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Annex 1:
Sterile Medicinal Products 附录1：无菌药品（ISPE翻译版）
《Good Manufacturing Practice (2010 revision)
》
Michael Lee, Zhao Chunhua
Zhao Yunxia, He Guoling, Ji Yiyun
Initial Translation from NNE Pharmaplan
Chinese
GMP revised in 2010
附录1：
Annex 1:
无菌药品
Sterile Medicinal Products
目录
Table of
Contents
第一章 范围.....................................................................................................
4
Chapter 1
Scope
...............................................................................................
4
第二章 原则.....................................................................................................
4
Chapter 2
Principle............................................................................................
4
第三章 洁净度级别及监测...............................................................................
5
Chapter 3
Cleanliness classification and monitoring
........................................ 5
第四章 隔离操作技术....................................................................................15
Chapter 4
Isolator technology
.........................................................................15
第五章 吹灌封技术........................................................................................16
Chapter 5
Blow/fill/seal technology
.................................................................16
第六章 人员...................................................................................................17
Chapter 6
Personnel
.......................................................................................17
第七章 厂房..........................................................................................……..19
Chapter 7
Premises.........................................................................................19
第八章 设备...................................................................................................21
Chapter 8
Equipment
......................................................................................21
第九章 消毒...................................................................................................23
Chapter 9
Sanitation........................................................................................23
3
第十章 生产管理............................................................................................24
Chapter 10
Processing....................................................................................24
第十一章 灭菌工艺........................................................................................29
Chapter 11
Sterilisation
...................................................................................29
第十二章 灭菌方法........................................................................................31
Chapter 12
Sterilisation
method......................................................................31
第十三章 无菌药品的最终处理......................................................................37
Chapter 13
Finishing of sterile
products..........................................................37
第十四章 质量控制........................................................................................38
Chapter 14
Quality control
..............................................................................38
第十五章 术语...............................................................................................39
Chapter 15
Glossary
.......................................................................................39
4
第一章 范围
Chapter 1
Scope
第一条
无菌药品是指法定药品标准中列有无菌检查项目的制剂和原料药，
包括无菌制剂和无菌原料药。
Article 1
The sterile medicinal products, including sterile drug products and
drug
substances, refer to the drug product and drug substances which are
subject to
sterility test items as required in the statutory drug specifications
第二条
本附录适用于无菌制剂生产全过程以及无菌原料药的灭菌和无菌生
产过程。
Article 2
This annex applies to the whole manufacture process for sterile
drug
products, and to the process of sterilisation and sterile production for sterile
drug
substances.
第二章 原则
Chapter 2
Principle
第三条
无菌药品的生产须满足其质量和预定用途的要求，应当最大限度降
低微生物、各种微粒和热原的污染。生产人员的技能、所接受的培训及其工作态
度是达到上述目标的关键因素，无菌药品的生产必须严格按照精心设计并经验证
的方法及规程进行，产品的无菌或其它质量特性绝不能只依赖于任何形式的最终
处理或成品检验（包括无菌检查）。
Article 3
The manufacture of sterile products should meet the requirements of
quality
and the intended use. It should minimize risks of microbiological
contamination, and of particulate and pyrogen contamination. The skill, training
and
attitudes of the personnel involved are critical factors. The manufacture of
5
sterile
products must strictly follow the established and validated methods of
preparation and procedure. The sterility or other quality characteristics of
products
cannot only rely on any form of terminal process or finished product
test
(including sterility test).
第四条
无菌药品按生产工艺可分为两类：采用最终灭菌工艺的为最终灭菌产
品；部分或全部工序采用无菌生产工艺的为非最终灭菌产品。
Article 4
Sterile medicinal products, according to the manufacturing process, can
be divided
into two categories: Termininally sterilised products, where the
products
are terminally sterilised; and non-terminally sterilised products, where
the
manufacture processes are partially or completely aseptic.
第五条
无菌药品生产的人员、设备和物料应通过气锁间进入洁净区，采用
机械连续传输物料的，应当用正压气流保护并监测压差。
Article 5
The manufacture of sterile products should be carried out in clean areas
entry to
which shall be through airlocks for personnel and/or for equipment and
materials.
If equipment is used to achieve continuous transfer of materials,
positive
pressure air flow shall be used to protect materials and pressure
difference
shall be monitored.
第六条
物料准备、产品配制和灌装或分装等操作必须在洁净区内分区域
（室）进行。
Article 6
The various operations of component preparation, product preparation
and
filling should be carried out in separate areas within the clean area.
第七条
应当根据产品特性、工艺和设备等因素，确定无菌药品生产用洁净区的
级别。每一步生产操作的环境都应当达到适当的动态洁净度标准，尽可能降低产品或
所处理的物料被微粒或微生物污染的风险。
Article 7
Clean areas for the manufacture of sterile products are classified
according
to the properties of products, the characteristics of process and
equipment
used. Each step of manufacturing operation requires an appropriate
environmental cleanliness level in the operational state in order to minimise
the
risks of
particulate or microbial contamination of the product or materials being
handled.
6
第三章 洁净度级别及监测
Chapter 3
Cleanliness Classification and Its Monitoring
第八条
洁净区的设计必须符合相应的洁净度要求，包括达到“静态”和“动态”
的标准。
Article 8
The design of each clean room or suite of clean rooms shall meet the
requirements of corresponding cleanliness classification, of which
“in
operation”
and
“at
rest” states shall be defined.
第九条
无菌药品生产所需的洁净区可分为以下4
个级别：
A
级：高风险操作区，如灌装区、放置胶塞桶和与无菌制剂直接接触的敞口包
装容器的区域及无菌装配或连接操作的区域，应当用单向流操作台（罩）维持该
区的环境状态。单向流系统在其工作区域必须均匀送风，风速为0.36-0.54m/s（指
导值）。应当有数据证明单向流的状态并经过验证。
在密闭的隔离操作器或手套箱内，可使用较低的风速。
B
级：指无菌配制和灌装等高风险操作A
级洁净区所处的背景区域。
C
级和D
级：指无菌药品生产过程中重要程度较低操作步骤的洁净区。
以上各级别空气悬浮粒子的标准规定如下表：
悬浮粒子最大允许数/立方米
洁净度级别 静态 动态(3)
≥0.5μm
≥5.0μm(2)
≥0.5μm ≥5.0μm
A
级(1)
3520 20 3520 20
B
级
3520 29
352000 2900
C
级
352000
2900 3520000 29000
D
级
3520000
29000
不作规定 不作规定
Article 9
For the manufacture of sterile medicinal products 4 grades can be
distinguished.
Grade A:
The local zone for high risk operations, e.g. filling zone, stopper bowls,
open
7
containers
that are in direct contact with sterile preparations, making aseptic
connections. Normally such conditions are provided by a uni-directional air flow
work
station. uni-directional air flow systems should provide a homogeneous air
speed in a
range of 0.36
– 0.54 m/s (guidance value) at the working
position in
open clean
room applications.Uni-directional state must be validated, and data
must be
available to prove the validation status.
A lower
velocities may be used in closed isolators and glove boxes.
Grade B:
For aseptic preparation and filling, this is the background environment
for the
grade A zone.
Grade C
and D: Clean areas for carrying out less critical operation stages in the
manufacture of sterile products.
The
maximum permitted airborne particle concentration for each grade is given
in the
following table.
Maximum
permitted number of particles per m3
equal to
or
greater
than the tabulated size
At rest In
operation
(3)
Grade
≥0.5μm
≥5.0μm(2)
≥0.5μm ≥5.0μm
A
(1)
3520 20 3520 20
B 3520 29
352000 2900
C 352000
2900 3520000 29000
D 3520000
29000 Not defined Not defined
注：
（1）为确认A级洁净区的级别，每个采样点的采样量不得少于1立方米。A级洁
净区空气悬浮粒子的级别为ISO 4.8，以≥5.0μm的悬浮粒子为限度标准。B级洁净区
（静态）的空气悬浮粒子的级别为ISO 5，同时包括表中两种粒径的悬浮粒子。对
于C级洁净区（静态和动态）而言，空气悬浮粒子的级别分别为ISO 7和ISO 8。对
于D级洁净区（静态）空气悬浮粒子的级别为ISO 8。测试方法可参照ISO14644-1。
（2）在确认级别时，应当使用采样管较短的便携式尘埃粒子计数器，避免
≥5.0μm悬浮粒子在远程采样系统的长采样管中沉降。在单向流系统中，应当采用
等动力学的取样头。
8
（3）动态测试可在常规操作、培养基模拟灌装过程中进行，证明达到动态的
洁净度级别，但培养基模拟灌装试验要求在“最差状况”下进行动态测试。
Note:
(1) To
determine the cleanliness level for Grade A zones, a minimum sample
volume of
1m3should be taken per sample location. For Grade A the airborne
particle
classification follows ISO 4.8 dictated by the limit for particles
≥5.0
μm.
For Grade
B (at rest) the airborne particle classification follows ISO 5, containing
both
particle sizes listed in the above table. For Grade C (at rest & in operation)
the
airborne particle classification follows ISO 7 and ISO 8 respectively. For
Grade D
(at rest) the airborne particle classification follows ISO 8. For measuring
procedure,
refer to ISO 14644-1.
(2)
Portable particle counters with a short length of sample tubing should be
used for
classification purposes because of the relatively higher rate of precipitation
of
particles
≥5.0μm
in remote sampling systems with long lengths of tubing. Isokinetic
sample
heads shall be used in uni-directional airflow systems.
(3)
“In
operation” classification may be demonstrated during
normal operations
or
simulated operations. Nevertheless worst-case scenario must be required for
media
fills during
“In
operation” classification .
第十条
应当按以下要求对洁净区的悬浮粒子进行动态监测：
Article 10
The monitoring for aireborne particles of grade A, B, and C zones in
operation
should be performed according to procedures as follows,
（一）根据洁净度级别和空气净化系统确认的结果及风险评估，确定取样点
的位置并进行日常动态监控。
(1)
The
determination of sampling locations should be based on cleanliness level,
results
from the qualification of air purification system and the risk assessment.
There must
be routine monitoring for in-operation cleanliness.
（二）在关键操作的全过程中，包括设备组装操作，应当对A
级洁净区进行
悬浮粒子监测。生产过程中的污染（如活生物、放射危害）可能损坏尘埃粒子计
数器时，应当在设备调试操作和模拟操作期间进行测试。A
级洁净区监测的频率及
取样量，应能及时发现所有人为干预、偶发事件及任何系统的损坏。灌装或分装
时，由于产品本身产生粒子或液滴，允许灌装点≥5.0μm
的悬浮粒子出现不符合标
9
准的情况。
(2) For
Grade A zones, particle monitoring should be undertaken for the full
duration
of critical processing, including equipment assembly, except where
justified
by contaminants in the process that would damage the particle counter
or present
a hazard, e.g. live organisms and radiological hazards. In such cases,
monitoring
should be undertaken during routine equipment set up operations, or
during
simulated operations. The Grade A zone should be monitored at such a
frequency
and with suitable sample size that all interventions, transient events
and any
system deterioration would be captured if alert limits are exceeded. It is
accepted
that it may not always be possible to demonstrate low levels of
≥5.0
μm particles at the
point of fill when filling is in progress, due to the generation of
particles
or droplets from the product itself.
（三）在B
级洁净区可采用与A
级洁净区相似的监测系统。可根据B
级洁净
区对相邻A
级洁净区的影响程度，调整采样频率和采样量。
(3) It is
recommended that a similar monitoring system be used for Grade B
zones as
the one used for Grade A zone. The sampling frequency and the
sample
size can be adjusted according to the effectiveness of the segregation
between
the adjacent Grade A and B zones.
（四）悬浮粒子的监测系统应当考虑采样管的长度和弯管的半径对测试结果的影
响。
(4) Where
airborne particle monitoring systems are used, the length of tubing
and the
radii of any bends in the tubing must be considered in the context of the
effect on
test result.
（五）日常监测的采样量可与洁净度级别和空气净化系统确认时的空气采样量不
同。
(5) The
sample sizes taken for monitoring purposes is not necessary to be the
same as
that used for formal qualification of clean rooms and air handling
systems..
（六）在A级洁净区和B级洁净区，连续或有规律地出现少量≥5.0
μm的悬浮粒子
时，应当进行调查。
(6) In
Grade A and B zones, it should be investigated if a few particle
≥5.0
μm
ocurrs
10
consecutively or on a regular basis.
（七）生产操作全部结束、操作人员撤出生产现场并经15～20
分钟（指导值）
自净后，洁净区的悬浮粒子应当达到表中的“静态”标准。
(7)The
particle limits given in the table for the
“at rest”
state should be achieved
after a
short
“clean
up” period of 15-20 minutes (guidance value) in an
unmanned
state
after completion of operations
（八）应当按照质量风险管理的原则对C级洁净区和D级洁净区（必要时）进行动
态监测。监控要求以及警戒限度和纠偏限度可根据操作的性质确定，但自净时间
应当达到规定要求。
(8)The
monitoring of Grade C and D areas in operation (when necessary) should
be
performed in accordance with the principles of quality risk management. The
requirements and alert/action limits will depend on the nature of the operations
carried
out, but the recommended
“clean up period”
should be attained.
（九）应当根据产品及操作的性质制定温度、相对湿度等参数，这些参数不应对
规定的洁净度造成不良影响。
(9)
Temperature and relative humidity depend on the product and nature of the
operations
carried out. These parameters should not interfere with the defined
cleanliness standard.
第十一条
应当对微生物进行动态监测，评估无菌生产的微生物状况。监测
方法有沉降菌法、定量空气浮游菌采样法和表面取样法（如棉签擦拭法和接触碟
法）等。动态取样应当避免对洁净区造成不良影响。成品批记录的审核应当包括
环境监测的结果。
对表面和操作人员的监测，应当在关键操作完成后进行。在正常的生产操作
监测外，可在系统验证、清洁或消毒等操作完成后增加微生物监测。
Article 11
Monitoring in operation should be done on microbe to evaluate its
status.
The monitoring methods are settle plates, volumetric air and surface
sampling
(e.g. swabs and contact plates),etc. Sampling methods used in
operation
should not negatively impact cleanliness level in the zone. Results
11
from
monitoring should be reviewed as a part of batch documentation for
finished
product release.
Surfaces
and personnel should be monitored after critical operations. Additional
microbiological monitoring is also required outside production operations, e.g.
after
validation
of systems, cleaning and sanitisation.
洁净区微生物监测的动态标准(1)如下
Limits for microbiological monitoring of
clean
areas during operation:
表面微生物
洁净度
级别
浮游菌
cfu/m3
沉降菌（φ90mm）
cfu /4
小时(2)
接触（φ55mm）
cfu /碟
5
指手套
cfu /手套
A
级
<1
<1
<1
<1
B
级
10 5 5 5
C
级
100 50 25
－
D
级
200 100 50
－
注：
（1） 表中各数值均为平均值。
Surface
microbiological
Grade
air sample
bacteria
cfu/m3
settle
plates
bacteria
（φ90mm）
cfu
/4hours(2)
contact
plates
（φ55mm）
cfu /plate
Glove
print
5 fingers
cfu /glove
A
<1
<1
<1
<1
B 10 5 5 5
C 100 50
25
－
D 200 100
50
－
12
（2）单个沉降碟的暴露时间可以少于4小时，同一位置可使用多个沉降碟连
续进行监测并累积计数。
Notes
(1) These
are average values.
(2)
Individual settle plates may be exposed for less than 4 hours..At each points,
several
settle plates may be used for continuously monitoring and cumulatively
counting.
第十二条
应当制定适当的悬浮粒子和微生物监测警戒限度和纠偏限度。操作
规程中应当详细说明结果超标时需采取的纠偏措施。
Article 12
Appropriate alert and action limits should be set for the results of
particulate and microbiological monitoring. Corrective actions shall be defined
in
operating
procedures in case such limits are exceeded ..
第十三条
无菌药品的生产操作环境可参照表格中的示例进行选择。
洁净度级别 最终灭菌产品生产操作示例
C
级背景下的
局部A
级 高污染风险(1)的产品灌装（或灌封）
C
级
1.产品灌装（或灌封）；
2.高污染风险(2)产品的配制和过滤；
3.眼用制剂、无菌软膏剂、无菌混悬剂等的配制、灌装（或
灌封）；
4.直接接触药品的包装材料和器具最终清洗后的处理。
D
级
1.轧盖；
2.灌装前物料的准备；
3.产品配制（指浓配或采用密闭系统的配制）和过滤直接接
触药品的包装材料和器具的最终清洗。
Article 13
The selection of production operations environment for sterile
medicinal
products, refer to the examples in the following table.
Classification Examples of operations for terminally sterilised products
Grade A
environment
with
aGrade
C
background
Filling
(or sealing)of products, when risk of contamination is
high(1)
Grade C
1. Filling
(or sealing) of products;
2.
Preparation and filtration of products, when risk of
contamination is high(2);
13
3.
Preparation and filling(or sealing) of ophthalmic
preparation, sterile ointment, sterile emulsion or
suspension, etc.
4.
Handling of primary packaging materials and tools
after
final washing, which are in direct contact with
medicinal
products
Grade D
1.
Capping;
2.Material
preparation before filling;
3.Preparation and filtration of products(concentration or
dilution
in a closed system) and ,final washing of primary
packaging
material tools a which directly contact with
medicinal
products.
注：
（1）此处的高污染风险是指产品容易长菌、灌装速度慢、灌装用容器为广
口瓶、容器须暴露数秒后方可密封等状况；
（2）此处的高污染风险是指产品容易长菌、配制后需等待较长时间方可灭菌
或不在密闭系统中配制等状况。
Note:
(1) Here
the high risk of contamination refers to the situations where the product
promotes
microbial growth, and filling operation is slow or the containers - are
wide-
necked or must be exposed for more than a few seconds before sealing.
(2) Here
the high risk of contamination refers to the situations where the product
promotes
microbial growth or must be held for a long period before sterilisation
or is not
processed in closed systems.
洁净度级别 非最终灭菌产品的无菌生产操作示例
B
级背景下
的A
级
1.处于未完全密封(1)状态下产品的操作和转运，如产品灌装（或灌封）、
分装、压塞、轧盖(2)等；
2.灌装前无法除菌过滤的药液或产品的配制；
3.直接接触药品的包装材料、器具灭菌后的装配以及处于未完全密封状
态下的转运和存放；
4.无菌原料药的粉碎、过筛、混合、分装。
B
级
1.处于未完全密封(1)状态下的产品置于完全密封容器内的转运；
2
直接接触药品的包装材料、器具灭菌后处于密闭容器内的转运和存放。
C
级
1.灌装前可除菌过滤的药液或产品的配制；
2.产品的过滤。
D
级 直接接触药品的包装材料、器具的最终清洗、装配或包装、灭菌
14
注：
（1）轧盖前产品视为处于未完全密封状态。
（2）根据已压塞产品的密封性、轧盖设备的设计、铝盖的特性等因素，轧盖
操作可选择在C
级或D
级背景下的A
级送风环境中进行。A
级送风环境应当至少
符合A
级区的静态要求。
Note:
(1) The
products before capping are deemed as not completely sealed.
(2)According to the sealing reliability, design of capping equipment,
characteristics
of
aluminium caps etc, capping operation can be conducted -in Grade A air
supply
environment with a Grade C or D background. The Grade A air supply
environment should conform with at least the requirement of Grade A at rest.
Classificatio
n
Examples
of operations for aseptic preparations
Grade A
environment
with a
Grade B
background
1.
Operation and transfer of those products which are not completely
sealed in
process(1), such as filling/sealing, subpackaging,
stoppering
capping(2)
of products etc.
2.
Preparation of solutions or products which are not able to go
through
sterile-filtration before filling;
3.
Assembling of sterilised primary packaging materials and
apparatus
which will directly contact with medicinal products.
Transfer
and storage ofthose sterilised and partially sealed
apparatus
and materials.Milling, sieving, mixing and subpackaging
of sterile
drug substances.
Grade B
1.
Transfer of partially sealed products in fully sealed containers.
2.
Transfer and storage of sterized primary packaging materials and
apparatus
, which will direct contact with medicinal products. in
sealed
containers
Grade C
1.
Preparation of solutions or products which could be sterile filtered
before
filling.
2.
Filtration of products.
Grade D
Final
washing, assembling or packaging, and sterilisation of primary
packaging
materials and apparatus which will directly contact with
medicinal
products.
15
第四章 隔离操作技术
Chapter 4
Isolator technology
第十四条
高污染风险的操作宜在隔离操作器中完成。隔离操作器及其所处
环境的设计，应当能够保证相应区域空气的质量达到设定标准。传输装置可设计
成单门或双门，也可是同灭菌设备相连的全密封系统。
物品进出隔离操作器应当特别注意防止污染。
隔离操作器所处环境取决于其设计及应用，无菌生产的隔离操作器所处的环
境至少应为D
级洁净区。
Article 14
Operations associated with high contamination risk should be
performed
inside isoloator. The isolator and the background environment should
be
designed so that the required air quality for the respective zones can be
realised.
Transfer devices may vary from a single door or double door designs to
fully
sealed systems incorporating sterilisation mechanisms.
Special
attention should be paid to prevent contamination when transferring of
materials
into and out of the isolator.
The air
classification required for the background environment depends on
the design
of the isolator and its application. It should be controlled and for
aseptic
processing it should be at least grade D.
第十五条
隔离操作器只有经过适当的确认后方可投入使用。确认时应当考
虑隔离技术的所有关键因素，如隔离系统内部和外部所处环境的空气质量、隔离
操作器的消毒、传递操作以及隔离系统的完整性。
Article 15
Isolators should be applied for routine operations only after
appropriate validation. Validation should take into account all critical factors
of
isolator
technology, for examples, the quality of the air inside and outside
(background) the isolator, sanitisation of the isolator, the transfer process
and
isolator
integrity.
第十六条
隔离操作器和隔离用袖管或手套系统应当进行常规监测，包括经
16
常进行必要的检漏试验。
Article 16
Monitoring should be carried out routinely and should include frequent
leak
testing of the isolator and glove/sleeve system.
第五章 吹灌封技术
Chapter 5
Blow/fill/seal technology
第十七条
用于生产非最终灭菌产品的吹灌封设备自身应装有A
级空气风淋
装置，人员着装应当符合A/B
级洁净区的式样，该设备至少应当安装在C
级洁净
区环境中。在静态条件下，此环境的悬浮粒子和微生物均应当达到标准，在动态
条件下，此环境的微生物应当达到标准。
用于生产最终灭菌产品的吹灌封设备至少应当安装在D
级洁净区环境中。
Article 17
Blow/fill/seal equipment used for aseptic production which is fitted with
an
effective grade A air shower may be installed in at least a grade C
environment, provided that grade A/B clothing is used. Under at rest condition,
the
suspended particles and microorganism should meet the standards. Under
in
operation condition, the microorganism should meet the standards.
Blow/fill/seal equipment used for the production of products which are
terminally
sterilised
should be installed in at least a grade D environment.
第十八条
因吹灌封技术的特殊性，应当特别注意设备的设计和确认、在线清
洁和在线灭菌的验证及结果的重现性、设备所处的洁净区环境、操作人员的培训
和着装，以及设备关键区域内的操作，包括灌装开始前设备的无菌装配。
Article 18
Because of this special technology particular attention should be paid
to, at
least the following:
equipment design and qualification
validation and reproducibility of
cleaning-in-place and sterilisation-in-place
background clean room environment in which the
equipment is located
operator training and gowning
operations in the critical zone of the equipment including
any aseptic
assembly
or set-up? prior to the commencement of filling.
17
第六章 人员
Chapter 6
Personnel
第十九条
洁净区内的人数应当严加控制，检查和监督应当尽可能在无菌生
产的洁净区外进行。
Article 19
The total number of personnel shall be
rigorously
controlled
.
Inspections and controls should be conducted outside the clean areas as far as
possible.
第二十条
凡在洁净区工作的人员（包括清洁工和设备维修工）应当定期培
训，使无菌药品的操作符合要求。培训的内容应当包括卫生和微生物方面的基础
知识。未受培训的外部人员（如外部施工人员或维修人员）在生产期间需进入洁
净区时，应当对他们进行特别详细的指导和监督。
Article 20
All personnel (including those concerned with cleaning and
maintenance) employed in such areas should receive regular training in
disciplines relevant to the correct manufacture of sterile products. This
training
should
include reference to hygiene and to the basic elements of microbiology.
When
outside staff who have not received such training (e.g. building or
maintenance contractors) need to be brought in, particular care should be taken
over their
instruction and supervision.
第二十一条
从事动物组织加工处理的人员或者从事与当前生产无关的微生
物培养的工作人员通常不得进入无菌药品生产区，不可避免时，应当严格执行相
关的人员净化操作规程。
Article 21
Personnel who have been engaged in the processing of animal tissue
materials
or of cultures of micro-organisms other than those used in the current
manufacturing process shall not enter sterile-product areas unless rigorous and
clearly
defined cleaning procedures have been followed.
第二十二条
从事无菌药品生产的员工应当随时报告任何可能导致污染的异
常情况，包括污染的类型和程度。当员工由于健康状况可能导致微生物污染风险
增大时，应当由指定的人员采取适当的措施。
18
Article 22
Personnel involved in the manufacture of sterile preparations should
be
instructed to report any condition which may cause the shedding of abnormal
numbers or
types of contaminants. Actions to be taken about personnel who
could be
introducing undue microbiological hazard should be decided by a
designated
competent person.
第二十三条
应当按照操作规程更衣和洗手，尽可能减少对洁净区的污染或
将污染物带入洁净区。
Article 23
Changing and washing should follow a written procedure designed to
minimize
contamination of clean area or carry-through of contaminants to the
clean
areas.
第二十四条
工作服及其质量应当与生产操作的要求及操作区的洁净度级别
相适应，其式样和穿着方式应当能够满足保护产品和人员的要求。各洁净区的着
装要求规定如下：
Article 24
The garment and its quality should be appropriate for the process and
the grade
of the working area. It should be applied in such a way as to protect
the
products and personnel from contamination.
The
description of gowning required for each grade is given below:
D
级洁净区：应当将头发、胡须等相关部位遮盖。应当穿合适的工作服和鞋
子或鞋套。应当采取适当措施，以避免带入洁净区外的污染物。
Grade D:
Hair and,
where relevant, beard should be covered. A general
protective
suit and appropriate shoes or overshoes should be worn. Appropriate
measures
should be taken to avoid any contamination coming from outside the
clean
area.
C级洁净区：应当将头发、胡须等相关部位遮盖，应当戴口罩。应当穿手腕处可收
紧的连体服或衣裤分开的工作服，并穿适当的鞋子或鞋套。工作服应当不脱落
纤维或微粒。
Grade C: Hair and where relevant beard and
moustache should be covered. A
face mask
should be worn. A jump suit or two-piece trouser suit, gathered at the
wrists and
with high neck and appropriate shoes or overshoes should be worn.
They
should be virtually free of fibres or particulate matter.
A/B
级洁净区：应当用头罩将所有头发以及胡须等相关部位全部遮盖，头罩应
19
当塞进衣领内，应当戴口罩以防散发飞沫，必要时戴防护目镜。应当戴经灭菌且
无颗粒物（如滑石粉）散发的橡胶或塑料手套，穿经灭菌或消毒的脚套，裤腿应
当塞进脚套内，袖口应当塞进手套内。工作服应为灭菌的连体工作服，不脱落纤
维或微粒，并能滞留身体散发的微粒。
Grade A/B:
Headgear should totally enclose h
air and, where relevant, beard
and
moustache; it should be tucked into the neck of the suit; safety goggles
should be
worn; a face mask should be worn to prevent the shedding of droplets.
Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or
disinfected footwear should be worn. Trouser-legs should be tucked inside the
footwear
and garment sleeves into the gloves. The sterilized jump suit should be
used. The
suit should shed virtually no fibres or particulate matter and retain
particles
shed by the body.
第二十五条
个人外衣不得带入通向B
级或C
级洁净区的更衣室。每位员工
每次进入A/B
级洁净区，应当更换无菌工作服；或每班至少更换一次，但应当用
监测结果证明这种方法的可行性。操作期间应当经常消毒手套，并在必要时更换
口罩和手套。
Article 25
Outdoor clothing should not be brought into changing rooms leading to
grade B
and C rooms. Every worker should change clean sterile protective
garments
at every time when he enters a grade A/B area; or at least once a shift
while
feasibility of the methods should be verified by the results from monitoring.
Gloves
should be regularly disinfected during operations. Masks and gloves
should be
changed when necessary.
第二十六条
洁净区所用工作服的清洗和处理方式应当能够保证其不携带有
污染物，不会污染洁净区。应当按照相关操作规程进行工作服的清洗、灭菌，洗
衣间最好单独设置。
Article 26
Clean area garments should be cleaned and handled in such a
way that
it does not introduce additional contaminants which can later
contaminate clean areas. The operations should follow written procedures.
Separate
laundry facilities for such clothing’s cleaning and sterilisation are
desirable.
20
第七章 厂房
Chapter 7
Premises
第二十七条
洁净厂房的设计，应当尽可能避免管理或监控人员不必要的进
入。B
级洁净区的设计应当能够使管理或监控人员从外部观察到内部的操作。
Article 27
The design of the clean premise should avoid the unnecessary access
of
supervision or monitoring person . Grade B area should be designed as that
the inside
operations could be monitored by supervision or monitoring person
from
outside
第二十八条
为减少尘埃积聚并便于清洁，洁净区内货架、柜子、设备等不
得有难清洁的部位。门的设计应当便于清洁。
Article 28
To reduce accumulation of dust and to facilitate cleaning there should
be no
uncleanable recesses on shelves, cupboards and equipment in cleaning
area.
Doors should be designed to avoid those uncleanable recesses.
第二十九条
无菌生产的A/B
级洁净区内禁止设置水池和地漏。在其它洁净
区内，水池或地漏应当有适当的设计、布局和维护，并安装易于清洁且带有空气
阻断功能的装置以防倒灌。同外部排水系统的连接方式应当能够防止微生物的侵
入。
Article 29
Sinks and drains should be prohibited in grade A/B areas used for
aseptic
manufacture. In other areas, sinks and drains should have proper design,
layout and
maintainance. Cleanable facilities with air break function should be
fitted to
prevent backflow. The connection with outside drain system should be
designed
to prevent microbial contamination.
第三十条
应当按照气锁方式设计更衣室，使更衣的不同阶段分开，尽可能
避免工作服被微生物和微粒污染。更衣室应当有足够的换气次数。更衣室后段的
静态级别应当与其相应洁净区的级别相同。必要时，可将进入和离开洁净区的更
衣间分开设置。一般情况下，洗手设施只能安装在更衣的第一阶段。
Article 30
Changing rooms should be designed as airlocks and used to provide
physical
separation of the different stages of changing and so minimize microbial
and
particulate contamination of protective clothing. They should be flushed
21
effectively with filtered air. The final stage of the changing room should, in
the
at-rest
state, be the same grade as the area into which it leads. The use of
separate
changing rooms for entering and leaving clean areas is sometimes
desirable.
In general hand washing facilities should be provided only in the first
stage of
the changing rooms.
第三十一条
气锁间两侧的门不得同时打开。可采用连锁系统或光学或（和）
声学的报警系统防止两侧的门同时打开。
Article 31
Both airlock doors should not be opened simultaneously. An
interlocking system or a visual and/or audible warning system should be
operated
to prevent the opening of both doors at a time.
第三十二条
在任何运行状态下，洁净区通过适当的送风应当能够确保对周
围低级别区域的正压，维持良好的气流方向，保证有效的净化能力。
应当特别保护已清洁的与产品直接接触的包装材料和器具及产品直接暴露的
操作区域。
当使用或生产某些致病性、剧毒、放射性或活病毒、活细菌的物料与产品时，
空气净化系统的送风和压差应当适当调整，防止有害物质外溢。必要时，生产操
作的设备及该区域的排风应当作去污染处理（如排风口安装过滤器）。
Article 32
A filtered air supply should maintain a positive pressure and an air flow
relative
to surrounding areas of a lower grade under all operational conditions
and should
flush the area effectively.
Particular
attention should be paid to the protection of the zone of greatest risk,
that is,
the immediate environment to which a product and cleaned components
which
directly contact the product are exposed.
The
various recommendations regarding air supplies and pressure differentials
may need
to be modified where it becomes necessary to contain some materials,
e.g.
pathogenic, highly toxic, radioactive or live viral or bacterial materials or
products.
Decontamination of facilities and treatment (eg. Install a filter at the
exit) of
air leaving a clean area may be necessary for some operations.
第三十三条
应当能够证明所用气流方式不会导致污染风险并有记录（如烟
雾试验的录像）。
Article 33
It should be demonstrated and documented (e.g. the video of smoke
test) that
air-flow patterns do not present a contamination risk.
22
第三十四条
应设送风机组故障的报警系统。应当在压差十分重要的相邻级
别区之间安装压差表。压差数据应当定期记录或者归入有关文挡中。
Article 34
A warning system should be provided to indicate failure in the air
supply.
Indicators of pressure differences should be fitted between areas where
these
differences are important. These pressure differences should be recorded
regularly
or otherwise documented.
第三十五条
轧盖会产生大量微粒，应当设置单独的轧盖区域并设置适当的
抽风装置。不单独设置轧盖区域的，应当能够证明轧盖操作对产品质量没有不利
影响。
Article 35
There should be a separate zone and adequate air extraction device
for
capping due to the generation of particles from the operation. If there is no
separate
zone for capping, it should be demonstrated that the capping operation
will not
have negative impact on product quality.
第八章 设备
Chapter 8
Equipment
第三十六条
除传送带本身能连续灭菌（如隧道式灭菌设备）外，传送带不
得在A/B
级洁净区与低级别洁净区之间穿越。
Article 36
A conveyor belt should not pass through a partition between a grade A
or B area
and a processing area of lower air cleanliness, unless the belt itself is
continually sterilised (e.g. in a sterilising tunnel).
第三十七条
生产设备及辅助装置的设计和安装，应当尽可能便于在洁净区
外进行操作、保养和维修。需灭菌的设备应当尽可能在完全装配后进行灭菌。
Article 37
As far as practicable equipment, fittings and services should be
designed
and installed so that operations, maintenance and repairs can be
carried
out outside the clean area. If sterilisation is required, it should be carried
out,
wherever possible, after complete reassembly.
第三十八条
无菌药品生产的洁净区空气净化系统应当保持连续运行，维持
相应的洁净度级别。因故停机再次开启空气净化系统，应当进行必要的测试以确
23
认仍能达到规定的洁净度级别要求。
Article
38: HVAC system for the clean area of sterile medical products
manufacturing should keep running continuously in order to maintain the
corresponding cleanness classification. If the HVAC system is interrupted and
recommenced, testing is necessary to ensure the clean area can meet the
regulated
classification requirement.
第三十九条
在洁净区内进行设备维修时，如洁净度或无菌状态遭到破坏，
应当对该区域进行必要的清洁、消毒或灭菌，待监测合格方可重新开始生产操作。
Article 39
When equipment maintenance has been carried out within the clean
area, the
area should be cleaned, disinfected and/or sterilised where appropriate,
before
processing recommences if the required standards of cleanliness and/or
asepsis
have not been maintained during the work. The operation can be
restarted
when the monitoring result is acceptable.
第四十条
关键设备，如灭菌柜、空气净化系统和工艺用水系统等，应当经
过确认，并进行计划性维护，经批准方可使用。
Article 40
All equipment such as sterilisers, air handling system and process
water
systems etc., should be subject to validation and planned maintenance;
their
return to use should be approved.
第四十一条
过滤器应当尽可能不脱落纤维。严禁使用含石棉的过滤器。过
滤器不得因与产品发生反应、释放物质或吸附作用而对产品质量造成不利影响。
Article 41
Fibre-shedding characteristics of filters should be minimal. Asbestine
filters
are prohibited. The filter should not have negative impact on product
quality by
reaction with product , release of substances into it or absorption .
第四十二条
进入无菌生产区的生产用气体（如压缩空气、氮气，但不包括
可燃性气体）均应经过除菌过滤，应当定期检查除菌过滤器和呼吸过滤器的完整
性。
Article 42
The process gas (e.g. compressed air, nitrogen, except flammable gas)
should be
filtered before entering sterile area. The integrity test of sterilization
filters
and vent filters should be performed periodically.
24
第九章 消毒
Chapter 9
Sanitation
第四十三条
应当按照操作规程对洁净区进行清洁和消毒。一般情况下，所
采用消毒剂的种类应当多于一种。不得用紫外线消毒替代化学消毒。应当定期进
行环境监测，及时发现耐受菌株及污染情况。
Article 43
Clean areas should be cleaned thoroughly in accordance with an
operation
procedure. Where disinfectants are used, more than one type should
be
employed. UV should not replace chemical disinfectants. Monitoring should
be
undertaken regularly in order to detect the development of resistant strains.
第四十四条
应当监测消毒剂和清洁剂的微生物污染状况，配制后的消毒剂
和清洁剂应当存放在清洁容器内，存放期不得超过规定时限。A/B
级洁净区应当使
用无菌的或经无菌处理的消毒剂和清洁剂。
Article 44
Disinfectants and detergents should be monitored for microbial
contamination; Prepared disinfectants and cleaning agents should be stored in
cleaned
containers and should only be stored for defined periods. Disinfectants
and
detergents used in Grades A and B areas should be sterile or sterilized prior
to use.
第四十五条
必要时，可采用熏蒸的方法降低洁净区内卫生死角的微生物污
染，应当验证熏蒸剂的残留水平。
Article 45
Fumigation of clean areas may be useful for reducing microbiological
contamination in inaccessible places. The residue level of the fumigant should
be
validated.
第十章 生产管理
Chapter 10
Processing
第四十六条
生产的每个阶段（包括灭菌前的各阶段）应当采取措施降低污
染。
25
Article 46
Precautions to minimize contamination should be taken during all
processing
stages including the stages before sterilisation.
第四十七条
无菌生产工艺的验证应当包括培养基模拟灌装试验。
应当根据产品的剂型、培养基的选择性、澄清度、浓度和灭菌的适用性选择
培养基。应当尽可能模拟常规的无菌生产工艺，包括所有对无菌结果有影响的关
键操作，及生产中可能出现的各种干预和最差条件。
培养基模拟灌装试验的首次验证，每班次应当连续进行3
次合格试验。空气
净化系统、设备、生产工艺及人员重大变更后，应当重复进行培养基模拟灌装试
验。培养基模拟灌装试验通常应当按照生产工艺每班次半年进行1
次，每次至少
一批。
培养基灌装容器的数量应当足以保证评价的有效性。批量较小的产品，培养
基灌装的数量应当至少等于产品的批量。培养基模拟灌装试验的目标是零污染，
应当遵循以下要求：
Article 47
Validation of aseptic processing should include a process simulation
test using
a nutrient medium (media fill).
Selection
of the nutrient medium should be made based on dosage form of the
product
and selectivity, clarity, concentration and suitability for sterilisation of the
nutrient
medium.
The process simulation test should imitate as closely as
possible
the routine aseptic manufacturing process and include all the critical
subsequent
manufacturing steps which may affect the aseptic result. It should
also take
into account various
interventions known to occur during normal production as well as worst-case
situations.
Process
simulation tests should be performed as initial validation with three
consecutive
satisfactory simulation tests per shift and repeated at defined intervals and
after
any
significant modification to the HVAC-system, equipment, process and number of
shifts.
Normally
process simulation tests should be repeated twice a year per shift and
process.,
one batch at least in each time.
26
The number
of containers used for media fills should be sufficient to enable a
valid
evaluation. For small batches, the number of containers for media fills should
at
least
equal the size of the product batch. The target should be zero growth and
the
following should apply:
（一）灌装数量少于5000
支时，不得检出污染品。
（二）灌装数量在5000
至10000
支时：
1.有1支污染，需调查，可考虑重复试验；
2.有2支污染，需调查后，进行再验证。
（三）灌装数量超过10000支时：
1.有1支污染，需调查；
2.有2支污染，需调查后，进行再验证。
（四）发生任何微生物污染时，均应当进行调查。
1. When
filling fewer than 5000 units, no contaminated units should be
detected.
2. When
filling 5,000 to 10,000 units:
⑴
One (1) contaminated unit should result in an
investigation, including
consideration of a repeat media fill test;
⑵
Two (2) contaminated units should result in revalidation,
following
investigation.
3. When
filling more than 10,000 units:
⑴
One (1) contaminated unit should result in an
investigation;
⑵
Two (2) contaminated units should result in revalidation ,
following
investigation.
4. All
microbial contamination should be investigated.
第四十八条
应当采取措施保证验证不能对生产造成不良影响。
Article 48
Care should be taken that any validation does not compromise the
processes.
第四十九条
无菌原料药精制、无菌药品配制、直接接触药品的包装材料和
器具等最终清洗、A/B
级洁净区内消毒剂和清洁剂配制的用水应当符合注射用水的
27
质量标准。
Article 49
Water used in the purification of sterile APIs, preparation of sterile
medical
products, final rinsing of utensils and packing material which directly
contact
with products, and preparation of disinfectants and detergents used in
grades A
and B areas should meet the specifications of water for injection.
第五十条
必要时，应当定期监测制药用水的细菌内毒素，保存监测结果及
所采取纠偏措施的相关记录。
Article 50
Endotoxins for processing water should be monitored regularly.
Records
should be maintained of the results of the monitoring and of any
corrective
action taken.
第五十一条
当无菌生产正在进行时，应当特别注意减少洁净区内的各种活
动。应当减少人员走动，避免剧烈活动散发过多的微粒和微生物。由于所穿工作
服的特性，环境的温湿度应当保证操作人员的舒适性。
Article 51
Activities in clean areas and especially when aseptic operations are in
progress
should be kept to a minimum and movement of personnel should be
controlled
and methodical, to avoid excessive shedding of particles and
organisms
due to over-vigorous activity. The ambient temperature and humidity
should be
comfortable because of the nature of the garments worn.
第五十二条
应当尽可能减少物料的微生物污染程度。必要时，物料的质量
标准中应当包括微生物限度、细菌内毒素或热原检查项目。
Article 52
Microbiological contamination of starting materials should be minimal.
Specifications should include requirements for microbiological limits, bacterial
endotoxin
or pyrogen.
第五十三条
洁净区内应当避免使用易脱落纤维的容器和物料；在无菌生产
的过程中，不得使用此类容器和物料。
Article 53
Containers and materials with fibre-shedding characteristics should be
minimised
in clean areas. They are prohibited to be used in aseptic process.
第五十四条
应当采取各种措施减少最终产品的微粒污染。
Article 54
Where appropriate, measures should be taken to minimize the
particulate contamination of the end product.
第五十五条
最终清洗后包装材料、容器和设备的处理应当避免被再次污染。
28
Article 55
Components, containers and equipment should be handled after the
final
cleaning process in such a way that they are not recontaminated.
第五十六条
应当尽可能缩短包装材料、容器和设备的清洗、干燥和灭菌的
间隔时间以及灭菌至使用的间隔时间。应当建立规定贮存条件下的间隔时间控制
标准。
Article 56
The interval between the washing and drying and the sterilisation of
packaging
material, containers and equipment as well as between their
sterilisation and use should be minimised and subject to a time-limit
appropriate
to the
storage conditions.
第五十七条
应当尽可能缩短药液从开始配制到灭菌（或除菌过滤）的间隔
时间。应当根据产品的特性及贮存条件建立相应的间隔时间控制标准。
Article 57
The time between the start of the preparation of a solution and its
sterilisation or filtration through a micro-organism-retaining filter should be
minimised.
There should be a set maximum permissible time for each product
that takes
into account its composition and the prescribed method of storage.
第五十八条
应当根据所用灭菌方法的效果确定灭菌前产品微生物污染水平
的监控标准，并定期监控。必要时，还应当监控热原或细菌内毒素。
Article 58
There should be working limits on contamination immediately before
sterilisation, which are related to the efficiency of the method to be used.
Where
appropriate the level of endotoxins or pyrogen should be monitored.
第五十九条
无菌生产所用的包装材料、容器、设备和任何其它物品都应当
灭菌，并通过双扉灭菌柜进入无菌生产区，或以其它方式进入无菌生产区，但应
当避免引入污染。
Article 59
Components, containers, equipment and any other article required in a
clean area
where aseptic work takes place should be sterilised and passed into
the area
through double-ended sterilisers sealed into the wall, or by a procedure
which
achieves the same objective of not introducing contamination.
第六十条
除另有规定外，无菌药品批次划分的原则：
（一）大（小）容量注射剂以同一配液罐最终一次配制的药液所生产的均质
产品为一批；同一批产品如用不同的灭菌设备或同一灭菌设备分次灭菌的，应当
可以追溯；
29
（二）粉针剂以一批无菌原料药在同一连续生产周期内生产的均
质产品为
一批；
（三）冻干产品以同一批配制的药液使用同一台冻干设备在同一生产周期内
生产的均质产品为一批；
（四）眼用制剂、软膏剂、乳剂和混悬剂等以同一配制罐最终一次配制所生
产的均质产品为一批。
Article
60: Unless otherwise specified, the principle for batch classification
of sterile
pharmaceutical products:
1.
Large/small volume injection: Homogeneous products, which are derived
from the
solution that terminally prepared in one tank at once should be
regarded
as one batch. One batch of products which is sterilized in different
equipment
or in the same equipment but in several loads should be trackable.
2. Powder
for injection: Homogeneous products which are produced from
the same
batch of sterile APIs within the same continuous production cycle
should be
regarded as one batch.
3.
Lyophilized powder for injection: Homogeneous products which are
produced
by the same Lyophilizer with the same batch of solution within the
same
production cycle should be regarded as one batch.
4. Eye
Preparation, Sterile Ointment, Emulsion and Suspension:
Homogeneous products, which are terminally prepared in the same tank should
be
regarded as one batch.
30
第十一章 灭菌工艺
Chapter 11
Sterilisation
第六十一条
无菌药品应当尽可能采用加热方式进行最终灭菌，最终灭菌产
品中的微生物存活概率（即无菌保证水平，SAL）不得高于10-6。采用湿热灭菌方
法进行最终灭菌的，通常标准灭菌时间F0
值应当大于8
分钟，流通蒸汽处理不属
于最终灭菌。
对热不稳定的产品，可采用无菌生产操作或过滤除菌的替代方法。
Article 61
Where possible, heating sterilization is the method of choice for Sterile
products.
For terminally sterilized products, the microbial survival probability
(Sterility
Assurance Level ,SAL) should be not more than 10-6. For moist heat as
terminal
sterilization, the standard sterilization time F0
should be
more than 8
minutes.
Flow steam treatment should not be considered as terminal
sterilization.
Aseptic
process operation or sterile filtration should be considered as
alternatives for thermal instable products.
第六十二条
可采用湿热、干热、离子辐射、环氧乙烷或过滤除菌的方式进
行灭菌。每一种灭菌方式都有其特定的适用范围，灭菌工艺必须与注册批准的要
求相一致，且应当经过验证。
Article 62
Moist heat, dry heat, radiation, ethylene oxide or filtration could be
applied as
sterilization methods. Every sterilization method has its specific
application scope. In any case, the sterilisation process must be in accordance
with the
marketing and manufacturing authorisations. All sterilisation processes
should be
validated.
第六十三条
任何灭菌工艺在投入使用前，必须采用物理检测手段和生物指
示剂，验证其对产品或物品的适用性及所有部位达到了灭菌效果。
Article 63
Before any sterilisation process is adopted its suitability for the
product
and its efficacy in achieving the desired sterilising conditions in all parts
of each
type of load to be processed should be demonstrated by physical
31
measurements and by biological indicators where appropriate.
第六十四条
应当定期对灭菌工艺的有效性进行再验证（每年至少一次）。设
备重大变更后，须进行再验证。应当保存再验证记录。
Article 64
The validity of the sterilisation process should be verified at scheduled
intervals,
at leastannually. And whenever significant modifications have been
made to
the equipment, revalidation should be performed. Records should be
kept of
the results.
第六十五条
所有的待灭菌物品均须按规定的要求处理，以获得良好的灭菌
效果，灭菌工艺的设计应当保证符合灭菌要求。
Article 65
For effective sterilisation the whole of the material must be subjected
to the
required treatment and the process should be designed to ensure that this
is
achieved.
第六十六条
应当通过验证确认灭菌设备腔室内待灭菌产品和物品的装载方
式。
Article 66
Validated loading patterns should be established for the material
which is
sterilised in the chamber of sterilisation equipment.
第六十七条
应当按照供应商的要求保存和使用生物指示剂，并通过阳性对
照试验确认其质量。
使用生物指示剂时，应当采取严格管理措施，防止由此所致的微生物污染。
Article 67
Biological indicators should be stored and used according to the
manufacturer’s
instructions, and their quality checked by positive controls.
If
biological indicators are used, strict precautions should be taken to avoid
transferring microbial contamination from them.
第六十八条
应当有明确区分已灭菌产品和待灭菌产品的方法。每一车（盘
或其它装载设备）产品或物料均应贴签，清晰地注明品名、批号并标明是否已经
灭菌。必要时，可用湿热灭菌指示带加以区分。
Article 68
There should be a clear means of differentiating products which have
not been
sterilised from those which have. Each basket, tray or other carrier of
products
or components should be clearly labelled with the material name, its
32
batch
number and an indication of whether or not it has been sterilised.
Indicators
such as autoclave tape may be used, where appropriate.
第六十九条
每一次灭菌操作应当有灭菌记录，并作为产品放行的依据之一。
Article 69
Sterilisation records should be available for each sterilisation run.
They
should be approved as part of the batch release procedure.
第十二章 灭菌方法
Chapter 12
Sterilisation method
第七十条
热力灭菌通常有湿热灭菌和干热灭菌，应当符合以下要求：
Article 70
Sterilisation by heat include moist heat and dry heat, it should
conform to
the following requirements:
（一）在验证和生产过程中，用于监测或记录的温度探头与用于控制的温度探头
应当分别设置，设置的位置应当通过验证确定。每次灭菌均应记录灭菌过程的时
间-温度曲线。
(1) During
the validation and production, control instrumentation should normally
be
independent of monitoring instrumentation and recording charts. The position
of the
temperature probes used for controlling and/or recording should have
been
determined during the validation . Each heat sterilisation cycle should be
recorded
on a time/temperature chart.
采用自控和监测系统的，应当经过验证，保证符合关键工艺的要求。自控和
监测系统应当能够记录系统以及工艺运行过程中出现的故障，并有操作人员监控。
应当定期将独立的温度显示器的读数与灭菌过程中记录获得的图谱进行对照。
Where
automated control and monitoring systems are used for these
applications they
should be
validated to ensure that critical process requirements are met. System
and cycle
faults should be registered by the system and observed by the
operator.
The reading of the independent temperature indicator should be
routinely
checked against the chart recorder during the sterilisation period.
（二）可使用化学或生物指示剂监控灭菌工艺，但不得替代物理测试。
33
(2)Chemical or biological indicators may also be used to monitor aseptic
process,
but should
not take the place of physical measurements.
（三）应当监测每种装载方式所需升温时间，且从所有被灭菌产品或物品达到设
定的灭菌温度后开始计算灭菌时间。
(3)Sufficient time must be allowed for the whole of the load to reach the
required
temperature before measurement of the sterilising time-period is commenced.
This time
must be determined for each type of load to be processed.
（四）应当有措施防止已灭菌产品或物品在冷却过程中被污染。除非能证明
生产过程中可剔除任何渗漏的产品或物品，任何与产品或物品相接触的冷却用介
质（液体或气体）应当经过灭菌或除菌处理。
(4)
Precautions should be taken against contamination of a sterilised load
during
cooling. Any cooling fluid or gas in contact with the product should be
sterilised
unless it can be shown that any leaking container would not be
approved
for use.
第七十一条
湿热灭菌应当符合以下要求：
Article 71
Moist heat sterilization should conform to the following requirements:
（一）湿热灭菌工艺监测的参数应当包括灭菌时间、温度或压力。
腔室底部装有排水口的灭菌柜，必要时应当测定并记录该点在灭菌全过程中
的温度数据。灭菌工艺中包括抽真空操作的，应当定期对腔室作检漏测试。
(1)
Sterilization time, temperature and pressure should be used to monitor the
process.
For
sterilisers fitted with a drain at the bottom of the chamber, it may also be
necessary
to record the temperature at this position, throughout the sterilisation
period.
There should be frequent leak tests on the chamber when a vacuum
phase is
part of the cycle.
（二）除已密封的产品外，被灭菌物品应当用合适的材料适当包扎，所用材
料及包扎方式应当有利于空气排放、蒸汽穿透并在灭菌后能防止污染。在规定的
温度和时间内，被灭菌物品所有部位均应与灭菌介质充分接触。
(2) The
items to be sterilised, other than products in sealed containers, should
be wrapped
in a material which allows removal of air and penetration of steam
but which
prevents recontamination after sterilisation. All parts of the load should
34
be in
contact with the sterilizing agent at the required temperature for the
required
time.
第七十二条
干热灭菌符合以下要求：
（一）干热灭菌时，灭菌柜腔室内的空气应当循环并保持正压，阻止非无菌
空气进入。进入腔室的空气应当经过高效过滤器过滤，高效过滤器应当经过完整
性测试。
（二）干热灭菌用于去除热原时，验证应当包括细菌内毒素挑战试验。
（三）干热灭菌过程中的温度、时间和腔室内、外压差应当有记录。
Article 72
Dry heat sterilization should conform to the following requirements:
(1) The
process used should include air circulation within the chamber and
the
maintenance of a positive pressure to prevent the entry of non-sterile
air. Any
air admitted should be passed through a HEPA filter, which
should be
qualified by the integrity test.
(2) Where
this process is also intended to remove pyrogens, challenge
tests
using endotoxins should be used as part of the validation.
(3)
Temperature, time and pressure difference between inside and outside
of the
chamber should be recorded during sterilization process.
第七十三条
辐射灭菌应当符合以下要求：
Article 73
Sterilisation by radiation should conform to the following requirements:
（一）经证明对产品质量没有不利影响的，方可采用辐射灭菌。辐射灭菌应当符
合《中华人民共和国药典》和注册批准的相关要求。
(1)
Radiation sterilisation is permissible only when the absence of deleterious
effects on
the product has been confirmed experimentally. Radiation sterilisation
should
conform to <Chinese Pharmacopeia> and registered authorisation.
（二）辐射灭菌工艺应当经过验证。验证方案应当包括辐射剂量、辐射时间、包
装材质、装载方式，并考察包装密度变化对灭菌效果的影响。
(2)
Radiation sterilisation process should be validated. The validation protocol
should
include the radiation dose, radiation time, packaging material, loading
pattern.
Validation procedures should ensure that the effects of variations in
density of
the
35
packages
are considered.
（三）辐射灭菌过程中，应当采用剂量指示剂测定辐射剂量。
(3) During
the sterilisation procedure the radiation dose should be measured by
using
dosimetry indicators.
（四）生物指示剂可作为一种附加的监控手段。
(4)
Biological indicators may be used as an additional control.
（五）应当有措施防止已辐射物品与未辐射物品的混淆。在每个包装上均应有辐
射后能产生颜色变化的辐射指示片。
(5)
Measures should be taken to prevent mix-up between irradiated and
non-irradiated materials. Radiation sensitive colour disks should also be used
on
each
package to differentiate between packages.
（六）应当在规定的时间内达到总辐射剂量标准。
(6) The
total radiation dose should be administered within a predetermined time
span.
（七）辐射灭菌应当有记录。
(7)The
radiation sterilisation process should be recorded.
第七十四条
环氧乙烷灭菌应当符合以下要求：
Article 74
Sterilisation with ethylene oxide should conform to the following
requirements:
（一）环氧乙烷灭菌应当符合《中华人民共和国药典》和注册批准的相关要求。
(1) The
Sterilisation with ethylene oxide should conform to <Chinese
Pharmacopeia> and registered authorisation
（二）灭菌工艺验证应当能够证明环氧乙烷对产品不会造成破坏性影响，且针
对不同产品或物料所设定的排气条件和时间，能够保证所有残留气体及反应产物
36
降至设定的合格限度。
(2) During
process validation it should be shown that there is no damaging
effect on
the product and that the conditions and time allowed for degassing are
such as to
reduce any residual gas and reaction products to defined acceptable
limits for
the type of product or material.
（三）应当采取措施避免微生物被包藏在晶体或干燥的蛋白质内，保证灭菌气
体与微生物直接接触。应当确认被灭菌物品的包装材料的性质和数量对灭菌效果
的影响。
(3) Direct
contact between gas and microbial cells is essential; precautions
should be
taken to avoid the presence of organisms likely to be enclosed in
material
such as crystals or dried protein. The nature and quantity of packaging
materials
can significantly affect the process.
（四）被灭菌物品达到灭菌工艺所规定的温、湿度条件后，应当尽快通入灭菌
气体，保证灭菌效果。
(4) Before
exposure to the gas, materials should be brought into equilibrium with
the
humidity
and temperature required by the process.
（五）每次灭菌时，应当将适当的、一定数量的生物指示剂放置在被灭菌物品
的不同部位，监测灭菌效果，监测结果应当纳入相应的批记录。
(5) Each
sterilisation cycle should be monitored with suitable biological
indicators, using the appropriate number of test pieces distributed throughout
the
load. The
information so obtained should form part of the batch record.
（六）每次灭菌记录的内容应当包括完成整个灭菌过程的时间、灭菌过程中腔室
的压力、温度和湿度、环氧乙烷的浓度及总消耗量。应当记录整个灭菌过程的压
力和温度，灭菌曲线应当纳入相应的批记录。
(6) For
each sterilisation cycle, records should be made of the time taken to
complete
the cycle, of the pressure, temperature and humidity within the
chamber
during the process and of the gas concentration and of the total
amount of
gas used. The pressure and temperature should be recorded
37
throughout
the cycle on a chart. The record(s) should form part of the batch
record.
（七）灭菌后的物品应当存放在受控的通风环境中，以便将残留的气体及反应
产物降至规定的限度内。
(7) After
sterilisation, the load should be stored in a controlled manner under
ventilated
conditions to allow residual gas and reaction products to reduce to the
defined
level.
第七十五条
非最终灭菌产品的过滤除菌应当符合以下要求：
Article 75
Filtration of medicinal products which cannot be sterilised in their
final
container should conform to the following requirements:
（一）可最终灭菌的产品不得以过滤除菌工艺替代最终灭菌工艺。如果药品不能
在其最终包装容器中灭菌，可用0.22μm（更小或相同过滤效力）的除菌过滤器将
药液滤入预先灭菌的容器内。由于除菌过滤器不能将病毒或支原体全部滤除，可
采用热处理方法来弥补除菌过滤的不足。
(1)Filtration alone is not considered sufficient when sterilisation in the final
container
is
possible.
If the product cannot be sterilised in the final container, solutions or
liquids
can be filtered through a sterile filter of nominal pore size of 0.22 micron
(or less),
or with at least equivalent micro-organism retaining properties, into a
previously
sterilised container. Such filters can not remove all viruses or
mycoplasmas. Consideration should be given to complementing the filtration
process
with some degree of heat treatment.
（二）应当采取措施降低过滤除菌的风险。宜安装第二只已灭菌的除菌过滤器
再次过滤药液，最终的除菌过滤滤器应当尽可能接近灌装点。
(2) Due to
the potential additional risks of the filtration method as compared with
other
sterilization processes, a second filtration via a further sterilised
micro-organism
retaining
filter, immediately prior to filling, may be advisable. The final sterile
filtration
should be carried out as close as possible to the filling point.
（三）除菌过滤器使用后，必须采用适当的方法立即对其完整性进行检查并记
录。常用的方法有起泡点试验、扩散流试验或压力保持试验。
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(3) The
integrity of the sterilised filter should be confirmed immediately after use
by an
appropriate method such as a bubble point, diffusive flow or pressure hold
test.
（四）过滤除菌工艺应当经过验证，验证中应当确定过滤一定量药液所需时间
及过滤器二侧的压力。任何明显偏离正常时间或压力的情况应当有记录并进行调
查，调查结果应当归入批记录。
(4)The
time taken to filter a known volume of bulk solution and the pressure
difference
to be used across the filter should be determined during validation
and any
significant differences from this during routine manufacturing should be
noted and
investigated. Results of these checks should be included in the batch
record.
（五）同一规格和型号的除菌过滤器使用时限应当经过验证，一般不得超过一
个工作日。
(5) The
using time of filters with the same specification should be validated.
Normally
it should not be used for more than one working day.
第十三章 无菌药品的最终处理
Chapter 13
Finishing of sterile products
第七十六条
小瓶压塞后应当尽快完成轧盖，轧盖前离开无菌操作区或房间
的，应当采取适当措施防止产品受到污染。
Article 76
Crimping of the cap should be performed as soon as possible after
stopper
insertion. Appropriate measures should be taken to prevent
contamination if the product leaving the clean area/room before capping.
第七十七条
无菌药品包装容器的密封性应当经过验证，避免产品遭受污染。
熔封的产品（如玻璃安瓿或塑料安瓿）应当作100%的检漏试验，其它包装容
器的密封性应当根据操作规程进行抽样检查。
Article 77
The integrity of the sterile medical product containers should be
validated
to avoid the product contamination. Containers closed by fusion, e.g.
glass or
plastic ampoules should be subject to 100% integrity test. Samples of
other
containers should be checked for integrity according to appropriate
procedures.
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第七十八条
在抽真空状态下密封的产品包装容器，应当在预先确定的适当
时间后，检查其真空度。
Article 78
Containers sealed under vacuum should be tested for maintenance of
that
vacuum after an appropriate, pre-determined period.
第七十九条
应当逐一对无菌药品的外部污染或其它缺陷进行检查。如采用
灯检法，应当在符合要求的条件下进行检查，灯检人员连续灯检时间不宜过长。
应当定期检查灯检人员的视力。如果采用其它检查方法，该方法应当经过验证，
定期检查设备的性能并记录。
Article 79
Filled containers of parenteral products should be inspected
individually for extraneous contamination or other defects. When inspection is
done
visually, it should be done under suitable and controlled conditions of
illumination and background. Operators doing the inspection should pass regular
eye-sight
checks, and be allowed frequent breaks from inspection. Where other
methods of
inspection are used, the process should be validated and the
performance of the equipment checked at intervals. Results should be recorded.
第十四章 质量控制
Chapter 14
Quality control
第八十条
无菌检查的取样计划应当根据风险评估结果制定，样品应当包括
微生物污染风险最大的产品。无菌检查样品的取样至少应当符合以下要求：
（一）无菌灌装产品的样品必须包括最初、最终灌装的产品以及灌装过程中发
生较大偏差后的产品；
（二）最终灭菌产品应当从可能的灭菌冷点处取样；
（三）同一批产品经多个灭菌设备或同一灭菌设备分次灭菌的，样品应当从各
个/次灭菌设备中抽取。
Article 80
Sample plan for sterility testing should based on the result of risk
assessment, Samples should in particular include samples taken from parts of
40
the batch
considered to be most at risk of contamination. The sterility testing
samples
should at least comply with the followings:
a. for
products which have been filled aseptically, samples should include
containers
filled at the beginning and end of the batch and after any significant
intervention.
b. or
products which have been heat sterilised in their final containers,
consideration should be given to taking samples from the potentially coolest
part
of the
load.
c. For one
batch of product which are sterilised by different equipment or by the
same
equipment but in deferent sterilization cycles, samples should be taken
from each
equipment/cycle involved.
第十五章 术语
Chapter 15
Glossary
第八十一条
下列术语含义是：
Article 81
The definitions of the glossary are:
（一）吹灌封设备
指将热塑性材料吹制成容器并完成灌装和密封的全自动机器，可连续进行吹
塑、灌装、密封（简称吹灌封）操作。
(1)Blow/fill/seal units are purpose built machines in which, in one continuous
operation,
containers are formed from a thermoplastic granulate, filled and then
sealed,
all by the one automatic machine.
（二）动态
指生产设备按预定的工艺模式运行并有规定数量的操作人员在现场操作的状
态。
(2)The
“in
operation” state is the condition where the
installation is functioning in
the
defined operating mode with the specified number of personnel working.
（三）单向流
指空气朝着同一个方向，以稳定均匀的方式和足够的速率流动。单向流能持
41
续清除关键操作区域的颗粒。
(3)
Laminar flow means the method that the air flows unidirectional with the
stable
symmetrical way and enough rate. It can continuously remove the
particles
at the critical operation area.
（四）隔离操作器
指配备B
级（ISO 5
级）或更高洁净度级别的空气净化装置，并能使其内部
环境始终与外界环境（如其所在洁净室和操作人员）完全隔离的装置或系统。
(4)
Isolator is a barrier or system that is equiped with Grade B (ISO 5) or
even
higher cleanness air handling units and can isolate completely the internal
environment from external environment (e.g clean room and operators).
（五）静态
指所有生产设备均已安装就绪，但没有生产活动且无操作人员在场的状态。
The
“at-rest”
state is the condition where the installation is installed, complete
with
production equipment but with no operating personnel present and no
production
activities.
（六）密封
指将容器或器具用适宜的方式封闭，以防止外部微生物侵入。
(6) Seal
means using an appropriate method to keep the containers or
utensils
in closed in order to prevent outside microbe entering.
Annex 1
reviewed by Michael Lee, Ji Yiyun, He Guoling
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