EC_Q7a
operations for
which they are unsuitable.
9.12
Records
should
be
maintained
for
each
shipment
of
labels
and
packaging
materials
showing
receipt,
examination,
or
testing,
and
whether accepted or rejected.
9.2 Packaging Materials
9.20
Containers
should
provide
adequate
protection
against
deterioration
or
contamination
of
the
intermediate
or
API
that
may
occur
during
transportation
and
recommended storage.
9.21
Containers
should
be
clean
and,
where
indicated
by
the
nature
of
the
intermediate
or
API,
sanitized
to
ensure
that
they
are
suitable
for
their intended use. These containers should
not be reactive, additive, or
absorptive so as to
alter
the
quality
of
the
intermediate
or
API
beyond the
specified limits.
9.22
If
containers
are
reused,
they
should
be
cleaned
in
accordance
with
documented
procedures,
and
all
previous
labels
should
be
removed or defaced.
9.3 Label Issuance and Control
9.30
Access to the label
storage areas should be
limited to
authorized personnel.
9.31
Procedures
should
be
established
to
reconcile
the
quantities
of
labels
issued,
used,
and
returned
and
to
evaluate
discrepancies
found
between
the
number
of
containers
labeled
and
the
number
of
labels
issued.
Such
discrepancies
should
be
investigated,
and
the
investigation should be
approved by the quality
unit(s).
9.32
All excess
labels bearing batch numbers or
other
batch-related
printing
should
be
destroyed.
Returned
labels
should
be
maintained and stored in a manner that
prevents
9.12
每次运来的标签和包装材料
应当有接
收、
检查或测试、以及合格还是拒收的记录。
9.2
包装材料
9.20
容器应当能够对中间体和原
料药提供足
够的保护，使其在运输和建议的贮存条件下
不会变质
或受到污染。
9.21
容器应当清洁，如果中间体
或原料药有
要求时，应当进行消毒，以确保适合于其预
期的用途
。这些容器应无反应活性、加和性
或吸附性，一面改变中间体或原料药的质量
使其超出质量标准的限度。
9.22
容器被重新使用时，应当按
照规定程序
进行清洁，并出去或涂毁以前的所有标签。
9.3
标签发放与控制
9.30
只有获准人员才能进入标签贮存区。
9.31
应当建立规程来平衡发出的
、使用的和
退回的标签的数量，并评估已贴签的容器数
和发出的
标签数之间的偏差值。此种差异应
当加以调查，
调查应当由质量
保证部门批准。
9.32
所有剩余的印有批号或与批
有关内容的
标签都应当销毁。收回的标签应当以防止混
淆并提供
适当标识的方式加以保留和贮存。
40
EC_Q7a
mix-ups and provides proper
identification.
9.33
Obsolete
and
out-dated
labels
should
be
destroyed.
9.34
Printing
devices
used
to
print
labels
for
packaging
operations
should
be
controlled
to
ensure that all imprinting conforms to
the print
specified in the batch
production record.
9.35
Printed labels issued
for a batch should be
carefully
examined
for
proper
identity
and
conformity
to
specifications
in
the
master
production
record.
The
results
of
this
examination should be
documented.
9.36
A
printed
label
representative
of
those
used should be
included in the batch production
record.
9.4
Packaging and Labeling Operations
9.40
There
should
be
documented
procedures
designed
to
ensure
that
correct
packaging
materials and labels are used.
9.41
Labeling
operations should be designed to
prevent
mix-ups.
There
should
be
physical
or
spatial
separation
from
operations
involving
other
intermediates or APIs.
9.42
Labels used on
containers of intermediates
or APIs
should indicate the name or identifying
code,
batch
number,
and
storage
conditions
when such information is critical to
ensure the
quality of intermediate or
API.
9.43
If the
intermediate or API is intended to be
transferred
outside
the
control
of
the
manufacturer
’
s
material
management
system,
the
name
and
address
of
the
manufacturer,
quantity
of
contents,
special
transport
conditions,
and
any
special
legal
requirements
should
also
be
included
on
the
label.
For
intermediates
or
APIs
with
an
expiry
date,
the
9.33
废弃的和过期的标签应当销毁。
9.34
包装操作中用于印刷标签的
印刷设备应
当加以监控，以确保所有印刷内容符合批生
产记录中
的内容。
9.35
应当仔细检查发放给某批的
打印好的标
签，其标识是否正确，并符合主生产记录的
内容。检
查结果应当记录在批生产记录中。
9.36
批生产记录中应当附一张代
表那些所用
标签的印制好的标签。
9.4
包装和贴签操作
9.40
应当有文件化的规程确保使
用正确的包
装材料和标签。
9.41
帖签操作应当防止混淆。应
当与涉及其
它中间体或原料药的操作有物理的或空间的
隔离。<
/p>
9.42
用于中间体或原料药容器的标签应当注
明：确保中间体或原料药
质量的关键信息，
如名称、识别代码、产品批号和储存条件。
9.43
如果中间体或原料药要向生产商的物料
管理系统控制范围以外运输，标签上还应当
包括生产商的名称、地址，装量，特殊的运
输要求，和其它特殊的法定
要求。对于有失
效期的中间体或原料药，标签和分析报告单
上应
当注明失效期。对于有复验期的中间体
或原料药，标签和
/
或分析报告单上应当注明
复验期。
41