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 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).[separator]

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.

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 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。

（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 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 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 －





（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);
   
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
   
5. 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 sterilization 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
   
   Classificatio
   
   n
   
   Examples of operations for aseptic preparations
   
   Grade A
   
   environment
   
   with a Grade B
   
   background
   
6. 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.
   
7. Preparation of solutions or products which are not able to go through sterile-filtration before filling;
   
8. 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
   
9. Transfer of partially sealed products in fully sealed containers.
   
10. Transfer and storage of sterized primary packaging materials and apparatus , which will direct contact with medicinal products. In sealed containers
    
    Grade C
    
11. Preparation of solutions or products which could be sterile filtered before filling.
    
12. 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.
    
    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.