无菌生产工艺
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（摘自ISPE 无菌生产指南）
From ISPE Guideline of Sterile Manufacturing Facilities
8
例：无菌冻干粉针生产工艺 Typical LYO Process
无菌过滤
Sterile Filtration
原辅料
R.M.
称量
Weighing
配料
Liq. Prep.
非最终灭菌工艺
Process without final sterilization
3
非最终灭菌工艺
Process without final sterilizing
适用于产品不耐高温，不能采用通常的热力学方法最后 进行灭菌以去除产品中的微生物。
For those product which are thermal-sensitive and the microbe in it can not be removed by thermal sterilization.
<1 5 － －
18
无菌生产区的气流组织、送风口和回（排）风口位置、相 对邻近区域的压差等均需经过合理设计
Air flow pattern, Location of air outlets, Air pressure differences
必须关注无菌生产区A级单向流的回风对B级环境气流的 影响
2012 ISPE CHINA ANNUAL CONFERENCE
5
无菌生产工艺设计的关键
无菌生产核心区的确定
Critical Area/Core Area
2012 ISPE CHINA ANNUAL CONFERENCE
6
什么是无菌生产核心区?
What is Critical/Core Area
瓶、胶塞
Vials, Stoppers
洗瓶、洗塞
Washing
灭菌
Sterilization
灌装、半加塞
Filling, SemiStopper
成品
Finished Goods
贴签、包装
Labeling & Packaging
轧盖
Capping
冻干、压塞
Lyophilizing
2012 ISPE CHINA ANNUAL CONFERENCE
15
空气的处理 Air Treatment
室外空气中含有大量的微粒和微生物
Large amount of particles and microbe in atmosphere
空气必须经高效过滤
Air must be filtered with HEPA filter
无菌生产区的空气洁净等级必须满足GMP的要求
25
进入无菌区的物料外包装必须彻底消毒
A proper sterilization of the product packaging is needed
Aseptic – No Viable Microbe Exists
• 无菌药品 - 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。
-- 摘自中国GMP（2010年修订）
Aseptic Drug Product – The drug product which needs to be tested for their sterility by the legal standards, including aseptic formulation and APIs. -- From Chinese GMP(2010)
4
无菌生产工艺的特点
Characteristics of Aseptic Process
在无菌生产工艺中，产品、容器、密封件等分别经过灭菌 后再进行灌装、封口，而液体产品则通过无菌过滤以去除微 生物。由于产品装入最终容器后不再作进一步的灭菌处理， 因此整个生产过程必须保证不被微生物所污染。
无菌区必须采用注射用水
Only the WFI allowed into aseptic area
环境消毒液必须采用注射用水配制，并经除菌过滤
Disinfectant must be prepared by WFI and be filtered before use
2012 ISPE CHINA ANNUAL CONFERENCE
All the product/container/closures are pre-sterilized All the product-liquid must be sterile filtered No further sterilization required after filling and closing Microbe contamination must be avoided during the whole processing
23
物料所致的污染Material Contamination
物料本身未经过彻底灭菌/除菌处理
Materials not thoroughly sterilized/filtered
物料进出无菌生产区的传递过程
Pass way through aseptic area (in/out)
物料间的相互交叉污染
contact with sterile product (vials, stoppers)
工艺用水及气体 Process water and gas 成品 Finished goods 生产废品 Wastes during production
2012 ISPE CHINA ANNUAL CONFERENCE
Minimizing the influence of return air flow of class A to air supply pattern of class B area
尘埃粒子和微生物进行动态监控
Monitoring of particles and microbe in aseptic area
Cross contamination
2012 ISPE CHINA ANNUAL CONFERENCE
24
物料的控制 Material Controls
液体物料必须经过除菌过滤
Liquid materials must be filtered
无菌物料暴露操作必须在A级保护下进行
Class A protection for the exposed operation of product
The microbe standards of production area
表面微生物 洁净级别 浮游菌
cfu/m3
沉降菌
（φ90mm） cfu /4小时
接触碟
（φ55mm） cfu /碟 <1 5 25 50
5指手套
cfu /手套
A级 B级 C级 D级
<1 10 100 200
<1 5 50 100
2012 ISPE CHINA ANNUAL CONFERENCE
13
无菌生产风险类型
The type of risks in Aseptic Manufacturing Area
尘埃粒子污染
Particles Contamination
微生物污染
Microbe Contamination
物料的交叉污染
人员流向 人员流向 包物流向 11
铝盖
冻干生产核心区示意 Typical Core Area of LYO Production
核心区 A
Critical area
无菌生产区 B Aseptic Area
核心区 A
Critical area
Байду номын сангаас
D
C
B
A
12
无菌生产区的风险控制
Risk Control of Aseptic Manufacturing Area
Clean air class in compliance with GMP principle
2012 ISPE CHINA ANNUAL CONFERENCE
16
无菌药品生产环境的洁净度标准
The cleanliness standards of production area
悬浮粒子最大允许数/立方米 洁净级别
无菌工艺设计及风险控制
杨军
中国石化集团上海工程有限公司
16th – 17th April 2012, Beijing
ASEPTIC ENGINEERING AND RISK CONTROL
SINOPEC SHANGHAI ENGINEERING CO., LTD.
1
• 无菌 – 没有活体微生物存在。
≥0.5μm A级 B级 C级 D级 3,520 3,520 352,000 3,520,000
静态
≥5μm 20 29 2,900 29,000 ≥0.5μm 3520 352,000 3,520,000 --
动态
≥5μm 20 2,900 29,000 --
17
无菌药品生产环境的微生物检测标准
常用于冻干粉针、粉针、无菌原料药的生产。
Normally used in manufacturing of freeze drying powders, aseptic powders and APIs
非最终灭菌工艺又称为无菌生产工艺。
This process is also called Aseptic Processing
Return Air
Filling Room
侧下回风，B级气流全部顶送下回，无短路和上升气流现象
21
粒子在线监控点Particle Monitoring
粒子监控点
Monitoring Point
粒子监控点
Monitoring Point
22
物料的控制
Material Control
无菌区的物料 Materials in Sterile Area 原料、辅料 Raw and aux. materials 内包装材料（小瓶、胶塞）Packaging materials direct
2012 ISPE CHINA ANNUAL CONFERENCE
2
无菌药品的生产工艺
Type of Manufacturing Process
按去除微生物方法的不同：
Removing of microbe from product:
最终灭菌工艺
Process with final sterilization
核心区就是无菌产品、容器、包装物及其产品接触的表面 直接暴露在环境条件下的区域，该区域的设计必须保证产品 的无菌度要求。(FDA/ISPE) A CRITICAL AREA is one in which the sterilized drug product, containers/closures or product contact surfaces are exposed to environmental conditions that must be designed to maintain product sterility. (FDA/ISPE)
Cross Contamination
2012 ISPE CHINA ANNUAL CONFERENCE
14
风险的来源 The Sources of Risk
空气 Air 物料 Materials 设备、器具 Equipment/Tools 人员 Operators
2012 ISPE CHINA ANNUAL CONFERENCE
2012 ISPE CHINA ANNUAL CONFERENCE
19
A级单向流罩回风位置的影响 - 顶回风
LF 顶回风 LF HEPA 气流短路
A B
Filling Room
上升气流
传统单向流罩顶回风，有气流上升和短路现象
20
A级单向流罩回风位置的影响 - 下侧回风
Return Air
LF
HEPA
2012 ISPE CHINA ANNUAL CONFERENCE
7
如何确定无菌生产核心区？
How to define the Critical/Core Area?
产品流向 Product Flows 容器/包装物流向 Container/Closure Flow 操作人员 Operators 工艺设备 Process Equipment
9
无菌冻干粉针工艺布置图 Typical Layout
2012 ISPE CHINA ANNUAL CONFERENCE
10
无菌冻干粉针生产人物流向分析
Operator and Material Flow for LYO Production
包装物流向 产品流向
瓶塞
原辅料
物料流向
成品 人员 人员
From ISPE Guideline of Sterile Manufacturing Facilities
8
例：无菌冻干粉针生产工艺 Typical LYO Process
无菌过滤
Sterile Filtration
原辅料
R.M.
称量
Weighing
配料
Liq. Prep.
非最终灭菌工艺
Process without final sterilization
3
非最终灭菌工艺
Process without final sterilizing
适用于产品不耐高温，不能采用通常的热力学方法最后 进行灭菌以去除产品中的微生物。
For those product which are thermal-sensitive and the microbe in it can not be removed by thermal sterilization.
<1 5 － －
18
无菌生产区的气流组织、送风口和回（排）风口位置、相 对邻近区域的压差等均需经过合理设计
Air flow pattern, Location of air outlets, Air pressure differences
必须关注无菌生产区A级单向流的回风对B级环境气流的 影响
2012 ISPE CHINA ANNUAL CONFERENCE
5
无菌生产工艺设计的关键
无菌生产核心区的确定
Critical Area/Core Area
2012 ISPE CHINA ANNUAL CONFERENCE
6
什么是无菌生产核心区?
What is Critical/Core Area
瓶、胶塞
Vials, Stoppers
洗瓶、洗塞
Washing
灭菌
Sterilization
灌装、半加塞
Filling, SemiStopper
成品
Finished Goods
贴签、包装
Labeling & Packaging
轧盖
Capping
冻干、压塞
Lyophilizing
2012 ISPE CHINA ANNUAL CONFERENCE
15
空气的处理 Air Treatment
室外空气中含有大量的微粒和微生物
Large amount of particles and microbe in atmosphere
空气必须经高效过滤
Air must be filtered with HEPA filter
无菌生产区的空气洁净等级必须满足GMP的要求
25
进入无菌区的物料外包装必须彻底消毒
A proper sterilization of the product packaging is needed
Aseptic – No Viable Microbe Exists
• 无菌药品 - 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。
-- 摘自中国GMP（2010年修订）
Aseptic Drug Product – The drug product which needs to be tested for their sterility by the legal standards, including aseptic formulation and APIs. -- From Chinese GMP(2010)
4
无菌生产工艺的特点
Characteristics of Aseptic Process
在无菌生产工艺中，产品、容器、密封件等分别经过灭菌 后再进行灌装、封口，而液体产品则通过无菌过滤以去除微 生物。由于产品装入最终容器后不再作进一步的灭菌处理， 因此整个生产过程必须保证不被微生物所污染。
无菌区必须采用注射用水
Only the WFI allowed into aseptic area
环境消毒液必须采用注射用水配制，并经除菌过滤
Disinfectant must be prepared by WFI and be filtered before use
2012 ISPE CHINA ANNUAL CONFERENCE
All the product/container/closures are pre-sterilized All the product-liquid must be sterile filtered No further sterilization required after filling and closing Microbe contamination must be avoided during the whole processing
23
物料所致的污染Material Contamination
物料本身未经过彻底灭菌/除菌处理
Materials not thoroughly sterilized/filtered
物料进出无菌生产区的传递过程
Pass way through aseptic area (in/out)
物料间的相互交叉污染
contact with sterile product (vials, stoppers)
工艺用水及气体 Process water and gas 成品 Finished goods 生产废品 Wastes during production
2012 ISPE CHINA ANNUAL CONFERENCE
Minimizing the influence of return air flow of class A to air supply pattern of class B area
尘埃粒子和微生物进行动态监控
Monitoring of particles and microbe in aseptic area
Cross contamination
2012 ISPE CHINA ANNUAL CONFERENCE
24
物料的控制 Material Controls
液体物料必须经过除菌过滤
Liquid materials must be filtered
无菌物料暴露操作必须在A级保护下进行
Class A protection for the exposed operation of product
The microbe standards of production area
表面微生物 洁净级别 浮游菌
cfu/m3
沉降菌
（φ90mm） cfu /4小时
接触碟
（φ55mm） cfu /碟 <1 5 25 50
5指手套
cfu /手套
A级 B级 C级 D级
<1 10 100 200
<1 5 50 100
2012 ISPE CHINA ANNUAL CONFERENCE
13
无菌生产风险类型
The type of risks in Aseptic Manufacturing Area
尘埃粒子污染
Particles Contamination
微生物污染
Microbe Contamination
物料的交叉污染
人员流向 人员流向 包物流向 11
铝盖
冻干生产核心区示意 Typical Core Area of LYO Production
核心区 A
Critical area
无菌生产区 B Aseptic Area
核心区 A
Critical area
Байду номын сангаас
D
C
B
A
12
无菌生产区的风险控制
Risk Control of Aseptic Manufacturing Area
Clean air class in compliance with GMP principle
2012 ISPE CHINA ANNUAL CONFERENCE
16
无菌药品生产环境的洁净度标准
The cleanliness standards of production area
悬浮粒子最大允许数/立方米 洁净级别
无菌工艺设计及风险控制
杨军
中国石化集团上海工程有限公司
16th – 17th April 2012, Beijing
ASEPTIC ENGINEERING AND RISK CONTROL
SINOPEC SHANGHAI ENGINEERING CO., LTD.
1
• 无菌 – 没有活体微生物存在。
≥0.5μm A级 B级 C级 D级 3,520 3,520 352,000 3,520,000
静态
≥5μm 20 29 2,900 29,000 ≥0.5μm 3520 352,000 3,520,000 --
动态
≥5μm 20 2,900 29,000 --
17
无菌药品生产环境的微生物检测标准
常用于冻干粉针、粉针、无菌原料药的生产。
Normally used in manufacturing of freeze drying powders, aseptic powders and APIs
非最终灭菌工艺又称为无菌生产工艺。
This process is also called Aseptic Processing
Return Air
Filling Room
侧下回风，B级气流全部顶送下回，无短路和上升气流现象
21
粒子在线监控点Particle Monitoring
粒子监控点
Monitoring Point
粒子监控点
Monitoring Point
22
物料的控制
Material Control
无菌区的物料 Materials in Sterile Area 原料、辅料 Raw and aux. materials 内包装材料（小瓶、胶塞）Packaging materials direct
2012 ISPE CHINA ANNUAL CONFERENCE
2
无菌药品的生产工艺
Type of Manufacturing Process
按去除微生物方法的不同：
Removing of microbe from product:
最终灭菌工艺
Process with final sterilization
核心区就是无菌产品、容器、包装物及其产品接触的表面 直接暴露在环境条件下的区域，该区域的设计必须保证产品 的无菌度要求。(FDA/ISPE) A CRITICAL AREA is one in which the sterilized drug product, containers/closures or product contact surfaces are exposed to environmental conditions that must be designed to maintain product sterility. (FDA/ISPE)
Cross Contamination
2012 ISPE CHINA ANNUAL CONFERENCE
14
风险的来源 The Sources of Risk
空气 Air 物料 Materials 设备、器具 Equipment/Tools 人员 Operators
2012 ISPE CHINA ANNUAL CONFERENCE
2012 ISPE CHINA ANNUAL CONFERENCE
19
A级单向流罩回风位置的影响 - 顶回风
LF 顶回风 LF HEPA 气流短路
A B
Filling Room
上升气流
传统单向流罩顶回风，有气流上升和短路现象
20
A级单向流罩回风位置的影响 - 下侧回风
Return Air
LF
HEPA
2012 ISPE CHINA ANNUAL CONFERENCE
7
如何确定无菌生产核心区？
How to define the Critical/Core Area?
产品流向 Product Flows 容器/包装物流向 Container/Closure Flow 操作人员 Operators 工艺设备 Process Equipment
9
无菌冻干粉针工艺布置图 Typical Layout
2012 ISPE CHINA ANNUAL CONFERENCE
10
无菌冻干粉针生产人物流向分析
Operator and Material Flow for LYO Production
包装物流向 产品流向
瓶塞
原辅料
物料流向
成品 人员 人员