毛衣针ICH中英文对照版本

2021年1月27日发(作者：gang)

.

人用药物注册技术要求国际协调会议

( I C H

：

International Conference

on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use)

ICH

三方协调指南

原料药的优良制造规范（

GMP

）指南

ICH

指导委员会

2000

年

11

月

10

日按

ICH

规程第

4

步建议采用

本指南根据

ICH

< br>规程由合适的

ICH

专家工作组起草并经向法规部门咨询 。

在规程的第

4

步，建议欧洲共同体、 日本和美国的药政部门采用其最终的草

案。

原料药 的优良制造规范（

GMP

）指南

ICH

三方协调指南

ICH

指导委员会

< br>2000

年

11

月

10

日的会议按

ICH

规程 第

4

步

Word

资料

.

建议

I CH

的三个药政部门采用本指南

目

录

1

引言

INTRODUCTION

.. .................................................. .................................................. ....................................... 6

1.1

目的

Objective < /p>

........................................ .................................................. .................................................. 6

1.2

法规的适用性

Regulatory Applicability

... .................................................. ............................................... 7

1.3

范围

Range

.

.......... .................................................. .................................................. .................................. 7

2

质量管理

QUALITY MANAGEMENT

............................ .................................................. ........................................ 9

2.1

原则

Principles ............................ .................................................. .................................................. ............ 9

2.2

质量部门的职责

Responsibilities of the Quality Unit(s) .................................................. ........................ 10

2.3

生产作业的职责

Responsibility for Production Activities

............................ ........................................... 12

2.4

内部审计（自检）

Internal Audits (Self Inspection)

< p>
.

................................ .............................................. 13

2.5

产品质量审核

Product Quality Review

.

........................................... .................................................. ..... 13

3

人员

PERSONNEL ............................. .................................................. .................................................. ............... 14

3.1

员工的资质

Personnel qualifications ................................... .................................................. ................. 14

3.2

员工的卫生

Personnel Hygiene .......................................... .................................................. ................... 14

3.3

顾问

Consultants

......................................... .................................................. ........................................... 15

4

建筑和设施

BUILDINGS AND FACILITIES

.

......................................... .................................................. ................. 15

4.1

设计和结构

Design and Construction ..................................... .................................................. ............. 15

4.2

公用设施

Utilities

.

............................. .................................................. .................................................. ...... 16

4.3

水

Water ................................. .................................................. .................................................. .............. 17

4.4

限制

Containment

......................................... .................................................. ........................................ 18

4.5

照明

Lighting

.

....... .................................................. .................................................. ................................. 18

4.6

排污和垃圾

Sewage and Refuse ..................... .................................................. ..................................... 18

4.7

清洁和保养

Sanitation and Maintenance

.

....................................... .................................................. ... 19

5

工艺设备

PROCESS EQUIPMENT ..................... .................................................. ................................................. 19

5.1

设计和结构

Design and Construction ............... .................................................. ................................... 19

5.2

设备保养和清洁

Equipment Maintenance and Cleaning

........................................... ........................ 20

5.3

校验

Calibration

......................................... .................................................. ............................................ 21

Word

资料

.

5.4

计算机控制系统

Computerized Systems .................. .................................................. ............................ 22

6

文件和记录

DOCUMENTATION AND RECORDS ............. .................................................. ................................ 23

6.1

文件系统和规格

Documentation System and Specifications

.

........................... .................................. 23

6.2

设备的清洁和使用记录

Equipment Cleaning and Use Record

........................ ..................................... 24

6.3

原料、中间体、原料药的标签和包装材料的记录

Records

of

Materials

,

Intermediates,

API

Labeling

and Packaging Materials ........................................ .................................................. .................................... 25

6.4

生产工艺规程

Master Production Instructions .......................... .................................................. ............ 25

6.5

批生产记录

Batch Production Records

.

................... .................................................. ............................. 26

6.6

实验室控制记录

Laboratory Control Records

.

....................................... ................................................ 27

6.7

批生产记录审核

Batch Production Record Review ........ .................................................. .................... 28

7

物料管理

MATERIALS MANAGEMENT

.

................ .................................................. ............................................. 29

7.1

控制通则

General Controls ......................................... .................................................. ........................... 29

7.2

接收和待验

Receipt and Quarantine ....................................... .................................................. ........... 30

7.3

进厂物料的取样和测试

Sampling and Testing of Incoming Production Materials

............................. 30

7.4

储存

Storage

.

........ .................................................. .................................................. ................................ 32

7.5

重新评估

Re- evaluation ....................................... .................................................. ................................. 32

8

生产和中间控制

PRODUCTION AND IN-PROCESS CONTROLS

.

............................... ........................................ 32

8.1

生产操作

Production Operations ................. .................................................. ........................................ 32

8.2

时间限制

Time Limits

................ .................................................. .................................................. ............. 33

8.3

工序间的取样和控制

In- process Sampling and Controls .................... .................................................. 34

8.4

中间体或原料药的混合

Blending Batches of Intermediates or APIs

.

...................... .............................. 35

8.5

污染的控制

Contamination Control

.

< p>
............................................ .................................................. ........ 36

9

原< /p>

料

药

和

中

间

体

的

包

< p>
装

和

贴

签

PACKAGING

AND

IDENTIFICATION

LABELING

OF

APIs

AND

INTERMEDIATES

.

..................................... .................................................. .................................................. .............. 36

9.1

总则

General

............................................. .................................................. ............................................. 36

9.2

包装材料

Packaging Materials ................... .................................................. .......................................... 37

9.3

标签的发放和控制

Labeling Issuance and Control ......... .................................................. .................... 37

9.4

包装和贴签操作

Packaging and Labeling Operations .......................... .............................................. 38

10

储存和分发

STORAGE AND DISTRIBUTION

.

......................................... .................................................. ........... 39

10.1

入库程序

Warehousing Procedures ....................................... .................................................. ............ 39

10.2

分发程序

Distribution Procedures ....................................... .................................................. ................ 39

Word

资料

.

11

实验室控制

LABORATORY CONTROLS

.............................. .................................................. ............................ 40

11.1

控制通则

General Controls ......................................... .................................................. ........................ 40

11.2

中间体和原料药的测试

Testing of Intermediates and APIs ..... .................................................. .......... 41

11.3

分析程序的验证－参 见

12

章

Validation of Analytical Procedures - See Section 12. (11.3)............ 42

11.4

分析报告单

Certificates of Analysis .............. .................................................. ...................................... 42

11.5

原料药的稳定性监测

Stability Monitorint of APIs........... .................................................. ...................... 43

11.6

有效期和复验日期

Expiry and Retest Dating

..................... .................................................. ................. 44

11.7

留样

Reserve/Retention Samples ............. .................................................. ......................................... 45

12

验证

VALIDATION ............................ .................................................. .................................................. ............. 45

12.1

验证方针

Validation Policy

.

.................... .................................................. ............................................. 45

12.2

验证文件

Validation Documentation .............. .................................................. .................................. 46

12.3

确认

Qualification

.

.. .................................................. .................................................. ........................... 46

12.4

工艺验证的方法

Approaches to Process Validation

.

................................. ......................................... 47

12.5

工艺验证的程序

Process Validation Program ............ .................................................. ........................ 48

12.7

清洗验证

Cleaning Validation

.

............................... .................................................. ............................. 49

12.8

分析方法的验证

Validation of Analytical Methods

.

................................. ........................................... 51

13

变更的控制

CHANGE CONTROL ........................ .................................................. ........................................... 51

14

物料的拒收和再用

REJECTION AND RE-USE OF MATERIALS

< p>
.

................................ .......................................... 52

14.1

拒收

Rejection

.

...... .................................................. .................................................. ............................. 52

14.2

返工

Reprocessing < /p>

........................................ .................................................. ....................................... 53

14.3

重新加工

Reworking

.

...... .................................................. .................................................. .................... 53

14.4

物料和溶剂的回收

Recovery of Materials and Solvents ........................ ............................................. 54

14.5

退货

Returns

.

........ .................................................. .................................................. ............................... 54

15

投诉和召回

COMPLAINTS AND RECALLS

........................... .................................................. ........................... 55

16

< p>
协议制造商

(

包括实验室

) CONTRACT MANUFACTURES (INCLUDING LABORATORIES) ................................ 56

17

代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者

.................................................. ....................... 57

AGENTS,BROKERS, TRADERS,DISTRIBUTORS,REPACKERS ,AND RELABELLERS

......................................... ........... 57

17.1

适用性

Applicability

....................................... .................................................. ...................................... 57

17.2

已分发原料药的可追溯性

Traceability of Distributed APIs and Intermediates

.................................. 57

17.3

质量管理

Quality Management .................... .................................................. ..................................... 57

17.4

原料药和中间体的重新包装、重新贴签和待检

Repackaging,Relabeling,and

Holding

of

APIs

and

Word

资料

.

Intermediates. ........................ .................................................. .................................................. ..................... 58

17.5

稳定性

Stability ... .................................................. .................................................. ................................ 58

17.6

信息的传达

Transfer of Information

.

.......................................... .................................................. .......... 58

17.7

投诉和召回的处理

Handing of Complaints and Recalls

.

. .................................................. ................. 59

17.8

退货的处理

Handing of Returns .......................................... .................................................. ................ 59

18

用细胞繁殖

/

发酵生产的原料药的特殊指南

.

............................. .................................................. ......................... 59

SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION ..................................... 59

18.1

总则

General

.................... .................................................. .................................................. .................. 59

18.2

细胞库的维护和记录的保存

Cell Bank Maintenance and Record Keeping

...................................... 62

18.3

细胞繁殖

/

发酵

Cell Culture/Fermentation

.

...... .................................................. .................................. 62

18.4

收取、分离和精制

Harvesting, Isolation and Purifation .. .................................................. .................. 63

18.5

病 毒的去除

/

灭活步骤

Viral Removal/Inactivation Steps ...... .................................................. ............ 64

19

用于临床研究的原料药

(APIS FOR USE IN CLINICAL TRIALS)

........... .................................................. .............. 65

19.1

总则

General

............................................. .................................................. ........................................... 65

19.2

质量

quality

.

........ .................................................. .................................................. ................................ 65

19.3

设备和设施

Equipment and Facilities

.

......................................... .................................................. ....... 66

19.4

原料的控制

Control of Raw Materials

.

............. .................................................. ................................... 66

19.5

生产

Production ............................ .................................................. .................................................. ..... 66

19.6

验证

Validation ............... .................................................. .................................................. .................... 67

19.7

变更

Changes ...... .................................................. .................................................. .............................. 67

19.8

实验室控制

Laboratory Controls

.

.................. .................................................. ...................................... 67

19.9

文件

Documentation ............ .................................................. .................................................. ............. 67

20.

术语表

（

G LOOSSARY

）

....... .................................................. .................................................. ...................... 68

Word

资料

.

原料药的优良制造规范

(GMP)

指南

Guidance for Industry

Q7A Good Manufacturing Practice Guidance

for Active Pharmaceutical Ingredients

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It

does

not

create

or

confer

any

rights

for

or

on

any

person

and

does

not

operate

to

bind

FDA

or

the

public.

An

alternative

approach

may

be

used

if

such

approach

satisfies

the

requirements

of

the

applicable statutes and regulations.

1

引言

INTRODUCTION

1.1

目的

Objective

< p>
本文件

(

指南

)

旨在为在合适的质量管理体系下制造活性药用成分

(

原料药以下称原料药

)

提供有关优良药品生产

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。

(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。在本 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

< br>“优良生产管理规范(GMP)”是等同的。

(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

statutes. For the purposes of this guidance, the terms

current good manufacturing practices

and

good

manufacturing practices

are equivalent.)

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。

(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.) < /p>

本指南没打算规定注册

/

归挡的要求、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

Word

资料

.

授权 或药品申请方面建立特定注册

/

归挡要求的能力。注册

/

归挡的所有承诺必须做到。

(This

guidance

is

not

intended to define registration and/or filing requirements or modify pharmacopoeias 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

法规的适用性

Regulatory Applicability

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。

(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

范围

Range

本文件适用于人用药品（ 医疗用品）所含原料药的制造。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。

本文件适用 于通过化学合成、

提取、

细胞培养

/< /p>

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

/

< br>发酵生产的原料药的特殊指南则在第

18

章论述。

(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

guidance 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 described in Section XVIII (18).)

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。值得注意的是细胞酶解物

(

哺乳动物、植物、昆虫或微生物的细胞、组织

或动物来源物，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、散装药品< /p>

(

医疗用品

)

， 和放射性药物的特殊的制造

/

控制。

(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.)

Word

资料

.

第

19

章 的指南只适用于用在药品

(

医疗产品

)

生产中的原料药制造，特别是临床实验用药

(

< br>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。

(Section XIX (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.)

生产厂商要定义并用书面文 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< /p>

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。

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.

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。

本文件的指南通常适用于表

1

中的灰色步骤。这并不意味必需完成所有步骤。原料药生产中的

< br>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。原料药的物料加工，如制粒、包衣或颗粒

度的物理处 理

(

例如制粉、微粉化

)

至少应当按本指南的标准进行。

(From

this

point

on,

appropriate

GMP

as

defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This

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 step as critical. The guidance in this document would normally be applied to the

steps shown in gray in Table 1. However, all steps shown may not need to 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

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。

(This

GMP

guidance

does

not

apply to steps prior to the introduction of the defined API starting material.)

Word

资料

.

2

质量管理

QUALITY MANAGEMENT

2.1

原则

Principles

2.1.0

参与原料药制造的每一个人都应当对质量负责。

Quality

should

be

the

responsibility

of

all

persons

involved in manufacturing.

2.1.1

每家制造商都应当建立、证明其有，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。

(Each

manufacturer

should

establish,

document,

and

implement

an

effective

system

for

managing

quality

that

involves

the

active

participation

of

management

and

appropriate

manufacturing personnel.)

2.1.2

质量管理体系应当包括 组织结构、程序、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，并有文件证明。

(The system for managing quality

should encompass the organizational structure, procedures, processes 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. )

2.1.3

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。

依照组织结构的

< p>
大小，可以是分开的

QA

和

QC

部门，或者只是一个人或组。

(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.)

2.1.4

应当指定授权发放中间体和原料药的人员。

The persons authorized to release intermediates and APIs

should be specified.

2.1.5

所有有关质量的活动应当在其执行时就记录。

All

quality-related

activities

should

be

recorded

at

the

time they are performed.

2.1.6

任何偏离确定程序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。

Any

deviation

from

established

procedures

should

be

documented

and

explained.

Critical

deviations

should

be

investigated,

and

the

investigation

and

its

conclusions

should

be

documented.

2.1.7

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

)

。

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

X

(10)

or

the

use

of

raw

materials

or

intermediates

pending

completion

of

evaluation).

Word

资料

.

2.1.8

应当有程序能确保公 司的责任管理人员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

)

< br>的通知。

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).

2.2

质量部门的职责

Responsibilities of the Quality Unit(s)

2.2.0

质量部门应当参与所有与质量有关的事务。

The quality unit(s) should be involved in all quality-related

matters.

2.2.1

所有与质量有关的文件应当由质量部门审核批准。

The

quality

unit(s)

should

review

and

approve

all

appropriate quality-related documents.

2.2.2

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：

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.

所有原料药的放行和否决。< /p>

用于制造商控制范围以外的中间体的放行和否决；

Releasi ng or rejecting all APIs.

Releasing or rejecting intermediates for use outside the control of the manufacturing company

2.

建立一个放行或拒收原材料、

中间体、

包装材料和标签的系统；

Establishing a system to release or reject

raw materials, intermediates, packaging, and labeling materials

3.

在供分发的原料药放行前，

审核已完成的关键步骤的批生产记录和实 验室控制记录；

Reviewing completed

batch production and laboratory control records of critical process steps before release of the API

for distribution

4.

确保已经对重大的偏差进行了调查，并已解决；

Making sure that critical deviations are investigated and

resolved

5.

批准所有的规格标准和主生产规程；

Approving all specifications and master production instructions

6.

批准所有可能影响原料药或中间体质量的程序；

Approving

all

procedures

affecting

the

quality

of

intermediates or APIs

7.

确保进行内部审计

(

自查

)

；

Making sure that internal audits (self-inspections) are performed

8.

批准中间体和原料药的委托生产商；

Approving intermediate and API contract manufacturers

9.

批准可能影响到中间体或原料药质量的变更；

Approving changes that potentially affect intermediate

or API quality

10.

审核并批准验证方案和报告；

Reviewing and approving validation protocols and reports

11.

确保调查并解决质量问题的投诉；

Making sure that quality-related complaints are investigated and

resolved

12.

确保用有效的体系来维修和校验关键设备；

Making sure that effective systems are used for maintaining

Word

资料

.

and calibrating critical equipment

表

1

：

本指南在原料药生产中的应用

4

Table 1: Application of this Guidance to API Manufacturing

生

产

类

型

Type of

Manufacturing

化学品的生产

Chemical

Manufacturing

本指南在用于各类生产的工艺步 骤

(

灰色背景

)

中的应用

Application of this guidance to steps (shown in gray) used in this type of manufacturing

原料药起始物料引

原料药起始物料

物理加工和包

入工艺过程

< p>
的生产

中间体的生产

分离和精制

装

Physical

Introduction of

Production of

Production of

Isolation and

processing,

the API starting

the API starting

Intermediate(s)

purification

and

material into

material

packaging

process

器官、

分泌物或组< /p>

原料药起始物料引入

物理加工和包

切割、 混合和

/

或初

织的收集

工艺过程

分离和精制

装

Physical

步加工

Cutting,

Collection of

Introduction of the

Isolation and

processing,

mixing, and/or

organ, fluid, or

API starting material

purification

and

initial processing

tissue

into process

packaging

植物的收集

Collection of

plant

切割和初步提取

Cutting and initial

extraction(s)

原料药起始物料引入

< p>
工艺过程

Introduction of the

API starting material

into process

分离和精制

Isolation and

purification

物理加工和包

装

Physical

processing,

and

packaging

物理加工和包

装

Physical

processing,

and

packaging

物理加工和包

装

Physical

processing,

and

packaging

物理加工和包

装

Physical

processing,

and

packaging

从动物源得到的原

料药

API derived from

animal sources

从植物源提取的原

料药

API extracted

from plant

sources

草药提取物用作原

料药

Herbal extracts

used as API

由粉碎的或粉末状

药草组成的原料药

API consisting of

comminuted or

powdered herbs

生物技术：发酵

/

细

胞培养

Biot echnology:

Fermentation /

cell culture

植物的收集

Collection of

plants

植物的收集和

/

或

培养和收获

Collection of

plants and/or

cultivation and

harvesting

主细胞库和工作

细胞库的建立

Establishment of

master cell

bank and

working cell

bank

切割和初步提取

Cutting and initial

extraction

进一步提取

Further

extraction

切割

/

粉碎

Cutting/

comminuting

工作细胞库的维护

Maintenance of

working cell bank

细胞培养和

< p>
/

或发酵

Cell culture and/or

fermentation

分离和精制

Isolation and

purification

Word

资料

.

“经典”发酵生产

原料药

Fermentation to

produce an API

细胞库的建立

Establishment of

cell bank

细胞库的维护

Maintenance of

the cell bank

细胞引入发酵

Introduction of the

cells into

fermentation

分离和精制

Isolation and

purification

物理加工和包

装

Physical

processing,

and

packaging

13.

确保物料都经过了适当的检测并报告结果；

Making sure that materials are appropriately tested and the

results are reported

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；

Making

sure

that

there

is

stability

data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where

appropriate

15.

开 展产品质量审核

(

详见

2.5

节

)

；

Performing product quality reviews (as defined in Section 2.5)

2.3

生产作业的职责

Responsibility for Production Activities

生产作业的责任应当以文字形式加以说明，并应当包括，但不限 于以下内容：

The

responsibility

for

production

activities

should

be

described

in

writing

and

should

include,

but

not

necessarily

be

limited to:

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规程

;

Preparing,

reviewing,

approving,

and

distributing

the

instructions

for

the

production

of

intermediates

or

APIs

according

to

written

procedures

2.

按照已批准的生产规程生产原料药，或者中间体

;

Producing

APIs

and,

when

appropriate,

intermediates

according to pre-approved instructions

3.

审核所有的批生产记录确保其填写完整，

有签名

; Reviewing all production batch records and ensuring that

these are completed and signed

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；

Making sure that all production deviations are reported and evaluated and that critical deviations

are investigated and the conclusions are recorded

5.

确保生产设施的清洁，必要时要消毒；

Making sure that production facilities are clean and, when appropriate, disinfected

6.

确保进行必要的校验，并有记录；

Making sure that the necessary calibrations are performed and records kept

Word

资料

.

7.

确保对厂房和设备进行保养，并有记录；

Making sure that the premises and equipment are maintained and records kept

8.

确保验证计划、方案和报告的审核和批准；

Making sure that validation protocols and reports are reviewed and approved

9.

对产品、工艺或设备拟作的变更进行评估；

Evaluating

proposed

changes

in

product,

process

or

equipment

10.

确保新的或是有变动的生产设施和设备经过了确认。

Making sure that new and, when appropriate,

modified facilities and equipment are qualified

2.4

内部审计（自检）

Internal Audits (Self Inspection)

2.4.0

< br>为证实符合原料药

GMP

原则，应当按照批准的计划进行 定期的内部审计。

To verify compliance with the

principles

of

GMP

for

APIs,

regular

internal

audits

should

be

performed

in

accordance

with

an

approved schedule.

2.4.1

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。

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

产品质量审核

Product Quality Review

2.5.0

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：

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:

-

关键工艺控制和原料药关键测试结果的审核；

A review of critical in-process control and critical API test

results

-

所有不符合规格标准的产品批号的审核；

A

review

of

all

batches

that

failed

to

meet

established

specification(s)

-

所有关键的偏差或违规行为及有关调查的审核；

A

review

of

all

critical

deviations

or

nonconformances

and related investigations

-

任何工艺或分析方法变动的审核；

A review of any changes carried out to the processes or analytical

methods;

-

稳定性监测结果的审核；

A review of results of the stability monitoring program

-

所有与质量有关的退货、投诉和召回的审核；

A

review

of

all

quality-related

returns,

complaints

and

recalls

Word

资料

.

-

整改措施的适当性的审核；

A review of adequacy of corrective actions

2.5.1

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。此类纠正措施的理由应当用文

件来证明。获准的整改措施应当 及时、有效地完成。

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

人员

PERSONNEL

3.1

员工的资质

Personnel qualifications

3.1.0

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

/< /p>

或经历等资格。

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.

3.1.1

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。

The responsibilities of all personnel engaged

in the manufacture of intermediates and APIs should be specified in writing.

3.1.2

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。

T raining

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

员工的卫生

Personnel Hygiene

3.2.0

员工应当养成良好的卫生和健康习惯。

Personnel should practice good sanitation and health habits.

3.2.1

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。

< br>

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.

3.2.2

员工应当避免与中间体或原料药的直接接触。

Personnel should avoid direct contact with intermediates

or APIs.

3.2.3

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。

Smoking, eating, drinking, chewing and

the

storage

of

food

should

be

restricted

to

certain

designated

areas

separate

from

the

manufacturing areas

Word

资料

.

3.2.4

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

< br>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。

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 where the health 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

顾问

Consultants

3.3.0

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 。

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.

3.3.1

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。

Records should be maintained stating the

name, address, qualifications, and type of service provided by these consultants.

4

建筑和设施

BUILDINGS AND FACILITIES

4.1

设计和结构

Design and Construction

4.1.0

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。

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.

4.1.1

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。

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.

4.1.2

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。

Buildings

and

facilities

should have adequate space for the orderly placement of equipment and materials to prevent

mix-ups

and

< br>contamination.

工

Where

the

equipment

itself

(e.g.,

closed

or

contained

systems)

provides adequate protection of the material, such equipment can be located outdoors.

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.

4.1.3

通过厂房和设施的物流和人流的设计应当能防止混杂或污染。

The

flow

of

materials

and

personnel

through the building or facilities should be designed to prevent mix-ups or contamination.

4.1.4

以下活动应当有指定区域或其它控制系统：

There should be defined areas or other control systems for

the following activities:

-

来料的接收、鉴别、取样和待检，等待放行或拒收

;

Receipt,

identification,

sampling,

and

quarantine

of

incoming materials, pending release or rejection

-

中间体和原料药放行或拒收前的待验；

Quarantine before release or rejection of intermediates and APIs

-

中间体和原料药的取样；

Sampling of intermediates and APIs

-

不合格物料处理

(

如退货，返工或销毁

)

前的贮存；

Holding

rejected

materials

before

further

disposition

(e.g., return, reprocessing or destruction)

-

已放行物料的贮存；

Storage of released materials

-

生产操作

Production operations

-

包装及贴签签操作；

Packaging and labeling operations

-

实验室操作。

Laboratory operations

4.1.5

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< /p>

)

、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。

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.

4.1.6

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>

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

公用设施

Utilities

4.2.0 < /p>

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。

All utilities that could affect

product

quality

(e.g.,

steam,

gas,

compressed

air,

heating,

ventilation,

and

air

conditioning)

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资料

.

should

be

qualified

and

appropriately

monitored

and

action

should

be

taken

when

limits

are

exceeded. Drawings for these utility systems should be available.

4.2.1

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、< /p>

微生物

(

如果适用

)

、

灰尘、

湿度和温度的设备。

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 given to areas where APIs are exposed to the environment.

4.2.2

< p>
如果空气再循环到生产区域，应当采取适当的措施控制污染和交叉污染的风险。

If

air

is

recirculated

to

production

areas,

appropriate

measures

should

be

taken

to

control

risks

of

contamination

and

cross-contamination.

4.2.3

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。

Permanently installed pipework should

be

appropriately

identified.

This

can

be

accomplished

by

identifying

individual

lines,

documentation, computer control systems, or alternative means. Pipework should be located to

avoid risks of contamination of the intermediate or API.

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。

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

水

Water

4.3.0

原料药生产中使用的水应当证明适合于其预定的用途。

Water used in the manufacture of APIs should be

demonstrated to be suitable for its intended use.

4.3.1

除非有其它理由，工艺用水最低限度应当符合国际卫生组织

(W HO)

的饮用水质量指南。

Unless

otherwise

justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines

for drinking (potable) water quality.

4.3.2

如果饮用水不足以确保原料药 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 当制定合适的物

理

/

化学特性、微生物 总数、控制菌和

/

或内毒素的规格标准。

If drinking (potable) 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.

4.3.3

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。

Where water used in the process is treated by the manufacturer to achieve a defined quality, the

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.

treatment process should be validated and monitored with appropriate action limits.

4.3.4

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。

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

限制

Containment

4.4.0

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。

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 cephalosporins.

4.4.1

当涉及具有感染性、高药理活性或毒性的物料时， 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。

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.

4.4.2

< p>
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。

Appropriate

measures

should

be

established

and

implemented

to

prevent

cross- contamination

from

personnel and materials moving from one dedicated area to another.

4.4.3

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。

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

照明

Lighting

4.5.0

所有区域都应当提供充足的照明，

以便于清洗、

保养或其他操作。

Adequate lighting should be provided

in all areas to facilitate cleaning, maintenance, and proper operations.

4.6

排污和垃圾

Sewage and Refuse

4.6.0

进入和流 出厂房及邻近区域的污水、垃圾和其他废物

(

如生产中的固态、 液态或气态的副产物

)

，应当安全、及

时、卫生地处理。废物的容器和

/

或管道应当显著地标明。

Sewage, refuse, and other waste (e.g., solids,

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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

清洁和保养

Sanitation and Maintenance

4.7.0

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。

Buildings

used

in

the

manufacture

of

intermediates

and

APIs

should

be

properly

maintained

and

repaired

and

kept

in

a

clean

condition.

4.7.1

应当制订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。

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.

4.7.2

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订书面程序，以避免对

设备、

原料、包装

/

标签、

中间体和原料药的污染。

When necessary,

written procedures should also 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.

5

工艺设备

PROCESS EQUIPMENT

5.1

设计和结构

Design and Construction

5.1.0

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。

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.

5.1.1

设备的构造中与原料 、中间体或原料药接触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它

已 规定的规格标准。

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.

5.1.2

< p>
生产设备应当只在确认的操作范围内运行。

Production

equipment

should

only

be

used

within

its

qualified operating range.

5.1.3

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。

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.

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.

5.1.4

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。

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.

5.1.5

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。

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.

5.1.6

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>。

A

set

of

current

drawings

should

be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

5.2

设备保养和清洁

Equipment Maintenance and Cleaning

5.2.0

应当制订设备预防性保养的计划和程序

< p>
(

包括职责的分配

)

。< /p>

Schedules

and

procedures

(including

assignment

of

responsibility)

should

be

established

for

the

preventative

maintenance

of

equipment.

5.2.1

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

设备进行可重新的、有效的清洗 。这些程序应当包括：

Written

procedures

should

be

established

for

cleaning equipment and its subsequent 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:

－

设备清洗职责分配；

Assignment of responsibility for cleaning of equipment

－

清洗计划，必要时包括消毒计划；

Cleaning

schedules,

including,

where

appropriate,

sanitizing

schedules

－

< p>
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；

·

A

complete

description

of

the

methods and materials, including dilution of cleaning agents used to clean equipment

－

为确保正确地清洗，

根据具体情况还应当包括包装设备拆卸和安装的方法；

< p>

When appropriate, instructions

for disassembling and reassembling each article of equipment to ensure proper cleaning

－

拿走或抹掉上一批的标识；

Instructions for the removal or obliteration of previous batch identification

－

使

用

前

防

止

已

清

洁

的

设

备

被

污

染

< br>；

Instructions

for

the

protection

of

clean

equipment

from

contamination prior to use

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资料

.

－

如果可行，

使用前对设备进行检查；

Inspection of equipment for cleanliness immediately before use, if

practical

－

根据情况，规定生产结束和清洗之间允许的最大时间间隔。

Establishing

the

maximum

time

that

may

elapse between the completion of processing and equipment cleaning, when appropriate

5.2.2

设备和用具 应当清洁、存放，必要时还应进行消毒或灭菌，以防止污染或遗留物质影响中间体或原料药的质

< br>量导致其不符合法定的或其它已规定的规格标准。

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.

5.2.3

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，应当在适宜的时间间隔对设备进

行清洗，

以防污染物

（如降解物或达到有害程度的微生物）

的积累和夹 带。

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).

5.2.4

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。

Nondedicated

equipment

should

be

cleaned between production of different materials to prevent cross-contamination.

5.2.5

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。

Acceptance criteria for residues

and the choice of cleaning procedures and cleaning agents should be defined and justified.

5.2.6

设备内容物及其清洁状况应当用合适的方法标明。

Equipment should be identified as to its contents and

its cleanliness status by appropriate means.

5.3

校验

Calibration

5.3.0

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。

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.

5.3.1

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。

Equipment

calibrations

should

be

performed using standards traceable to certified standards, if they exist.

5.3.2

校验记录应当加以保存。

Records of these calibrations should be maintained.

5.3.3

应当知道并可证实关键设备的当前校验状态。

The

current

calibration

status

of

critical

equipment

should be known and verifiable.

5.3.4

不应当使用不符合校验标准的仪器。

Instruments

that

do

not

meet

calibration

criteria

should

not

be

used.

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.

5.3.5

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。

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

intermediate(s)

or

API(s)

manufactured

using

this

equipment

since

the

last

successful

calibration.

5.4

计算机控制系统

Computerized Systems

5.4.0

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。

GMP-related

computerized

systems

should

be

validated.

The

depth

and

scope

of

validation

depends on the diversity, complexity, and criticality of the computerized application.

5.4.1

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。

Appropriate installation

and

operational

qualifications

should

demonstrate

the

suitability

of

computer

hardware

and

software to perform assigned tasks.

5.4.2

经证明合格的 商用软件不需要进行相同水平的检验。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。

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.

5.4.3

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。

任何数据的更改、

上一次输入、

谁作的 更改和什么时候更改都应当有记录。

Computerized

systems 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.

5.4.4

应当有计算机化系统操作和维护的书面程序。

Written procedures should be available for the operation

and maintenance of computerized systems.

5.4.5

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。

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.

5.4.6

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偶发事件，并 作调查。

11

Incidents related to computerized systems that could affect the quality of intermediates or APIs or

the reliability of records or test results should be recorded and investigated.

5.4.7

对计算机化系统所做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。

Changes

to

computerized

systems

should

be

made

according

to

a

change

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.

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.

5.4.8

如果系统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。

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 systems.

5.4.9

除计算机系统之外，数据可以用第二种方式记录。

Data

can

be

recorded

by

a

second

means

in

addition to the computer system.

6

文件和记录

DOCUMENTATION AND RECORDS

6.1

文件系统和规格

Documentation System and Specifications

6.1.0

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。

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.

6.1.1

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。

The issuance, revision, superseding,

and withdrawal of all documents should be controlled by maintaining revision histories.

6.1.2 < /p>

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、

< p>
控制记录和分发记录

)

的程序。

< br>应当规定这些文件的保存期。

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.

6.1.3

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。

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.

6.1.4

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。

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.

6.1.5

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

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.

即时恢复的记录也可以接受。

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.

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.

6.1.6

质量规格、指导书、程序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。

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.

6.1.7

应当制订原料、中间体

(

必要时

)

、原料药和标签及包装材料的 规格。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 量的物料制订规格。

中间控制应当制定可接受的保证，

并成文备 查。

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 documented for in-process controls.

6.1.8

如果文件采用电子签名，

它们应当经过证实，

并且安全。

If electronic signatures are used on documents,

they should be authenticated and secure.

6.2

设备的清洁和使用记录

Equipment Cleaning and Use Record

6.2.0

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。

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.

6.2.1

如果设备专用于一种 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踪性的顺序，那就不需要

有 单独的设备记录。专用设备的清洁、保养及使用记录可以作为批记录的一部分或单独保存。

If

equipment

is

dedicated

to

manufacturing

one

intermediate

or

API,

individual

equipment

records are not necessary if batches of the intermediate or API follow in traceable sequence. In

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.

cases where dedicated equipment is employed, the records of cleaning, maintenance, and use

can be part of the batch record or maintained separately.

6.3

原料、中间体、原料药的标签和包装材料的记录

Records of Materials , Intermediates, API Labeling and

Packaging Materials

6.3.0

需保存的文字记录应当包括：

Records should be maintained including:

-

制造 商名称，每批原料、中间体或原料药标签和包装材料的每次到货的标识和数量；供应商名称；供货者的

< p>
管理编号，

如果知道的话，

或其它识别号码；

接收号；

接收日期；

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

-

所进行的任何测试或检查结果，以及由此得出的结论；

The

results

of

any

test or

examination

performed

and the conclusions derived from this

-

跟踪物料使用的记录；· Records tracing the use of 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；

Documentation

of

the

examination

and review of API labeling and packaging materials for conformity with established specifications

-

拒收原料、中间体或原料药的标签和包装材料的最终决定。

The

final

decision

regarding

rejected

raw

materials, intermediates, or API labeling and packaging materials

6.3.1

标准标签

(

批准的

)

应当保留，

用来与发放的标签作比较。

< br>Master (approved) labels should be maintained

for comparison to issued labels.

6.4

生产工艺规程

Master Production Instructions

(

主生产和控制记录

) (Master Production and Control Records)

6.4.0

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。

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).

6.4.1

生产工艺规程应当包括：

Master production instructions should include:

－

< p>
要生产的中间体或原料药的名称，

如有可能，

写明 文件编号；

The name of the intermediate or API being

manufactured and an identifying document reference code, if applicable

－

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；

A complete list of raw materials and

intermediates

designated

by

names

or

codes

sufficiently

specific

to

identify

any

special

quality

characteristics

－

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；

An

accurate

statement

of

the

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.

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

－

生产地点及使用的主要设备；

The production location and major production equipment to be used

－

详细的生产规程，包括：

Detailed production instructions, including the:

-

操作顺序，

sequences to be followed

-

工艺参数的范围

ranges of process parameters to be used

-

取样指南，中间控制及其标准，

sampling instructions and in-process controls with their acceptance

criteria,

-

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，以及按工艺步骤或时间计算的预期 产率范围；

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

－

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；

Where

appropriate,

special

notations

and

precautions

to

be

followed,

or

cross-references

to

these

－

中间体 或原料药的适宜贮存规定，包括标签、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。

The

instructions

for

storage

of

the

intermediate

or

API

to

ensure

its

suitability

for

use,

including

the

labelling

and

packaging

materials

and

special

storage

conditions

with

time

limits,

where

appropriate.

6.5

批生产记录

Batch Production Records

批生产和控制记录

(Batch Production and Control Records)

6.5.0

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，应当检查版本是否正确，是否是相应生产工艺规程的准确明了的再现。如果批记录是按主文 件的另一

独立部分制定的，

该一文件应当包括对现行的生产工艺 规程的参考。

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.

6.5.1

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。

These records should be numbered with a unique

batch

or

identification

number,

dated

and

signed

when

issued.

In

continuous

production,

the

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.

product

code

together

with

the

date

and

time

can

serve

as

the

unique

identifier

until

the

final

number is allocated.

6.5.2

在批生产记录

(

批生产记录和控制记录

)

上提供每一重要步骤完成的证明应当包括：

Documentation

of

completion

of

each

significant

step

in

the

batch

production

records

(batch

production

and

control records) should include:

－

日期，某些情况下还有时间；

Dates and, when appropriate, times

－

主要设备

（如反应釜，

干燥器，

整粒机等）

的标 识；

Identity of major equipment (e.g., reactors, driers, mills,

etc.) used

－

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；

Specific

identification of each batch, including weights, measures, and batch numbers of raw materials,

intermediates, or any reprocessed materials used during manufacturing

－

记录关键工艺参数的实际值；

Actual results recorded for critical process parameters

－

取样；

Any sampling performed

－

每个关 键操作步骤的操作者和直接指导者或检查者的签名；

Signatures

of

the

persons

performing

and

directly supervising or checking each critical step in the operation

－

中间控制和化验室的测试结果；

In-process and laboratory test results

－

适当阶段或时间的实际产率；

Actual yield at appropriate phases or times

－

中间体或原料药的包 装材料和标签的描述；

Description of packaging and label for intermediate or API

－

原料药或中间体的商业标签的样张；

Representative label of API or intermediate if made commercially

available

－

< p>
发现的任何异常情况，

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；

Any deviation noted,

its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored

separately

－

放行测试的结果。

Results of release testing

6.5.3

应当建 立并执行一种书面程序，对在符合规格标准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他批号。

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.

6.6

实验室控制记录

Laboratory Control Records

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 查和测定：

Laboratory control records should include complete data derived from all tests

conducted

to

ensure

compliance

with

established

specifications

and

standards,

including

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.

examinations and assays, as follows:

－

所收到 检测样品的描述，包括物料名称或来源、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；

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

－

每个所用检测方法的陈述或参引；

A statement of or reference to each test method used

－

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照；< /p>

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

－

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；

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

－

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；

A

record

of

all

calculations

performed in connection with the test, including, for example, units of measure, conversion factors,

and equivalency factors

－

检测结果的陈述以及与规定的接受标准的比较；

A statement of the test results and how they compare

with established acceptance criteria

－

每项测试的操作者的签名以及测试的日期；

The signature of the person who performed each test and

the date(s) the tests were performed

－

< p>
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

14

已复核过。

The date and

signature of a second person showing that the original records have been reviewed for accuracy,

completeness, and compliance with established standards

6.6.1

应当保存完整的下列记录：

Complete records should also be maintained for:

－

规定的分析方法的任何修改；

Any modifications to an established analytical method

－

实验室仪器、设备、仪表和记录装置的周期性校验；

Periodic

calibration

of

laboratory

instruments,

apparatus, gauges, and recording devices

－

原料药的所有稳定性测试；

All stability testing performed on APIs

－

超标

(O OS)

的调查。

Out-of- specification (OOS) investigations

6.7

批生产记录审核

Batch Production Record Review

6.7.0

应当制订 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。

Written

procedures

should

be

established

and

followed

for

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.

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.

6.7.1

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他部门审核。

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).

6.7.2

在批放行前，

所有偏差，

调查和超标报告都应当作为批记录的一部分进行审核。

All deviation, investigation,

and

OOS

reports

should

be

reviewed

as

part

of

the

batch

record

review

before

the

batch

is

released.

6.7.3

质量部门可将发放中间体的职责和权力委派给生产 部门，

运往制造商控制范围以外的中间体除外。

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

物料管理

MATERIALS MANAGEMENT

7.1

控制通则

General Controls

7.1.0

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。

< p>

There should be written

procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing,

and approval or rejection of materials.

7.1.1

原料药和

/

或中间体制造商应当有对关键原料供应商的评估 系统。

Manufacturers of intermediates and/or

APIs should have a system for evaluating the suppliers of critical materials.

7.1.2

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。

aterials

should

be

purchased against an agreed specification, from a supplier, or suppliers, approved by the quality

unit(s).

7.1.3

如果 关键物料的供应商不是该物料的制造商，原料药或中间体的制造商应当获知该物料制造商的名称和地址。

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.

7.1.4

关键原料的供应商的变更应当参照第

13

章“变更控制”进行。

Changing the source of supply of critical raw materials should be treated according to Section 13,

Change Control.

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7.2

接收和待验

Receipt and Quarantine

7.2.0

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

料应当存放在待检区，直至它们被取 样、检查或酌情测试，并放行使用。

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.

7.2.1

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。

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.

7.2.2

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：

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:

-

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

7.2.3

大的贮存容器及其随附的管路、填充和排放管都应当适当标明。

Large

storage

containers

and

their

attendant manifolds, filling, and discharge lines should be appropriately identified.

7.2.4

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。

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.

7.3

进厂物料的取样和测试

Sampling and Testing of Incoming Production Materials

7.3.0 < /p>

除去

7.32

中指出的物料，

< p>
对于每批物料至少要作一个鉴别试验。

在制造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它项目的测试。

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

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manufacturer has a system in place to evaluate suppliers.

7.3.1

对供 应者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

)

证明该制造商始终都能提供符合规

格的物料。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< /p>

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。

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.

7.3.2

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可以不用测试，

前提是能取得制造商的分析报 告，证明这些原料符合规定的规格标准。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，并用文件作证。

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.

7.3.3

取样应当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。

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 quantity needed for analysis.

7.3.4

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。

Sampling should be

conducted

at

defined

locations

and

by

procedures

designed

to

prevent

contamination

of

the

material sampled and contamination of other materials.

7.3.5

被取样的容器应当小心开启，

随后重新密封。

< br>这些容器应当作标记表明样品已抽取。

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.

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7.4

储存

Storage

7.4.0

物料的搬运和贮存应当防止降解、污染和交叉污染。

Materials

should

be

handled

and

stored

in

a

manner to prevent degradation, contamination, and cross-contamination.

7.4.1

纤维板筒、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验。

Materials

stored

in

fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced

to permit cleaning and inspection.

7.4.2

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。

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.

7.4.3

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。

Certain materials in suitable containers can be stored outdoors, provided identifying labels

remain legible and containers are appropriately cleaned before opening and use.

7.4.4

不合格物料应当作标识，并用隔离系统控制，以防止未经许可而用于生产。

Rejected materials should be

identified and controlled under a quarantine system designed to prevent their unauthorized use in

manufacturing.

7.5

重新评估

Re- evaluation

7.5.0

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

)

。

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

生产和中间控制

PRODUCTION AND IN-PROCESS CONTROLS

8.1

生产操作

Production Operations

8.1.0

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。

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.

8.1.1

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接受该物料，并应当表明下列消息：

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:

-

物料的 名称和

/

或货号；

Material name and/or item code

-

接收号或控制号；

Receiving or control number

-

新容器中物料的重量或计量。

Weight or measure of material in the new container

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-

如有必要，表明复验期。

· Re

-evaluation or retest date if appropriate

8.1.2

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

< p>
的中间体或原料药的批记录中指定的。

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.

8.1.3

其他关键活动应当有人作证或接受相应的控制。

Other

critical

activities

should

be

witnessed

or

subjected to an equivalent control.

8.1.4

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。

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.

8.1.5

任何偏差都应当记录，并作解释。任何关键的偏差应当做调查。

Any

deviation

should

be

documented

and explained. Any critical deviation should be investigated.

8.1.6

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。

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.

8.1.7

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。

Materials

to

be

reprocessed

or

reworked

should

be

appropriately

controlled

to

prevent

unauthorized use.

8.2

时间限制

Time Limits

8.2.0

如果生产工艺规程

(

检

6.41)

中规定了时间限制，

这些时间限制应当遵守 ，

以保证中间体和原料药的质量。

所有

偏差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、干燥到预设标准

)

，时间限制可能

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。

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 and 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.

8.2.1

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。

Intermediates held for further

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processing should be stored under appropriate conditions to ensure their suitability for use.

8.3

工序间的取样和控制

In- process Sampling and Controls

8.3.0

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。

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.

8.3.1

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

(< /p>

如分

离，纯化

)

。

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 appropriate in early processing steps, whereas tighter controls may be

appropriate for later processing steps (e.g., isolation and purification steps).

8.3.2

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。

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).

8.3.3

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，全部归档作证。

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

tests

and

results

should

be

fully

documented as part of the batch record.

8.3.4

应当制定书面程序，说明中间物质、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< /p>

。

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.

8.3.5

工序间取样应当按能防止 污染所取的样品、其他中间体或原料药的程序进行。应当制订保证样品收集后的完

整性的 程序。

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.

8.3.6

通常不必要对旨在监测和

/

或调节过程而做的工艺间测试进行异常数据调查。

Out-of-specification

(OOS)

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investigations are not normally needed for in-process tests that are performed for the purpose of

monitoring and/or adjusting the process.

8.4

中间体或原料药的混合

Blending Batches of Intermediates or APIs

8.4.0

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规格内的物料混在一起的

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

)

的工艺间的混和，或者混和从几

个批号来的部分作进一步加工，

看作是生产工艺的一部分，

< br>而不是混合。

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.

8.4.1

超标的批号不能与其他批号混合在一起来达到符合 规格标准的目的。混合的每一个批号都应当是用规定的工

艺生产的，混合前应当单独检测 ，并符合相应的质量规格。

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.

8.4.2

可接受的混合操作包括但不限于：

Acceptable blending operations include, but are not limited to:

-

将小批混和，增大批量

Blending of small batches to increase batch size

-

将多批 同一中间体或原料药的零料

(

即量较小的分离出来的物料

)

混合成为一个批号。

Blending of tailings (i.e.,

relatively

small

quantities

of

isolated

material)

from

batches

of

the

same

intermediate

or

API

to

form a single batch

8.4.3

混粉过程应当充分控 制并记录，混合后的批号应当根据情况进行测试，以确认是否达到规格标准。

Blending

processes should be adequately controlled and documented, and the blended batch should be

tested for conformance to established specifications, where appropriate.

8.4.4

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。

The batch record of the blending process

should allow traceability back to the individual batches that make up the blend.

8.4.5

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

混后 批号的均匀性。验证应当包括测试可能受混粉过程影响的关键属性

(

例如，粒径分布，松密度和堆密度

)

。

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.

8.4.6

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。

If the blending could adversely

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affect stability, stability testing of the final blended batches should be performed.

8.4.7

混合批号的有效期或复验日期应当以混和中生产日 期最早的零料或批号为基准。

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

污染的控制

Contamination Control

8.5.0

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建立的原料药的杂质情况有

不

良

影

响

。

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.

8.5.1

生产操作应当防止中间体或原料药被其他物料污染。

Production operations should be conducted in a

manner that prevents contamination of intermediates or APIs by other materials.

8.5.2

处理精制后的原料药应当采取预防污染的措施。

Precautions to avoid contamination should be taken when APIs are handled after purification.

9

原

料< /p>

药

和

中

间

体

的

包

装

< p>
和

贴

签

PACKAGING

AND

IDENTIFICATION

LABELING

OF

APIs

AND

INTERMEDIATES

9.1

总则

General

9.1.0

应当有书面程序描述包装和贴签用物料的接收、鉴别、待检、取样、检查和

/

或测试、放行和搬运。

There

should

be

written

procedures

describing

the

receipt,

identification,

quarantine,

sampling,

xamination, and/or testing, release, and handling of packaging and labeling materials.

9.1.1

包装和贴签用物料应当符合规定的规格标准。不合 格者要拒收，不得用于不适合于其的操作中。

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.

9.1.2

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。

Records

should

be

maintained for each shipment of labels and packaging materials showing receipt, examination,

or testing, and whether accepted or rejected.

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9.2

包装材料

Packaging Materials

9.2.0

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。

Containers

should

provide

adequate

protection

against

deterioration

or

contamination

of

the

intermediate or API that may occur during transportation and recommended storage.

9.2.1

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，

以免改变中间体或原料药的质量使其超出质量 规格的限度。

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.

9.2.2

容器被重新使用时，

< p>
应当按照规定程序进行清洁，

并除去或涂毁以前的所有标签。

If containers are reused,

they

should

be

cleaned

in

accordance

with

documented

procedures,

and

all

previous

labels

should be removed or defaced.

9.3

标签的发放和控制

Labeling Issuance and Control

9.3.0

只有指定人员才能进入标签贮存区。

Access to the label storage areas should be limited to authorized

personnel.

9.3.1

应当采用程序来平衡发出的、使用的和退回的标签的数量，并评估以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。

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).

9.3.2

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。

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 mix-ups

and provides proper identification.

9.3.3

废弃的和过期的标签应当销毁。

Obsolete and out-dated labels should be destroyed.

9.3.4

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。

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.

9.3.5

< br>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。

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.

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