三四级市场美国FDA原料药生产质量管理规范( 中英文)

。

2.18

Procedures

should

exist

for

notifying

responsible

management

in

a

timely

manner

of

regulatory

inspections,

serious

GMP

deficiencies,

product

defects

and

related

actions

(e.g.,

quality-related complaints, recalls, and regulatory actions).

2.18

应当有规程能确保公司的责任管理部门能及时得到有 关药政检查、严重的

GMP

缺陷、

产品 缺陷及其相关活动（如质量投诉，召回，药政活动等）的通知。

2.2 Responsibilities of the Quality Unit(s)

2.2

质量部门的责任

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

2.20

质量部门应当参与所有与质量有关的事物。

2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

2.21

所有与质量有关的文件应当由质量部门审核批准。

2.22 The main responsibilities of the independent quality unit(s) should not be delegated. These

responsibilities should be described in writing and should include, but not necessarily be limited

to:

1.

Releasing

or

rejecting

all

APIs.

Releasing

or

rejecting

intermediates

for

use

outside

the

control of the manufacturing company

2.

Establishing

a

system

to

release

or

reject

raw

materials,

intermediates,

packaging,

and

labeling materials

3.

Reviewing

completed

batch

production

and

laboratory

control

records

of

critical

process

steps before release of the API for distribution

4.

Making sure that critical deviations are investigated and resolved

5.

Approving all specifications and master production instructions

6.

Approving all procedures affecting the quality of intermediates or APIs

7.

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

8.

Approving intermediate and API contract manufacturers

9.

Approving changes that potentially affect intermediate or API quality

10.

Reviewing and approving validation protocols and reports

11.

Making sure that quality-related complaints are investigated and resolved

12.

Making

sure

that

effective

systems

are

used

for

maintaining

and

calibrating

critical

equipment

13.

Making sure that materials are appropriately tested and the results are reported

14.

Making

sure

that

there

is

stability

data

to

support

retest

or

expiry

dates

and

storage

conditions on APIs and/or intermediates, where appropriate

15.

Performing product quality reviews (as defined in Section 2.5)

2.22

独立的质量部门的主要职责不应当委派给他人。这些 责任应当以文字形式加以说明，

而且应当包括，但不限于：

1.

所有原料药的放行与否。用于生产商控制范围以外 的中间体的放行与否；

2.

建立一个放行与拒收原材料、中间体、包装材料和标签的系统；

3.

在供销售的原料药放行前，审核已完成的关键步骤 的批生产记录和实验室检验记录；

4.

确保已对重大偏差进行了调查并已解决；

5.

批准所有的规格标准和主生产指令；

6.

批准所有可能影响原料药和中间体质量的规程；

7.

确保进行内部审计（自检）

；

8.

批准中间体或原料药的委托生产商；

9.

批准可能影响到中间体或原料药质量的变更；

10.

审核并批准验证方案和报告；

11.

确保调查并解决质量问题的投诉；

12.

确保用有效的体系来维护和校验关键设备；

13.

确保物料都经过了适当的检验并报告结果；

14.

确保有稳定性数据支持中间体或原料药的复验期或 有效期和储存条件；

15.

开 展产品质量审核（详见

2.5

节）

。< /p>

2.3 Responsibility for Production Activities

2.3

生产作业的职责

The responsibility for production activities should be described in writing and should include, but

not necessarily be limited to:

1.

Preparing,

reviewing,

approving,

and

distributing

the

instructions

for

the

production

of

intermediates or APIs according to written procedures

2.

Producing APIs and, when appropriate, intermediates according to pre-approved instructions

3.

Reviewing all production batch records and ensuring that these are completed and signed

4.

Making

sure

that

all

production

deviations

are

reported

and

evaluated

and

that

critical

deviations are investigated and the conclusions are recorded

5.

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

6.

Making sure that the necessary calibrations are performed and records kept

7.

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

8.

Making sure that validation protocols and reports are reviewed and approved

9.

Evaluating proposed changes in product, process or equipment

10.

Making

sure

that

new

and,

when

appropriate,

modified

facilities

and

equipment

are

qualified

生产作业的职责应当以文字形式加以说 明，并应当包括，但不限于以下内容：

1.

按书面程序起草、审核、批准和分发中间体或原料药的生产指令；

2.

按照已批准的指令生产原料药或者中间体；

3.

审核所有的批生产记录确保其完整并有签名；

4.

确保所有的生产偏差都已报告、评价，对关键的偏 差已做了调查，并记录结论；

5.

确保生产设施的清洁，必要时要消毒；

6.

确保进行必要的校验，并有记录；

7.

确保对厂房和设备进行保养，并有记录；

8.

确保验证方案和报告的审核与批准；

9.

对产品、工艺或设备拟作的变更进行评估；

10.

确保新的或已改进的生产设施和设备经过了确认。

2.4 Internal Audits (Self Inspection)

2.4

内部审计（自检）

2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be

performed in accordance with an approved schedule.

2.40

为确实符合原料药

GMP< /p>

原则，应当按照批准的计划进行定期的内部审计。

2.41 Audit findings and corrective actions should be documented and brought to the attention of

responsible management of the firm. Agreed corrective actions should be completed in a timely

and effective manner.

2.41

审 计结果及整改措施应当形成文件，并引起公司责任管理人员的重视。获准的整改措

施应当 及时、有效地完成。

2.5 Product Quality Review

2.5

产品质量审核

2.50

Regular

quality-reviews

of

APIs

should

be

conducted

with

the

objective

of

verifying

the

consistency

of

the

process.

Such

reviews

should

normally

be

conducted

and

documented

annually and should include at least:

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

A review of all batches that failed to meet established specification(s)

A review of all critical deviations or nonconformances and related investigations

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

A review of results of the stability monitoring program

A review of all quality-related returns, complaints and recalls

A review of adequacy of corrective actions

2.50

原料药的定期质量审核应当以证实工艺的一致性为目的来进行。此种审核通常应当每

年 进行一次，并记录，内容至少应当包括：

关键工艺控制以及原料药关键测试结果的审核；

所有不符合既定质量标准的产品批号的审核；

所有关键的偏差或违规行为及有关调查的审核；

任何工艺或分析方法变动的审核；

稳定性监测的审核；

所有与质量有关的退货、投诉和召回的审核；

整改措施的适当性的审核。

2.51

The

results

of

this

review

should

be

evaluated

and

an

assessment

made

of

whether

corrective

action

or

any

revalidation

should

be

undertaken.

Reasons

for

such

corrective

action

should be documented. Agreed corrective actions should be completed in a timely and effective

manner.

应当对质量审核结果进行评估，并做出是否需要整改或做任何再验证的评价。此类整改措

施的理由应当文件化。获准的整改措施应当及时、有效地完成。

3. PERSONNEL

3.

人员

3.1 Personnel Qualifications

3.1

员工的资质

3.10

There

should

be

an

adequate

number

of

personnel

qualified

by

appropriate

education,

training,

and/or

experience

to

perform

and

supervise

the

manufacture

of

intermediates

and

APIs.

3.10

应当有足够 数量的员工具备从事和监管原料药和中间体生产的教育、培训和

/

或经历等

资格。

3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs

should be specified in writing.

3.11

参与原料药和中间体生产的所有人员的职责应当书面规定。

3.12

Training

should

be

regularly

conducted

by

qualified

individuals

and

should

cover,

at

a

minimum,

the

particular

operations

that

the

employee

performs

and

GMP

as

it

relates

to

the

employee’s functions. Records of training should be maintained. Training should be periodically

assessed.

3.12

应当由有资格的人员定期进行培训，内容至少应当包括员工所从事的特定操作和与其

职能有关的

GMP

。培训记录应当保存，并应当定期对培训进行 评估。

3.2 Personnel Hygiene

3.2

员工的卫生

3.20 Personnel should practice good sanitation and health habits.

3.20

员工应当养成良好的卫生和健康习惯。

3.21 Personnel should wear clean clothing suitable for the manufacturing activity with which they

are

involved

and

this

clothing

should

be

changed,

when

appropriate.

Additional

protective

apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect

intermediates and APIs from contamination.

3.21

员工应当 穿着适合其所从事生产操作的干净服装，必要时应当更换。其它保护性用品

如头、脸、手 和臂等遮护用品必要时也应当佩带，以免原料药和中间体受到污染。

3.22 Personnel should avoid direct contact with intermediates and APIs.

3.22

员工应当避免与中间体或原料药的直接接触。

3.23 Smoking, eating, drinking, chewing and the storage of food should be restricted to certain

designated areas separate from the manufacturing areas.

3.23

吸烟、吃、喝、咀嚼及存放食品仅限于与生产区隔开 的指定区域。

3.24

Personnel

suffering

from

an

infectious

disease

or

having

open

lesions

on

the

exposed

surface of the body should not engage in activities that could result in compromising the quality

of APIs. Any person shown at any time (either by medical examination or supervisory observation)

to

have

an

apparent

illness

or

open

lesions

should

be

excluded

from

activities

where

the

condition

could

adversely

affect

the

quality

of

the

APIs

until

the

condition

is

corrected

or

qualified

medical

personnel

determine

that

the

person’s

inclusion

would

not

jeopardize

the

safety or quality of the APIs.

3.24

患传染性疾病或身体表面有开放性创伤 的员工不应当从事危及原料药质量的生产活

动。

在任何时候

（经医学检验或监控检查）

任何患有危及到原料药质量的疾病或创伤 的人员

都不应当参与作业，

直到健康状况已恢复，

或者有资格的医学人员确认该员工不会危及到原

料药的安全性和质量。

3.3 Consultants

3.3

顾问

3.30 Consultants advising on the manufacture and control of intermediates or APIs should have

sufficient

education,

training,

and

experience,

or

any

combination

thereof,

to

advise

on

the

subject for which they are retained.

3.30

中间体或原料药生产和控制的顾问应当有足够的学历 ，受训和经验，能胜任所承担的

工作。

3.31 Records should be maintained stating the name, address, qualifications, and type of service

provided by these consultants.

3.31

顾问的姓名、地址、资格和提供服务的类型都应当有文字记录。

4. BUILDINGS AND FACILITIES

4.

建筑和设施

4.1 Design and Construction

4.1

设计和结构

4.10 Buildings and facilities used in the manufacture of intermediates and APIs should be located,

designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to

the

type

and

stage

of

manufacture.

Facilities

should

also

be

designed

to

minimize

potential

contamination. Where microbiological specifications have been established for the intermediate

or

API,

facilities

should

also

be

designed

to

limit

exposure

to

objectionable

microbiological

contaminants, as appropriate.

4.10

用于中间体和原料药生产的厂房和设施的选址、设计 和建造应当便于清洁，维护和适

应一定类型和阶段的生产操作。

设施的设计应尽量减少潜在的污染。

如果中间体或原料药的

生产 有微生物限度要求，那么设施设计应相应的限制有害微生物的污染。

4.11 Buildings and facilities should have adequate space for the orderly placement of equipment

and materials to prevent mix-ups and contamination.

4.11

厂房和设施应有足够空间，以便有秩序地放置设备和 物料，防止混淆和污染。

4.12 Where the equipment itself (e.g., closed or contained system) provides adequate protection

of the material, such equipment can be located outdoors.

4.12

自身能对物料提供足够保护的设备（如关闭的或封闭 的系统）

，可以在户外放置。

4.13 The flow of materials and personnel through the building or facilities should be designed to

prevent mix-ups and contamination.

4.13

通过厂房和设施的物流和人流的设计应当能防止混杂和污染。

4.14 There should be defined areas or other control systems for the following activities:

以下活动应当有指定区域或其它控制系统：

4.15

Adequate

and

clean

washing

and

toilet

facilities

should

be

provided

for

personnel.

These

facilities

should

be

equipped

with

hot

and

cold

water,

as

appropriate,

soap

or

detergent,

air

dryers,

or

single

service

towels.

The

washing

and

toilet

facilities

should

be

separate

from,

but

easily

accessible

to,

manufacturing

areas.

Adequate

facilities

for

showering

and/or

changing

clothes should be provided, when appropriate.

4.15

应当为员工提供足够 和清洁的盥洗设施。

这些盥洗设施应当装有冷热水

（视情况而定 ）

、

肥皂或洗涤剂，

干手机和一次性毛 巾。盥洗室应当与生产区隔离，

但要便于达到。

应当根据

情况提供足够的淋浴和

/

或更衣设施。

4.16

Laboratory

areas/operations

should

normally

be

separated

from

production

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.

4.16

实验室区域

/< /p>

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，

< br>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。

4.2 Utilities

4.2

公用设施

4.20

All

utilities

that

could

affect

product

quality

(e.g.,

steam,

gas,

compressed

air,

heating,

ventilation,

and

air

conditioning)

should

be

qualified

and

appropriately

monitored

and

action

should

be

taken

when

limits

are

exceeded.

Drawings

for

these

utility

systems

should

be

available.4.20

对产品质量会有影响的所有公 用设施（如蒸汽，气体，压缩空气和加热，通

风及空调）

都应当 确认合格，并进行适当监控，在超出限度时应当采取相应措施。

应当有这

些公用设施的系统图。

4.21

Adequate

ventilation,

air

filtration

and

exhaust

systems

should

be

provided,

where

appropriate.

These

systems

should

be

designed

and

constructed

to

minimize

risks

of

contamination and cross-contamination and should include equipment for control of air pressure,

microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of

manufacture.

Particular

attention

should

be

giving

to

areas

where

APIs

are

exposed

to

the

environment.

4.21

应当根据情况，提供足够的通风、空气过滤和排气系 统。这些系统应当根据相应的生

产阶段，设计和建造成将污染和交叉污染降至最低限度，

并包括控制气压、

微生物

（如果适

用）

、灰尘、湿度和温度的设备。特别值得注意的是原料药暴露的区 域。

4.22 If air is recirculated to production areas, appropriate measures should be taken to control

risks of contamination and cross- contamination.

4.22

如果空气再循环到 生产区域，应当采取适当的控制污染和交叉污染的风险。

4.23

Permanently

installed

pipework

should

be

appropriately

identified.

This

can

be

accomplished

by

identifying

individual

lines,

documentation,

computer

control

system,

or

alternative

means.

Pipework

should

be

located

to

avoid

risks

of

contamination

of

the

intermediate or ApI.

4.23

永久性安装的管道应当有适宜的标识。这可以通过标 识每根管道、提供证明文件、计

算机控制系统，或其它替代方法来达到。管道的安装处应 当防止污染中间体或原料药。

4.24 Drains should be of adequate size and should be provided with an air break or a suitable

device to prevent back- siphonage, when appropriate.

4.24

排水沟应当有足够的尺寸，

而且应当根据情况装有空断器或适当的装 置，防止倒虹吸。

4.3 Water

4.3

水

4.30

Water

used

in

the

manufacture

of

APIs

should

be

demonstrated

to

be

suitable

for

its

intended use.

4.30

原料药生产中使用的水应当证明适合于其预定的用途。

4.31

Unless

otherwise

justified,

process

water

should,

at

a

minimum,

meet

World

Health

Organization (WHO) guidelines for drinking (portable) water quality.

除非有其它理由，工艺用水最低限度应当符合世界卫生组织（

WHO< /p>

）的饮用水质量指南。

4.32 If drinking (portable) water is insufficient to ensure API quality and tighter chemical and/or

microbiological

water

quality

specifications

are

called

for,

appropriate

specifications

for

physical/chemical attributes, total microbial counts, objectionable organisms, and/or endotoxins

should be established.

4.32

如果饮用水不足 以确保原料的质量，并要求更为严格的化学和

/

或微生物水质规 格标

准，应当指定合适的物理

/

化学特 性、微生物总数、控制菌和

/

或内毒素的规格标准。