-
INTERNATIONAL
CONFERENCE
ON
HARMONISATION
OF
TECHNICAL
REQUIREMENTS
FOR
REGISTRATION OF PHARMACEUTICALS FOR
HUMAN USE
ICH
H
ARMONISED
T
RIPARTITE
G
UIDELINE
G
OOD
M
ANUFACTURING
P
RACTICE
G
UIDE FOR
A
CTIVE
P
HARMACEUTICAL
I
NGREDIENTS
Q7
Current Step
4 version
dated 10 November
2000
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.
中英文对照
Q7
Document History
First Codification
History
Date
New Codification
November 2005
Q7A
Approval
by
the
Steering
Committee
under
Step
2
and
release for public consultation.
19 July
2000
Q7
Current Step 4 version
Q7A
Approval
by
the
Steering
Committee
under
Step
4
and
recommendation
for
adoption to the three ICH regulatory
bodies.
10 November 2000
Q7
G
OOD
M
ANUFACTURING
P
RACTICE
G
UIDE FOR
A
CTIVE
P
HARMACEUTICAL
I
NGREDIENTS
ICH Harmonised Tripartite Guideline
Having reached Step 4 of
the ICH Process at the ICH Steering Committee
meeting on 10 November 2000, this
guideline is recommended for adoption
to the three regulatory parties to ICH
Table of Contents
目录
1.
INTRODUCTION
1.
前言
1.1 Objective
1.1
目的
1.2 Regulatory Applicability
1.2
法规的适用性
1.3 Scope
1.3
范围
2. QUALITY
MANAGEMENT
2.
质量管理
2.1 Principles
2.1
总则
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
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
(BatchProduction and Control Records)
6.6 Laboratory Control Records
6.7
Batch Production Record Re
view
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
2.2
质量部门的责任
2.3
生产的职责
2.4
内部审计（自检）
2.5
产品质量回顾
3.
人员
3.1
人员资格
3.2
个人卫生
3.3
顾问
4.
建筑和设施
4.1
设计和建造
4.2
公用设施
4.3
水
4.4
特殊限制
4.5
照明
4.6
污物和废弃物
4.7
卫生和维护
5.
工艺设备
5.1
设计和建造
5.2
设备维护和清洁
5.3
校验
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
主生产指令（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
一般要求
7.2
接收和待验
7.3
来料的取样与检测
7.4
储存
7.5
再评价
8.
生产管理和生产过程控制
8.1
生产管理
8.2
时限
8.3
生产过程中的取样和控制
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
通则
9.2
包装材料
9.3 Label Issuance and Control
9.3
标签发放与管理
9.4
Packaging and Labeling Operations
9.4
包装和贴签管理
10.
STORAGE AND DISTRIBUTION
10.
储存和分发
10.1 Warehousing Procedures
10.1
入库程序
10.2
Distribution Procedures
10.2
分发程序
11.
LABORATORY CONTROLS
11.
实验室管理
11.1 General Controls
11.1
通则
11.2 Testing of Intermediates and APIs
11.2
中间体和原料药的检测
11.3 Validation of Analytical
Procedures
11.3
分析方法的验证
11.4 Certificates of Analysis
11.4
检验报告
11.5
Stability Monitoring of APIs
11.5
原料药的稳定性考察
11.6 Expiry and Retest Dating
11.6
有效期和复验期
11.7 Reserve/Retention Samples
11.7
留样
12. VALIDATION
12.
验证
12.1 Validation Policy
12.1
验证方针
12.2
Validation Documentation
12.2
验证文件
12.3 Qualification
12.3
确认
12.4
Approaches to Process Validation
12.4
工艺验证的方法
12.5 Process Validation Program
12.5
工艺验证的程序
12.6
Periodic Review of Validated Systems
12.6
对已验证的系统的定期回顾
12.7
Cleaning Validation
12.7
清洗验证
12.8 Validation of Analytical Methods
12.8
分析方法的验证
13.
CHANGE CONTROL
13.
变更控制
14. REJECTION AND RE-USE OF MATERIALS
14.
物料的拒收和再利用
14.1 Rejection
14.1
拒收
14.2
Reprocessing
14.2
返工
14.3 Reworking
14.3
重新加工
14.4 Recovery of Materials and Solvents
14.4
物料与溶剂的回收
14.5
Returns
14.5
退货
15. COMPLAINTS
AND RECALLS
15.
投诉与召回
16. CONTRACT MANUFACTURERS
16.
协议生产商（包括实验室）
(INCLUDING LABORATORIES)
17.
AGENTS, BROKERS, TRADERS, DI
STRIBUTORS,
17.
代
理商、经纪人、贸易商、经销商、重新包装者
REPACKERS, AND RELABELLERS
和重新贴签者
17.1 Applicability
17.1
适用性
17.2 Traceability of Distributed APIs
and Intermediates
17.2
已分发的原料药和中间体的可追溯性
17.3 Quality Management
17.3
质量管理
17.4
Repackaging, Relabeling, and Holding of APIs and
Intermediates
17.4
原料药和中间体的重新包装、重新贴签和待检
17.5 Stability
17.5
稳定性
17.6 Transfer of Information
17.6
信息的传达
17.7 Handling of Complaints and Recalls
17.7
投诉和召回的处理
17.8
Handling of Returns
17.8
退货的处理
18.
Specific Guidance for APIs Manufactured by Cell
18.
用细胞繁殖
/
发酵生产的原料药的特殊
指南
Culture/Fermentation
18.1 General
18.1
总则
18.2 Cell Bank
Maintenance and Record Keeping
18.2
细胞库的维护和记录的保存
18.3
Cell Culture/Fermentation
18.3
细胞繁殖
/
发酵
18.4 Harvesting,
Isolation and Purification
18.4
收取、分离和精制
18.5 Viral Removal/Inactivation steps
18.5
病毒的去除
/
灭活步骤
19.
APIs for Use in Clinical Trials
19.
用于临床研究的原料药
19.1
General
19.1
总则
19.2 Quality
19.2
质量
19.3 Equipment
and Facilities
19.3
设备和设施
19.4 Control of Raw Materials
19.4
原料的控制
19.5
Production
19.5
生产
19.6 Validation
19.6
验证
19.7 Changes
19.7
变更
19.8
Laboratory Controls
19.8
实验室控制
19.9
Documentation
19.9
文件
20. Glossary
20.
术语
1. INTRODUCTION
1.
简介
1.1 Objective
1.1
目的
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.
本文件旨在提供在适当的体系下
为了控制生产原料药的质量而实施的药品生产质量管理规范（
GMP
）的指南。它也有助于
帮助确保活性药物成分（
APIs<
/p>
）符合其应有的质量和纯度要求。
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.
本指南中的“生产”定义为包括物料接收、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。
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.
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。
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.
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 Regulatory
Applicability
1.2
法规的适用性
Within the
world community, materials may vary as to their
legal classification as an 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.
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。
1.3 Scope
1.3
范围
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.
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。
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 described
in Section 18.
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
章论述。
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.
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
< br>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。
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).
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
。
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.
“原料药的起始物料”是指一种原料、中间体或原料药，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。
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
process.
生产厂商要指定并用书面文件说明原料药的
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。
From this point on,
appropriate GMP as defined in this guidance should
be applied to these intermediate and/or API
manufacturing
would include the
validation of critical process steps determined to
impact the quality of the API. However, it should
be
noted that the fact that a company
chooses to validate a process step does not
necessarily define that steps as critical.
从这步开始，本指南中的有关
GMP
规范应当应用在这些中间体和
/
或原料药的制造中。这包括对原
料药质量有影响的关键
工艺步骤的验证。但是，值得注意的是厂商选择某一步骤进行验证
，并不一定将该步骤定为关键步骤。
The
guidance in this document would normally be
applied to the steps shown in gray in Table 1.
However, all steps shown may not
be
completed. The stringency of GMP in API
manufacturing should increase as the process
proceeds from early API steps to final
steps,purification, and packaging.
Physical processing of APIs, such as granulation,
coating or physical manipulation of particle
size (e.g.,milling, micronizing) should
be conducted according to this guidance.
本文件的指南通常适用于表
1
中的灰色步骤。但在表中体现的所有步骤并不是将应用
GMP
管理的所有步骤全部体现出来
了。原料药生产中的
GMP
要求应当随着工艺的进行，从原料药的前几步到最后几步，精制和包
装，越来越严格。原料药
的物理加工，如制粒、包衣或颗粒度的物理处理（例如制粉、微
粉化）应当按本指南的标准进行。
This GMP
guidance does not apply to steps prior to the
introduction of the defined API starting material.
本
GMP
指南不适用于引入定义了的“原料药的起始物料”以前的步骤。
Table 1: Application of this Guidance
to API Manufacturing
Type of
Manufacturing
Chemical
manufacturing
Application of this guidance to steps
(shown in gray) used in this type of manufacturing
Production of
the
API Starting
material
Collection of
organ, fluid, or
tissue
Introduction of the
API starting material
into process
Cutting, mixing,
and/or initial
processing
Production of
Intermediate(s)
Isolation and
purification
Physical processing,
and packaging
API derived from
animal sources
Introduction of the
API starting
material into
process
Introduction of the
API starting
material into
process
Isolation and
purification
Physical processing,
and packaging
API extracted
from plant
sources
Collection of
plant
Cutting and initial
extraction(s)
Isolation and
purification
Physical processing,
and packaging
Herbal extracts
used as API
API
consisting of
comminuted or
powdered herbs
Collection of
plants
Collection of plants
and/or
cultivation
and harvesting
Cutting and
initial
extraction
Cutting/comminuting
Further
extraction
Physical processing,
and packaging
Physical processing, and
packaging
Biotechnology:
fermentation/cell
culture
Establishment of
master cell bank
and working
cell
bank
Maintenance of
working cell
bank
Cell culture and/or
fermentation
Isolation and
purification
Physical processing, and
packaging
“Classical”
fermentation to
produce an API
Establishment of
cell bank
Maintenance of the cell
bank
Introduction of the
Isolation and
cells into
fermentation
purification
Physical processing, and
packaging
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
器官、
分泌物或组织
的收集
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
中间体的生产
分离和纯化
物理加工和包装
动物源原料药
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
分离和纯化
物理加工和包装
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
分离和纯化
物理加工和包装
植物的收集
切割和初步提取
进一步提取
物理加工和包装
< br>植物的收集和
/
或培
养和收获<
/p>
切割
/
粉碎
细胞培养和
/
或发酵
分离和纯化
物理加工和包装
主细胞库和工作细
胞库的建立
细胞库的建立
工作细胞库的维护
物理加工和包装
细胞库的维护
细胞引入发酵
分离和纯化
物理加工和包装
2. QUALITY MANAGEMENT
2
．质量管理
2.1 Principles
2.1
总则
2.10
Quality should be the responsibilities
of all persons involved in manufacturing.
2.10
参与原料药生产的每一个人都应当对质量负责。
2.11
Each manufacturer
should establish, document, and implement an
effective system for managing quality that
involves the
active participation of
management and appropriate manufacturing
personnel.
2.11
每一个生产商都应当建立并
执行一套有管理人员和有关员工积极参与的有效的质量管理体系，并使其文件化。
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.
2.12
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
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
asingle individual or group,
depending
upon the size and structure of the
organization.
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
(
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
The persons authorized
to release intermediates and APIs should be
specified.
2.14
应当指定授权发放中间体和原料药的人员。
2.15
All quality-related
activities should be recorded at the time they are
performed.
2.15
所有有关质量的活动应当在其执行时就记录。
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.
2.16
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
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).
2.17
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
< br>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
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, andregulatory actions).
2.18 <
/p>
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
< br>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。
2.2
Responsibilities of the Quality Unit(s)
2.2
质量部门的责任
2.20
The quality unit(s)
should be involved in all quality-related matters.
2.20
质量部门应当参与所有与质量有关的事物。
2.21
The quality unit(s)
should review and approve all appropriate quality-
related documents.
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
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 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
)
2.22
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；
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
Responsibility for Production Activities
2.3
生产作业的职责
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
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.
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 Internal Audits (Self Inspection)
2.4
内部审计（自检）
2.40
To verify compliance
with the principles of GMP for APIs, regular
internal audits should be performed in accordance
with an
approved schedule.
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。
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.
2.41
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 Product Quality Review
2.5
产品质量审核
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
2.50
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
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.
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. PERSONNEL
3.
人员
3.1 Personnel
Qualifications
3.1
员工的资质
3.10
There should be an adequate number of
personnel qualified by appropriate education,
training, and/or experience to perform
and supervise the manufacture of
intermediates and APIs.
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。
3.11
The responsibilities of all personnel
engaged in the manufacture of intermediates and
APIs should be specified in writing.
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
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.
3.12
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
< br>GMP
。培训记录应
当保存，并应当定期对培训进行评估
。
3.2 Personnel Hygiene
3.2
员工的卫生
3.20
Personnel should
practice good sanitation and health habits.
3.20
员工应当养成良好的卫生和健康习惯。
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.
3.21
< br>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
Personnel should avoid
direct contact with intermediates and APIs.
3.22
员工应当避免与中间体或原料药的直接接触。
3.23
Smoking, eating,
drinking, chewing and the storage of food should
be restricted to certain designated areas separate
from the
manufacturing areas.
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
Personnel suffering from an infectious
disease or having open lesions on the exposed
surface of the body should not engage in
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）
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 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.
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。
3.3
Consultants
3.3
顾问
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.
3.30
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
Records should be
maintained stating the name, address,
qualifications, and type of service provided by
these consultants.
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. BUILDINGS AND FACILITIES
4.
建筑和设施
4.1 Design and Construction
4.1
设计和结构
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 ofmanufacture.
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.
4.10
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，那么设施设计应相应的限制有害微生
物的污染。
4.11
Buildings and
facilities should have adequate space for the
orderly placement of equipment and materials to
prevent mix-ups
and contamination.
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
Where the equipment itself (e.g.,
closed or contained system) provides adequate
protection of the material, such equipment can
be located outdoors.
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。
4.13
The flow of
materials and personnel through the building or
facilities should be designed to prevent mix-ups
and
contamination.
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
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
4.14
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
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 washing
and toilet facilities should
beseparate
from, but easily accessible to,manufacturing
areas. Adequate facilities for showering and/or
changing clothes should be
provided,
when appropriate.
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。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
Laboratory
areas/operations should normally be separated from
production 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
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，<
/p>
或中间体，
或原料药也没有负面影响。
the laboratory and its operations do
not adversely affect the production
process,intermediate, or API.
4.2
Utilities
4.2
公用设施
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.
4.20
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
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.
4.21
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
If air is recirculated to production
areas,appropriate measures should be taken to
control risks of contamination and
cross-contamination.
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。
< br>
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.
4.23
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
Drains should be
of adequate size and should be provided with an
air break or a suitable device to prevent back-
siphonage,
when appropriate.
4.24
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 Water
4.3
水
4.30
Water used in the
manufacture of APIs should be demonstrated to be
suitable for itsintended use.
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
Unless otherwise
justified, process water should, at a minimum,
meet World Health Organization (WHO) guidelines
for
drinking(portable) water quality.
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
）的饮用水质量指南。
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.
4.32
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
/
化学特
性、微
生物总数、控制菌和
/
或内毒素的规格标准。
< br>
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.
4.33
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
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.
4.34
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 Containment
4.4
限制
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.
4.40
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
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 cleaningprocedures are
established and maintained.
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
Appropriate measures should be
established and implemented to preventcross-
contamination from personnel and materials
moving from one dedicated area to
another.
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。
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.
4.43
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
< br>/
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 Lighting
4.5
照明
4.50
Adequate lighting should be provided in
all areas to facilitate cleaning, maintenance, and
proper operations.
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 Sewage and Refuse
4.6
排污和垃圾
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
ners and/or pipes for waste
material
should be clearly identified.
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 Sanitation and Maintenance
4.7
卫生和保养
4.70
Buildings used in the
manufacture of intermediates and APIs should be
properly maintained and repaired and kept in a
clean
condition.
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
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.
4.71
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划、方法、设备和材料。
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
equipment, raw materials, packaging/labeling
materials, intermediates, and APIs.
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。
5. PROCESS EQUIPMENT
5.
工艺设备
5.1 Design
and Construction
5.1
设计和结构
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.
5.10
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
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.
5.11
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
Production equipment should only be
used within its qualified operating range.
5.12
生产设备应该只在其确认的操作范围内运行。
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.
5.13
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
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
fitne
ss for use.
Wherever
possible, food grade lubricants and oils should be
used.
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
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.
5.15
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，
< br>将污染的风险降至
最小。
5.16
A set of current
drawings should be maintained for equipment and
critical installations (e.g., instrumentation and
utility
systems).
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）。
5.2 Equipment Maintenance and Cleaning
5.2
设备保养和清洁
5.20
Schedules and
procedures (including assignment of
responsibility) should be established for the
preventative maintenance of
equipment.
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
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 cleaningof equipment
●
Cleaning
schedules, including, whereappropriate, sanitizing
schedules
●
A
complete description of the methods andmaterials,
including dilution of cleaningagents used to clean
equipment
●
When appropriate, instructions for
disassembling and reassembling eacharticle 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
5.21
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
Equipment and utensils
should be cleaned,stored, and, where appropriate,
sanitized or sterilized to prevent contamination
or
carry-over of a material that would
alter the quality of the intermediate or API
beyond the official or other established
specifications.
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
符合法定的或其它已规定的质量标准。
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).
5.23
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
Nondedicated equipment
should be cleaned between production of different
materials to prevent cross-contamination.
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
Acceptance criteria for
residues and the choice of cleaning procedures and
cleaning agents should be defined and justified.
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
Equipment should be identified as to
its contents and its cleanliness status by
appropriate means.
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 Calibration
5.3
校验
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.
5.30
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程序和规定的计划周期进行校验。
5.31
Equipment calibrations
should be performed using standards traceable to
certified standards, if they exist.
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
Records of these calibrations should be
maintained.
5.32
校验记录应当加以保存。
5.33
The current calibration status of
critical equipment should be known and verifiable.
5.33
应当知道并可证实关键设备的当前校验状态。
5.34
Instruments that do not
meet calibrationcriteria should not be used.
5.34
不应当使用不符合校验标准的仪器。
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.
5.35
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
Computerized Systems
5.4
计算机控制系统
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.
5.40
与
GMP
< br>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
Appropriate
installation and operational qualifications should
demonstrate the suitability of computer hardware
and software
to perform assigned tasks.
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
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.
5.42
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
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.
5.43
计算机化系统应当有足够的控制，
< br>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
Written procedures should be available
for the operation and maintenance of computerized
system.
5.44
应当有计算机化系统操作和维护的书面程序。
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.
5.45
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。
< p>
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.
5.46
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
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.
5.47 <
/p>
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
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.
5.48
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
Data can be recorded by a second means
in addition to the computer system.
5.49
除计算机系统之外，数据可以用第二种方式记录。
6. DOCUMENTATION AND RECORDS
6.
文件和记录
6.1 Documentation System and
Specifications
6.1
文件系统和质量标准
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.
6.10
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
The issuance, revision,
superseding, and withdrawal of all documents
should be controlled by maintaining revision
histories.
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
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 retention
periods for these documents should be specified.
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、
控制记录和销售记录）的程序。应当规定这些文件的保存期。
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.
6.13
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
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.
6.14
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
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.
6.15
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
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.
6.16
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
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 ance criteria should be
established and documented for in-
process controls.
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。
6.18
If
electronic signatures are used on documents, they
should be authenticated and secure.
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 Equipment
cleaning and Use Record
6.2
设备的清洁和使用记录
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.
6.20
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
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.
6.21
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
Records of Raw Materials,Intermediates, API
Labeling and PackagingMaterials
6.3
原料、中间体、原料药的标签和包装材料的记录
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 identific
ation
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
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，以及由此得出的结论；
●
跟踪物料使用的记录；
●
Documentation
of the examination and review of API labeling and
packaging materials for conformity with
established
specifications
●
The final
decision regarding rejected raw materials,
intermediates, or API labeling and packaging
materials
●
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材料的最终决定。
6.31
Master (approved)
labels should be maintained for comparison to
issued labels.
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 Master Production Instructions
(Master Production and Control Records)
6.4
生产工艺规程（主生产和控制记录）
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).
6.40
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
< br>一人独立进行检查、填写日期和签名。
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
-
expected yield ranges at appropriate phases of
processing or time
●
Where appropriate, special notations
and precautions to be followed, or cross-
references to these
●
The instructions for storage of the
intermediate or API to ensure its suitability for
use, including the labeling and packaging
materials and special storage
conditions with time limits, where appropriate.
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；<
/p>
●
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，
-
在某一工艺阶段或时间的预期产率。
●
根据情况，写明注意事项、要遵循
的预防措施，或它们的相互参照；
●
中间体或原料药的适宜贮存规定，
包括标签、
< br>包装材料，
某些情况下写明特殊的贮存条件、
时间限制，
以确保其使用。
6.5 Batch
Production Records (Batch Production and Control
Records)
6.5
批生产记录（批生产和控制记录）
6.50
Batch production
records should be prepared for each intermediate
and API and should include complete information
relating
to the production and control
of each batch. The batch production record should
be checked before issuance to ensure that it is
the
correct version and a legible
accurate reproduction of 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.
6.50
应当为每种中间体和原料药准备批生产记录，
内容应当包括与各批生产和控制有关的完整资料。
批记录发放之前，<
/p>
应
当检查版本是否正确，是否是相应生产规程的准确明了的再现。
如果批生产记录是按主文件的另一独立部分制定的，该文
件应当包括对现行的生产工艺规
程的参考。
6.51
These
records should be numbered with a unique batch or
identification number, dated and signed when
issued. In continuous
production, the
production code together with the date and time
can serve as the unique identifier until the final
number is allocated.
6.51
批记
录在发放时应当有一个唯一的批号或标识号，
有日期和签名。
连
续生产时，
在最终批号确定前，
可以将产品代码、
日期和时间结合起来作为唯一的识别符。
6.52
Documentation of completion of each
significant step in the batch production
records(batch production and control records)
should include:
6.52
在批生产记录（批生产记录和控制记录）中提供每一重要步骤完成的证明，应当包括：
< br>
●
Dates, and
when appropriate, times
●
Identify of major equipment (e.g.,
reactors,driers, mills, etc.) used
●
Specific
identification of each batch,including weights,
measures, and batch numbers of raw materials,
intermediates, or
any reprocessed
materials used during manufacturing
●
Actual results
recorded for critical processparameters
●
Any sampling
performed
●
Signatures of the persons performing
and directly supervising or checking each critical
step in the operation
●
In-process and laboratory test results
●
Actual yield at
appropriate phases or times
●
Description of
packaging and label for intermediate or API
●
Representative
label of API or intermediate if made commercially
available
●
Any
deviation noted, its evaluation,investigation
conducted (if appropriate) or reference to that
investigation if stored separately
●
Results of
release testing
●
日期，某些情况下还有时间；
●
主要设备（如反应釜，干燥器，磨粉机等）的标识；
●
每一批的识别特征，包括原料、中
间体或任何用于生产的返工物料的重量、计量单位、批号；
●
记录关键工艺参数的实际值；
●
取样；
●
每个关键步骤的操作者和直接指导者或检查者的签名；
●
过程控制和实验室的测试结果；
●
适当阶段或时间的实际产率；
●
中间体或原料药的包装材料和标签的描述；
●
原料药或中间体的商业标签的样张；
●
发现的任何偏差，进行的评估、调
查（视情况而定），和索引到单独存放的调查报告；
●
放行测试的结果。
6.53
Written procedures should be
established and followed for investigating
critical deviations or the failure of a batch of
intermediate or API to meet
specifications. The investigation should extend to
other batches that may have been associated with
the
specific failure or
deviation.
6.53
应
当建立并执行一种书面程序，
对在符合规格上有重大偏差或不合格的一批中间体或原料药
进行调查。
调查还应当延
伸到与这批失误或偏差有关的其它批号
。
6.6 Laboratory Control
Records
6.6
实验室控制记录
6.60
Laboratory control records should
include complete data derived from all tests
conducted to ensure compliance with
established specifications and
standards, including examinations and assays, as
follows:
●
A
description of samples received for testing,
including the material name or source, batch
number or other distinctive
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 method used
●
A statement of
the weight or measure of sample used for each test
as described by the method; data on or cross-
reference to
the preparation and
testing of reference standards, reagents and
standard solutions
●
A complete
record of all raw data generated during each test,
in addition to graphs,charts and spectra from
laboratory
instrumentation, properly
identified to show the specific material and batch
tested
●
A record
of all calculations performed in connection with
the test, including, for example, units of
measure, conversion
factors, and
equivalency factors
●
A statement of the test results and how
they compare with established acceptance criteria
●
The signature
of the person who performed each test and the
date(s) the tests were performed
●
The date and
signature of a second person showing that the
original records have been reviewed for accuracy,
completeness,
and compliance with
established standards
6.60
实
验室控制记录应当包括从为了确保符合规定的规格和标准所做的所有测试中得到的下列完整的数据，
包括下列检验
和测定：
●
所收到检测样品的描述，包括物料
名称和来源、批号或其它编号、取样日期，某些情况下记录收到样品的量和时间；
●
每个所用检测方法的陈述或参引；
●
按方法描述的所用样品重量或计量
；标准品、试剂和标准溶液的配制和测试的数据或相互参考；
●
除了正确地标明所测试的特定物料
和批号的实验室仪器的图谱、图表和光谱外，还有一套从每次测试得到的所有原始
数据的
完整记录；
●
与测试有关的所有计算记录，包括测量单位、转换因子以及等量因子等；
●
检测结果的陈述以及与规定的认可标准的比较；
●
每项测试的操作者的签名以及测试的日期；
●
日期和第二个人的签名，表明对原
记录的准确性、完整性和规定的标准的符合性已复核过。
6.61
Complete records should
also be maintained for:
●
Any modifications to an established
analytical method
●
Periodic calibration of laboratory
instruments, apparatus, gauges, and recording
devices
●
All
stability testing performed on APIs
●
Out-of-
specification (OOS) investigations
6.61
应当保存完整的下列记录：
●
既定的分析方法的任何修改；
●
实验室仪器、设备、仪表和记录装置的定期校验；
●
原料药的所有稳定性测试；
●
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 and followed for the review and
approval of batch production and laboratory
control
records, including packaging
and labeling, to determine compliance of the
intermediate or API with established
specifications
before a batch is
released or distributed.
6.70
应当制定并执行审核和批准批生产记录和实验室控制记录，
包括包装和贴签的书面程
序，
以便放行或分发前确定中间
体或原料药是否符合规定标准。
6.71
Batch
production and laboratory control 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).
6.71 <
/p>
在一批原料药放行或分发之前，
关键工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
All deviation,
investigation, and OOS reports should be reviewed
as part of the batch record review before the
batch is
released.
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
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.
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.
MATERIALS MANAGEMENT
7.
物料管理
7.1 General
Controls
7.1
控制通则
7.10
There should be written
procedures describing the receipt,
identification,quarantine, storage, handling,
sampling, testing,and
approval or
rejection of materials.
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
Manufacturers of
intermediates and/or APIs should have a system for
evaluating the suppliers of critical materials.
7.11
原料药和
/
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
Materials should be
purchased against an agreed specification, from a
supplier, or suppliers, approved by the quality
unit(s).
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
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.
7.13
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
Changing the source of
supply of critical raw materials should be treated
according to Section
13
,
Change Control.
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。
7.2
Receipt and Quarantine
7.2
接收和待验
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.
7.20
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。
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.
7.21
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
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:
●
certificate of
cleaning
●
testing for trace impurities
●
audit of the
supplier
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
●
残留物的测试
●
供应商审计
7.23
Large storage containers and their
attendant manifolds, filling, and discharge lines
should be appropriately identified.
7.23
大的储存容器及其随附的管路、填充和排放管都应当适当标明。
7.24
Each container or
grouping of containers(batches) of materials
should be assigned and identified with a
distinctive code, batch,
or receipt
number. This number should be used in recording
the disposition of each batch. A system should be
in place to identify
the status of each
batch.
7.24
每个或每组物料容器（几批）的物料
都应当指定并标上编号、批号或接收号。此号码应当用于记录每批的处置情况。
应当有一
个识别每批状态的系统。
7.3 Sampling and
Testing of Incoming Production Materials
7.3
进厂物料的取样与测试
7.30
At least one test to
verify the identity of 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.
7.30
除了
7.32
中指出的物料，对于每
批物料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
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 ility of certificates of analysis
should be checked at regular intervals.
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
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.
7.32
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
Samples should be representative of the
batch of material from which they are ng 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.
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
< br>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。
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.
7.34
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
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.
7.35
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
Storage
7.4
储存
7.40
Materials should be
handled and stored in a manner to prevent
degradation,contamination, and cross-
contamination.
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
Materials stored in
fiber drums, bags, or boxes should be stored off
the floor and, when appropriate, suitably spaced
to permit
cleaning and inspection.
7.41
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
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.
7.42
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
Certain materials in
suitable containers can be stored outdoors,
provided identifying labels remain legible and
containers are
appropriately cleaned
before opening and use.
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
Rejected
materials should be identified and controlled
under a quarantine system designed to prevent
their unauthorized use in
manufacturing.
7.44
< br>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 Re-evaluation
7.5
重新评估
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).
7.50 <
/p>
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. PRODUCTION AND
IN-PROCESS CONTROLS
8.
生产和过程控制
8.1
Production Operations
8.1
生产操作
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.
8.10
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
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
8.11
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
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.
8.12
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
Other critical
activities should be witnessed or subjected to an
equivalent control.
8.13
其它关键活动应当有人作证或接受相应的控制。
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.
8.14
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
Any deviation should be
documented and explained. Any critical deviation
should be investigated.
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。
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.
8.16
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
Materials to be reprocessed or reworked
should be appropriately controlled to prevent
unauthorized use.
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 Time Limits
8.2
时限
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.
8.20
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
Intermediates held for further
processing should be stored under appropriate
conditions to ensure their suitability for use.
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 In-process
Sampling and Controls
8.3
工序间的取样和控制
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.
8.30
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
The acceptance criteria and type and
extent of testing can depend on the nature of
theintermediate 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 appropriate in early processing
steps, whereas tighter controls may be appropriate
for
later processing steps (e.g.,
isolation and purification steps).
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）。
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).
8.32
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
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.
8.33
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
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.
8.34
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
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.
8.35
< br>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
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.
8.36
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
情况不需要调查。
8.4 Blending
Batches of Intermediates or APIs
8.4
中间体或原料药的混批
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
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.
8.40
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，看作是生产工艺的一部分，而不是混合。
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.
8.41
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
Acceptable blending
operations include,but are not limited to:
●
Blending of
small batches to increase batchsize
●
Blending of
tailings (i.e., relatively small quantities of
isolated material) from
batches of the
same intermediate or API to form a single batch
8.42
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
Blending processes
should be adequately controlled and documented,
and the blended batch should be tested for
conformance
to established
specifications, where appropriate.
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。
8.44
The
batch record of the blending process should allow
traceability back to the individual batches that
make up the blend.
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。
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.
8.45
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
If the blending could
adversely affect stability, stability testing of
the final blended batches should be performed.
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。
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.
8.47
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 Contamination Control
8.5
污染控制
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.
8.50
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
Production operations
should be conducted in a manner that prevents
contamination of intermediates or APIs by other
materials.
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
Precautions to avoid
contamination should be taken when APIs are
handled after purification.
8.52
处理精制后的原料药应当采取预防污染的措施。
9. PACKAGING AND IDENTIFICATION
LABELING OF APIs AND INTERMEDIATES
9.
原料药和中间体的包装和贴签
9.1
General
9.1
总则
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.
9.10
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
/
< br>或测试、放行和搬运。
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
operations for which they are unsuitable.