戴避孕套能怀孕吗-
Annex 1 : Manufacture of Sterile Products
无菌药品的生产
Document map
目录
8 Production and Specific Tech nologies
生产与具体技术
........................... .................................................. ..... 2
Terminally sterilized products
最终灭菌产品
................................... .................................................. ....... 2
Aseptic preparation and processing
无菌准备和处理
.
......................... .................................................. .... 2
Finishing of sterile products
无菌产品的最终处理
........................ .................................................. .......... 6
Sterilization
灭菌
........ .................................................. .................................................. ............................ 8
Sterilization by heat
热力灭菌
.
.................... .................................................. ........................................... 10
Moist heat sterilization
湿热灭菌
........ .................................................. .................................................. . 11
Dry heat sterilization
干热灭菌
..... .................................................. .................................................. ....... 13
Sterilization by radiation
辐射灭菌
..................................... .................................................. ................... 15
Sterilization with ethylene oxide
环氧乙烷灭菌
..................... .................................................. ................ 15
Filter sterilization of products which cannot be sterilized in their final container
非最终灭菌药品的无菌
过滤
.
....... .................................................. .................................................. ................................................ 16
Form-Fill-Seal
成型
-
灌
-
封................................................ .................................................. ...................... 20
Blow-Fill-Seal
吹
-
灌
-
封
.................... .................................................. .................................................. ... 20
Lyophilization
冻干
.
.... .................................................. .................................................. .......................... 22
Closed systems
密封系统
..................................... .................................................. .................................. 23
Single use systems (SUS)
一次性使用系统
.
....... .................................................. ................................... 24
9 Viable and non-viable environmental & process monitoring
活性和非活性环境和工艺监测
.................... 26
General
综述
... .................................................. .................................................. ...................................... 26
Environmental monitoring
环境检测
........ .................................................. ............................................. 26
Environmental monitoring- non-viable particles
非活性粒子的环境检测
.
...................... ....................... 27
Environmental and personnel monitoring-viable particles
环境和人员的监测
—
活粒子
....................... 29
Aseptic process simulation (APS) (also known as media fill)
无菌 模拟灌装
.......................................... 31
10 Quality Control (QC)
质量控制
....... .................................................. .................................................. ........ 38
Glossary
术语
.
..... .................................................. .................................................. .......................................... 40
1
8 Production and Specific Technologies
生产与具体技术
Terminally sterilized products
最终灭菌产品
8.1 Preparation of components and materials should be performed in at least a Grade D cleanroom in
order to limit the risk of microbial, pyrogen and particulate contamination, so that the product is suitable
for sterilization. Where the product is at a high or unusual risk of microbial contamination (e.g. the
product actively supports microbial growth, the product must be held for long periods before filling or the
product is not processed mostly in closed vessels), then preparation should be carried out in a Grade C
environment. Preparation of ointments, creams, suspensions and emulsions should be carried out in a
Grade C environment before terminal sterilization.
部件和物料的准备工作 至少应在
D
级洁净室中进行，以限制微生物、热原和微粒污染的风险，以便使产
品适合 灭菌。
如果产品存在微生物污染的高风险或异常风险
（例如产品适宜微生物的生长，
必 须在灌装
之前将产品放置很长时间，或者产品大多不在密闭容器中生产），应在
C
级环 境中进行准备工作。
在
最终灭菌之前，应在
C
级环境中制备软膏，霜剂，混悬剂和乳剂。
8.2 Primary packaging containers and components should be cleaned using validated processes to ensure
that particulate, pyrogen and bioburden contamination is appropriately controlled.
应使用经过验证的工艺清洁初级包装容器和组件，以确保适当地控 制颗粒，热原和生物负载污染。
8.3 Filling of products for terminal sterilization should be carried out in at least a Grade C environment.
终端灭菌产品的填充应至少在
C
级环境中进行。
8.4 Where the product is at an unusual risk of contamination from the environment because, for example,
the filling operation is slow, the containers are wide necked or are necessarily exposed for more than a
few seconds before closing, then the product should be filled in a Grade A zone with at least a Grade C
background.
当产品存在异常的环境污染风险，
如，
灌装操作缓慢，
广口容器或是必须要在密封前需暴露数秒钟，
或
是产品需要在最终灭菌 前需要存放较长时间，则产品灌装需要
C
级背景下的
A
级环境
8.5 Processing of the bulk solution should include a filtration step with a microorganism retaining filter,
where possible, to reduce bioburden levels and particulates prior to filling into the final product
containers and there should be a maximum permissible time between preparation and filling.
散装溶液的处理应包括一个带有微生物保留过滤器的过滤步骤，
以在灌装到最终产品容器中之前降低生
物负荷水平和微粒，并且在制备和灌装之间应有最大允许的时间。
8.6 Examples of operations to be carried out in the various grades are given in Table 4.
表
4
给出了各种等级的操作示例。
Table 4
:
Examples of operations and grades for terminally sterilized preparation and processing
operations
表
4
：最终灭菌的制备和加工操作的操作和等级示例
A
风险非常高的产品灌装
C
风险非常高的溶液配制。产品灌装
D
溶液配制和灌装前物料的准备
Aseptic preparation and processing
无菌准备和处理
8.7 Aseptic preparation and processing is the handling of sterile product, containers and/or devices in a
controlled environment in which the air supply, materials and personnel are regulated to prevent
microbial, pyrogenic and particulate contamination.
无菌准备和处理是在受控环境中对无菌产品、容器和
/
或设备进行处理，在该环境中对空气、物料和人
员进行管理以防止微生物、热原和微粒污染 。
8.8 The aseptic process should be clearly defined. The risks associated with the aseptic process, and any
2
associated requirements, should be identified, assessed and appropriately controlle
d. The site’s CCS
should clearly define the acceptance criteria for these controls, requirements for monitoring and the
review of their effectiveness. Methods and procedures to control these risks should be described and
implemented. Accepted residual risks should be formally documented.
应当明确 定义无菌过程。应当确定、评估和适当控制与无菌过程以及任何相关要求有关的风险。
现场的
C CS
应该明确定义这些控件的接受标准，
监视要求和有效性审查。
应描述和实施控制这 些风
险的方法和程序。可接受的残留风险应正式记录在案。
8.9 Precautions to minimize microbial, pyrogenic and particulate contamination should be taken, as per
the site’s CCS, during the preparation of the aseptic environment, during all processing stages (including
the stages before and after bulk product sterilization), and until the product is sealed in its final container.
The presence of materials liable to generate particulates and fibres should be minimized in cleanrooms.
根据现场的
CCS
，在无菌环境的准备过程中，所有加工阶段（包括大宗产 品灭菌前后的阶段）以及
密封产品之前，应采取预防措施，以尽量减少在最终包装中微生物、热原和颗粒 的污染。在洁净
室中，应尽量减少容易产生微粒和纤维的材料的存在。
8.10 Where possible, the use of equipment such as RABS, isolators or other systems, should be
considered in order to reduce the need for critical interventions into the Grade A zone and to
minimize the risk of contamination. Robotics and automation of processes can also be
considered to eliminate direct human critical interventions (e.g. dry heat tunnel, automated
lyophilizer loading, sterilization in place).
在可能的情况下，应考虑使用
RABS
、隔离器或其他系统等设备，以减少 对
A
级区的干扰并降低污
染风险。也可以考虑采用机器人技术和流程自动化来消除直接 的人为干预（例如干热通道、自动
冻干机装载、在线灭菌等）。
8.11 Examples of operations to be carried out in the various environmental grades are given in
the Table 5.
表
5
载列了在不同环境等级下进行的作业的例子。
Table 5
:
Examples of operations and grades for aseptic preparation and processing operations
表
5:
无菌准备和加工操作的示例和等级
A
Critical zone for
关键区域：
-Aseptic assembly of filling equipment.
灌装设备的无菌组装。
-Connections made under aseptic conditions (where sterilized product contact surfaces are
exposed) that are post the final sterilizing filter. These connections should be sterilized by
steam-in-place whenever feasible.
在无菌条件下
(
产品接 触表面已灭菌
)
进行连接，并在最后的无菌过滤器后进行连接。只要可行，
这些连接应 该用蒸汽在线灭菌。
-Aseptic compounding and mixing.
无菌配制和混合。
-Replenishment of sterile bulk product, containers and closures.
无菌产品、容器和密封的供应。
-Removal and cooling of unprotected (e.g. with no packaging) items from sterilizers.
将没有保护的
(
如无包装的
)
物品从灭菌器中取出并冷却。
-Staging and conveying of sterile primary packaging components.
无菌初级包装部件的准备和运输。
3
-Aseptic filling, sealing of containers such as ampoules, vial closure, transfer of open or partially
stoppered vials.
无菌灌装，密封容器，如安瓿，小瓶封口，转移开口或半压盖的小瓶。
-Loading of a lyophilizer.
装入冻干机。
B
Background support for the Grade A zone (when not in an isolator).
A
级区域的背景
(
当不在隔离器中时
)
。
-Transport, while protected from the surrounding environment, of equipment, components and
ancillary items for introduction into the Grade A zone.
在不受周围环境影响的情况下，将设备、部件和附属物品运入
A
级区域。
C
-Preparation of solutions to be filtered including weighing.
待过滤溶液的配制
D
-Cleaning of equipment.
清洁设备。
-Handling of components, equipment and accessories after washing.
清洗后的零部件、设备和附件的处理。
-Assembly of cleaned components, equipment and accessories prior to sterilization.
在灭菌前组装清洁过的部件、设备和附件。
-Assembly of closed and sterilized SUS using intrinsic aseptic connectors.
使用内部无菌连接器组装封闭和灭菌的
SUS
（一次性系统）。
8.12 For sterile products that cannot be filtered, the following should be considered:
对于不能过滤的无菌产品，应考虑以下事项
:
i.
All product and component contact equipment should be sterilized prior to use.
所有与产品和部件接触的设备在使用前都应灭菌。
ii.
All raw materials should be sterilized and aseptically added or subsequently sterilized by
filtration.
所有的原料都要经过灭菌，无菌添加或除菌过滤。
iii.
Bulk solutions should be sterilized by a validated process, e.g. by heat, chemical sterilization or
via sterile filtration.
散装溶液应通过经过验证的工艺进行灭菌，例如通过加热、化学灭菌或通过除菌过滤。
iv.
All materials added to the sterile bulk product should be sterilized prior to addition.
添加到无菌散装产品中的所有物料应在添加前进行灭菌。
8.13 The unwrapping, assembly and preparation of sterilized equipment, components and ancillary items
and the preparation and filling of the sterile product should be treated as an aseptic process and performed
in a Grade A zone with a Grade B background. Where an isolator or RABS is used, the background
should be in accordance with paragraphs 4.21 & 4.22.
灭菌设备、
部件和附属物品的拆卸、
装配和制备以及无菌产品 的制备和灌装应作为无菌工艺处理，
并在
具有
B
级背景的
A
级区域内进行。当使用隔离器或
RABS
时，背景应符合
4.21
和
4.22
章节要求。
8.14 Preparation and filling of sterile products such as ointments, creams, suspensions and emulsions
should be performed in a Grade A zone with a Grade B background when the product and components
are exposed to the environment and the product is not subsequently filtered (via a sterilizing filter) or
terminally sterilized. Where an isolator or RABS is used, the background should be in accordance with
4
paragraphs 4.21 & 4.22.
当产品和成分暴露在环境中且随后未对产品进行过滤（通过除菌过滤器）或最终 灭菌时，应在具有
B
级
背景的
A
级区域进行无菌产品（如软膏、乳膏 、悬浮液和乳剂）的制备和灌装。当使用隔离器或
RABS
时，背景应符合
4.21< br>和
4.22
章节的要求。
8.15 Aseptic connections should be performed in a Grade A zone with a Grade B background unless
subsequently sterilized in place or conducted with validated intrinsic sterile connection devices that
minimize any potential contamination from the immediate environment. Where an isolator or RABS is
used, the background should be in accordance with paragraphs 4.21 & 4.22. Aseptic connections should
be appropriately assessed and their effectiveness verified. For requirements regarding intrinsic sterile
connection devices refer to paragraph 8.120.
无菌连接应在具有
B级背景的
A
级区域中进行，除非随后进行在线灭菌或使用经过验证的固有无菌连接
设备进行，以最大程度地减少对周围环境的潜在污染。如果使用隔离器或
RABS
，则背景应符 合第
4.21
和
4.22
章节的规定。应当适当评估无菌连接并验证其有效性 。有关固有无菌连接设备的要求，请参见第
8.120
章节。
8.16 Aseptic manipulations (including non- intrinsic aseptic connections) should be minimized through
the use of engineering design solutions such as preassembled and sterilized equipment. Whenever feasible,
product contact piping and equipment should be pre-assembled, and sterilized in place.
无菌操作
(
包括非固有的无 菌连接
)
应尽量减少使用工程设计解决方案，如预先组装和灭菌设备。在可行
的情况下 ，产品接触管道和设备应预先组装，并在线灭菌。
8.17 There should be an authorized list of allowed interventions, both inherent and corrective, that may
occur during production. The procedures listing the types of inherent and corrective interventions, and
how to perform them, should be updated, as necessary to ensure consistency with the actual
manufacturing activities. In the event that an unauthorized intervention is required, details of the
intervention conducted should be recorded and fully assessed under the manufacturer's PQS.
应该有一份在生产过程中可能发生的 ，
允许的干预措施的授权清单，
包括固有干预措施和纠正措施。
列
出固有和纠 正性干预的类型以及如何执行的程序应根据需要进行更新，
以确保与实际生产活动的一致性。
如 果需要未经授权的干预，则应记录进行的干预的详细信息，并根据制造商的
PQS
进行全面评估 。
8.18 The duration of each aspect of aseptic preparation and processing should be limited to a defined
and
validated maximum time, including:
无菌准备和加工的每个方面的持续时间应限制在规定和验证的最长时间内，包括
:
i.
The holding time between equipment, component, and container cleaning, drying and
sterilization.
设备、部件和容器清洗、干燥和灭菌之间的保持时间。
ii.
The holding time for sterilized equipment, components, and containers before use and during
filling/assembly.
灭菌设备、部件和容器在使用前和灌装
/
装配期间的保持时间。
iii.
The holding time for a decontaminated environment, such as the RABS and isolator before and
during filling /assembly.
在灌装
/
组装之前和过程中，用于净化环境（如
RABS
和隔离器）的保持时间。
iv.
The time between the start of the preparation of a product and its sterilization or filtration through
a microorganism-retaining filter (if applicable), through to the end of the aseptic filling process.
There should be a maximum permissible time for each product that takes into account its
composition and the prescribed method of storage.
从产品开始制备到通过除菌过滤器（如果适用）进行除菌或过滤直到无菌 灌装过程结束之间的
时间。考虑到产品的成分和规定的存储方法，每种产品应有最大允许时间。
v.
The holding time for sterilized product prior to filling.
5
灌装前灭菌产品的保持时间。
vi.
The aseptic processing time.
无菌处理时间。
vii.
The filling time.
灌装时间。
viii.
The maximum exposure time of sterilized containers and closures in the critical processing zone
(including filling) prior to closure.
灭菌容器和封闭容器在关键加工区域
(
包括灌装
)
密封前 的最大暴露时间。
8.19 Aseptic operations (including APS) should be observed at a regular basis by personnel with specific
expertise in aseptic processing to verify the correct performance of operations and address inappropriate
practices if detected.
具有无菌处理专业知识的人员应定期观察无菌操作（包括
APS
），以验证操作的正确性能并在 发现错误
后解决不适当的做法。
Finishing of sterile products
无菌产品的最终处理
8.20 Open primary packaging containers (including partially stoppered vials or prefilled syringes) should
be maintained under Grade A conditions with Grade B background (e.g. Barrier Technology), or under
Grade A conditions with physical segregation from operators (e.g. UDAF carts) until the stopper is fully
inserted.
打开的初级包 装容器（包括部分加塞的小瓶或预充式注射器）应在具有
B
级背景的
A
级条件 下（例如屏
障技术），或在与操作员物理隔离的
A
级条件下（例如
UDAF< br>手推车）保存，直到塞子完全插入。
8.21 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g.
Blow-fill-seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags,
glass or plastic ampoules, should be subject to 100% integrity testing. Samples of containers closed by
other methods should be taken and checked for integrity using validated methods. The frequency of
testing should be based on the knowledge and experience of the
container and closure systems being used.
A scientifically valid sampling plan should be utilized. The sample size should be based on information
such as supplier approval, packaging component specifications and process knowledge. It should be noted
that visual inspection alone is not considered as an acceptable integrity test method.
容器应通过适当 验证的方法进行封闭。
通过熔合封闭的容器，
例如吹罐封
（
BFS
）
、
成型密封
（
FFS
）
、
小容量和大容量注射剂（
SVP
和
LVP
）袋、玻璃或塑料安瓿，应进行
100%
完 整性测试。应对用其他方
法封闭的容器取样，
并用经过验证的方法检查其完整性。
测试 频率应基于所使用的容器和封闭系统的知
识和经验。应使用科学有效的抽样计划。样品量应基于供应商批 准、包装组件规格和工艺知识等信息。
应当注意的是，仅凭目视检查并不被认为是一种可接受的完整性测 试方法。
8.22 Containers sealed under vacuum (where the vacuum is necessary for the product stability) should be
tested for maintenance of vacuum after an appropriate pre- determined period and during shelf life.
在真空下密封的容器
（真空对产品的稳定性是必要的）
应在适当的预定时间后和货架期内进行真 空保持
试验。
8.23 The container closure integrity validation should take into consideration any transportation or
shipping requirements that may negatively impact the integrity of the container (e.g. by decompression or
temperature extremes).
容器密封完整性验证应考 虑任何可能对容器完整性产生负面影响的运输或装运要求
(
例如通过减压或极
端温度< br>)
。
8.24 Where the equipment used to crimp vial caps can generate large quantities of non-viable particulates,
measures to prevent particulate contamination such as locating the equipment at a physically separate
station equipped with adequate air extraction should be taken.
如果用于压盖的设备会产生大 量不可行的颗粒，
则应采取措施来防止颗粒污染，
例如将设备放置在配备
6
有足够空气的物理独立位置上。
8.25 Vial capping can be undertaken as an aseptic process using sterilized caps or as a clean process
outside the aseptic core. Where the latter approach is adopted, vials should be protected by Grade A
conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be
protected with a Grade A air supply until the cap has been crimped. Where capping is a manual process it
should be performed under Grade A conditions either in an appropriately designed isolator or into Grade
A zone with a Grade B background.
小瓶的 轧盖可以采用灭菌后的盖以无菌操作或是无菌区外以洁净工艺完成。
如果采用后一种方法，
小瓶
应在离开无菌处理区之前受到
A
级条件的保护，之后加塞的小瓶应使用
A级空气保护，直到瓶盖卷压紧
为止。如果封盖是手工操作，则应在
A
级条件下进行 ，要么在设计适当的隔离器中进行，要么在
A
级区
域内进行，背景为
B
级。
8.26 Where capping of aseptically filled sterile product is conducted as a clean process with Grade A air
supply protection, vials with missing or displaced stoppers should be rejected prior to capping.
Appropriately qualified, automated methods for stopper height detection should be in place.
如果无菌灌装的无菌产品 压盖是作为具有
A
级空气保护的洁净工艺进行的，则在封盖之前，
应将无塞
或 跳塞的小瓶作报废处理。
应采用适当的合格的自动方法进行塞子高度的检测。
8.27 Where human intervention is required at the capping station, appropriate technological and
organizational measures should be used to prevent direct contact with the vials and to minimize microbial
contamination.
如果需 要在压盖站进行人为干预，
应采用适当的技术和组织措施，
以防止直接接触小瓶，
并尽 量减少微
生物污染。
8.28 RABS and isolators may be beneficial in assuring the required conditions and minimizing the
microbial contamination associated with direct human interventions into the capping operation.
RABS
和隔离器可能有助于确保所需的条件，并将与压盖操作中的人直接干预相关的微生物污染降至 最
低。
8.29 All filled containers of parenteral products should be inspected individually for extraneous
contamination or other defects. Defect classification and criticality should be determined during
qualification and based on risk and historical knowledge. Factors to consider include, but are not limited
to, the potential impact of the defect to the patient and the route of administration. Different defect types
should be categorized and batch performance analysed. Batches with unusual levels of defects, when
compared with routine defect numbers for the process (based on historical and trend data), should lead to
an investigation. A defect library should be generated and maintained which captures all known classes of
defects. The defect library should be used for the training of production and quality assurance personnel.
Critical defects should not be identified during any subsequent sampling and inspection of acceptable
containers. Any critical defect identified should trigger an investigation as it indicates a possible failure of
the original inspection process.
应对所有已灌装的注射用产品容器进行单独检查 ，
以确定是否存在外来污染或其他缺陷。
缺陷分类和严
重程度应在验证期间根据风险和 历史知识确定。
要考虑的因素包括但不限于缺陷对患者的潜在影响和给
药途径。
应对不 同的缺陷类型进行分类，
并批操作进行分析。
当与工艺的常规缺陷数
（基于历史和趋势
数据）
比较时，
具有异常缺陷水平的批次，
应该进行调查。
应该建立 并维护所获得的已知缺陷的缺陷库。
缺陷库应用于生产和质量保证人员的培训。
在随后对可接受 容器进行的任何抽样和检查期间，
不应识别
出关键缺陷。任何发现的关键缺陷都应引发调查，因 为它表明最初的检查过程可能失败。
8.30 When inspection is done manually, it should be performed under suitable and controlled conditions
of illumination and background. Inspection rates should be appropriately controlled and qualified.
Operators performing the inspection should undergo visual inspection qualification (whilst wearing
corrective lenses, if these are normally worn) at least annually. The qualification should be undertaken
using appropriate samples from the manufacturer's defect library sets and taking into consideration worst
case scenarios (e.g. inspection time, line speed where the product is transferred to the operator by a
conveyor system, container size or fatigue at the end of shift) and should include consideration of
eyesight checks. Operator distractions should be minimized and frequent breaks, of an appropriate
7
duration, from inspection should be taken.
当手动进行检查时，
应在合适的和受控的照明和背景条件下进行。
应适当控制检查率并确保合格。
执行
检查 的操作员应进行目视检查资格鉴定
（如果正常佩戴矫正镜片，
则应佩戴矫正镜片）
。< br>至少每年一次。
应使用制造商缺陷库中的适当样品进行鉴定，
并考虑最坏情况。
场景
（例如检验时间、
通过输送系统将
产品传送给操作员的生产线速度、
容器 尺寸或轮班结束时的疲劳程度）
并应考虑进行视力检查。
应尽量
减少操作者分散注意力 ，并应在适当的时间内经常中断检查。
8.31 Where automated methods of inspection are used, the process should be validated to detect
known
defects (which may impact the product quality, safety or efficacy) and be equal to, or better than, manual
inspection methods. The performance of the equipment should be challenged using representative defects
prior to start up and at regular intervals.
在使用自动化检验 方法的情况下，
应对流程进行验证，
以检测已知缺陷
（可能影响产品质量、
安 全性或
有效性）
，
且该流程应等于或优于人工检验方法。
应在启动前定期使用 代表性缺陷对设备进行性能检查。
8.32 Results of the inspection should be recorded and defect types and numbers trended. Reject levels for
the various defect types should also be trended based on statistical principles. Impact to product on the
market should be assessed as part of the investigation when adverse trends are observed.
应记录检查结果，
并对缺陷类型和数量进行趋势分析。
各种缺陷类型的报废 率也应根据统计原则进行趋
势分析。当观察到不利趋势时，作为调查的一部分，应评估产品对市场的影响 。
Sterilization
灭菌
8.33 Where possible, finished product should be terminally sterilized, using a validated and controlled
sterilization process, as this provides a greater assurance of sterility than a validated and controlled sterile
filtration process and/or aseptic processing. Where it is not possible for a product to undergo terminal
sterilization, consideration should be given to using terminal bioburden reduction steps, such as heat
treatments (e.g. pasteurization), combined with aseptic process to give improved sterility assurance.
在可能的情况下，
应使用经过验证和 控制的灭菌工艺对成品进行最终灭菌。
因为这提供了比验证和控制
的无菌过滤过程和
/
或无菌处理有更好的无菌性保证。如果不可能对产品进行最终灭菌，则应考虑使用
最终生物负荷 减少步骤，例如热处理巴氏杀菌），结合无菌工艺，以提供更好的无菌保证。
8.34 The selection, design and location of the equipment and cycle
/
programme used for sterilization
should be based on scientific principles and data which demonstrate repeatability and reliability of the
sterilization process. Critical parameters should be defined, controlled, monitored and recorded.
用于灭菌的设备和周期
/
程序的选择、设计和位置应 以科学原则和数据为依据，证明灭菌过程的可重复
性和可靠性。应定义、控制、监测和记录关键参数。< br>
8.35 All sterilization processes should be validated. Validation studies should take into account the
product composition, storage conditions and maximum time between the start of the preparation of a
product or material to be sterilized and its sterilization. Before any sterilization process is adopted, its
suitability for the product and equipment, and its efficacy in consistently achieving the desired sterilizing
conditions in all parts of each type of load to be processed should be validated notably by physical
measurements and where appropriate by biological indicators (BI). For effective sterilization, the whole
of the product, and surfaces of equipment and components should be subject to the required treatment and
the process should be designed to ensure that this is achieved.
所有灭菌过程都应经过验证。
验证应考虑产 品组成、
储存条件和从准备要灭菌的产品或材料开始到灭菌
之间的最长时间。
在采用任 何灭菌方法之前，
应通过物理测量并在适当情况下通过生物学指标来验证其
对产品和设备的适用 性，
以及在要处理的每种负载类型的所有部分中始终达到所需灭菌条件的能力。
为
了有 效灭菌，所有的产品、设备和部件的表面应进行所需的处理，工艺设计应确保这一点。
8.36 Particular attention should be given when the adopted sterilization method is not described in the
current edition of the Pharmacopoeia, or when it is used for a product which is not a simple aqueous
solution. Where possible, heat sterilization is the method of choice.
当所 采用的灭菌方法在现行药典中没有描述时，
或当被灭菌产品不是简单的水溶液，
应特别注意。< br>在可
能的情况下，热灭菌是首选的方法。
8
8.37 Validated loading patterns should be established for all sterilization processes and should be subject
to periodic revalidation. Maximum and minimum loads should also be considered as part of the overall
load validation strategy.
应为所有灭菌过程建立经验证的装载模式，< br>并应定期进行再验证。
最大和最小负载也应作为总体负载验
证策略的一部分加以考虑。< br>
8.38 The validity of the sterilizing process should be reviewed and verified at scheduled intervals based
on risk. Heat sterilization cycles should be revalidated with a minimum frequency of at least annually.
灭 菌过程的有效性应根据风险按预定的时间间隔进行审查和验证。热灭菌应至少每年重新验证一次。
8.39 Routine operating parameters should be established and adhered to for all sterilization processes, e.g.
physical parameters and loading patterns.
应为所有灭菌过程建立并遵守常规操作参数，例如物理参数和装载模式。
8.40 There should be mechanisms in place to detect a sterilization cycle that does not conform to the
validated parameters. Any failed sterilization or sterilization that deviated from the validated process (e.g.
have longer or shorter phases such as heating cycles) should be investigated.
应该有相应的机制来检测不符合验证参数的灭菌。任何失败的 灭菌或灭菌偏离验证过程
(
如有较长或较
短的阶段、加热周期
)
应进 行调查。
8.41 Suitable BIs placed at appropriate locations may be considered as an additional method to support
the validation of the sterilization process. BIs shoul
d be stored and used according to the manufacturer’s
instructions. Where BIs are used to support validation and/or to monitor a sterilization process (e.g. for
ethylene oxide), positive controls should be tested for each sterilization cycle. If BIs are used, strict
precautions should be taken to avoid transferring microbial contamination to
the manufacturing or other
testing processes. BI results in isolation do not give assurance of sterilization and should not be used to
override other critical parameters and process design elements.
可以考虑将放置在适当位置的合适的
BsS
作为支持灭菌过程确认的附加方 法。
BIs
应按照制造商的说明进
行储存和使用。其中
BIs
用于支 持确认和
/
或监控灭菌过程（例如环氧乙烷）以外，应为每个灭菌周期测
试阳性对照。 如果使用
BIs
，应采取严格的预防措施，以避免将微生物污染转移到制造或其他测试过程中。单独的
BI
结果不能保证灭菌，不应用于覆盖其他关键参数和工艺设计元素。
8.42 The reliability of BIs is important. Suppliers should be qualified and transportation and storage
conditions should be controlled in order that BI quality is not compromised. Prior to use of a new
batch/lot of BIs, the population and identity of the indicator organism of the batch/lot should be verified.
For other critical parameters, e.g. D-value, Z-value, the batch certificate provided by the qualified
supplier can normally be used.
BIs
的可靠性很重要。供应商应具备资格，运输和储存条件应得到控制，以确保
BI
质量不受影响 。在使
用新批
/
批次
BIS
之前，
应核核实该批
/
批次的指示生物的种群和身份。
对于其他关键参数，
如
D
值、
Z
值，
可正常使用合格供方提供的批次证明。
8.43 There should be a clear means of differentiating products, equipment and components, which have
not been subjected to the sterilization process from those which have. Containers used to carry products
such as baskets or trays, items of equipment and/or components should be clearly labelled (or
electronically tracked) with the material name, product batch number and an indication of whether or not
it has been sterilized. Indicators such as autoclave tape, or irradiation indicators may be used, where
appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilization process.
However, these indicators show only that the sterilization process has occurred, hey do not indicate
product sterility or achievement of the required sterility assurance level.
应该有一种 明确的方法来区分未经过灭菌处理的与经过灭菌处理的产品、
设备和部件。
用于装载产品的容器，如篮子或托盘，设备和（或）部件应清楚地贴上有物料名称、产品批号和是否灭菌的说明的标签
（或电子跟踪）
。
在适当的情况下，
可以使用诸如高压灭菌带或辐照指示器之类的指 示器来指示一批
（或
子批）
已经经过了灭菌过程。
然而，
这些指标只 表明发生了灭菌过程，
它们不表示产品无菌或达到要求
的无菌保证水平。
8.44 Sterilization records should be available for each sterilization run. Each cycle should have a unique
9
identifier. They should be reviewed and approved as part of the batch certification procedure.
每次灭菌都应有灭菌记录。
每个周期应该有一个唯一的标识符。
它们应作为批认证程序的一部分进行审
查和批准。
8.45 Where possible, materials, equipment and components should be sterilized by validated methods
appropriate to the specific material. Suitable protection after sterilization should be provided to prevent
recontamination. If sterilized items are not used immediately after sterilization, these should be stored
using appropriately sealed packaging. A maximum hold time should also be established. Where justified,
components that have been packaged with multiple sterile packaging layers need not be stored in a
cleanroom if the integrity and configuration of the sterile pack allows the items to be readily disinfected
during transfer by operators into the Grade A zone, (e.g. by the use of multiple sterile coverings that can
be removed at each transfer from lower to higher grade). Where protection is achieved by containment in
sealed packaging, this packaging process should be undertaken prior to sterilization.
在可能的情况下，
物料、
设备和部件应通 过适用于特定材料的经验证的方法进行灭菌。
灭菌后应提供适
当的保护，
以防止再污染 。
如果灭菌后的物品没有立即使用，
应使用适当的密封包装储存。
还应规定最
长保留时间。
在合理的情况下，
已经用多个无菌包装层包装的部件不需要存储在洁净室中，如果无菌包
允许物品在操作人员转移到
A
级区域期间容易灭菌（例如使用多层无菌 覆盖物，每次从低等级转到高等
级时可将其去除）。在通过密封包装实现保护的情况下，应在灭菌之前进 行这一包装过程。
8.46 Where materials, equipment, components and ancillary items are sterilized in sealed packaging and
then transferred into the Grade A zone, this should be done using appropriate, validated methods (for
example, airlocks or pass-through hatches) with accompanying disinfection of the exterior of the sealed
packaging. The use of rapid transfer port technology should also be considered. These methods should be
demonstrated to effectively control the potential risk of contamination of the Grade A zone and Grade B
area and, likewise, the disinfection procedure should be demonstrated to be effective in reducing any
contamination on the packaging to acceptable levels for entry of the item into the Grade B and Grade A
areas.
物料、设备、部件和附属物经密封包装灭菌后转入
A
级区的，应使用适当的 、经过验证的方法（例如气
闸或传递窗）
进行此项工作。
同时对密封包装的外部进行消 毒。
还应考虑使用快速传输端口技术。
应证
明这些方法可有效控制
A
级区和
B
级区的潜在污染风险，同时应证明是消毒程序有效的，证明消毒程序
能有效地 将包装上的任何污染降低到可接受的水平，以使物品进入
B
级和
A
级区域。< br>
8.47 Where materials, equipment, components and ancillary items are sterilized in sealed packaging or
containers, the packaging sealing process should be validated. The validation should consider the
integrity of the sterile protective barrier system and the maximum hold time before sterilization and
maximum shelf life assigned to the sterilized items. The integrity of the sterile protective barrier system
for each of the sterilized items should be confirmed prior to use.
在 密封包装或容器中对物料、
设备、
部件和附属物品进行灭菌的，
应当对包装密封过程进 行验证。
验证
应考虑无菌保护屏障系统的完整性、
灭菌前的最长保存时间以及分配给已 灭菌物品的最长保存期。
在使
用前，应确认每个已灭菌物品的无菌保护屏障系统的完整性。
8.48 For materials, equipment, components and ancillary items that are necessary for aseptic processing
but cannot be sterilized, an effective and validated disinfection and transfer process should be in place.
These items, once disinfected, should be protected to prevent recontamination. These items, and others
representing potential routes of contamination, should be included in the environmental monitoring
program.
对于无 菌工艺所必需但不能灭菌的材料、
设备、
部件和附属物品，
应建立有效和经验证的消毒 和转移流
程。这些物品一旦被消毒后，应加以保护，防止再次污染。这些物品和其他代表潜在污染途径的 物品，
应列入环境监测计划。
Sterilization by heat
热力灭菌
8.49 Each heat sterilization cycle should be recorded either electronically or by hardcopy, on equipment
with suitable accuracy and precision. Monitoring and recording systems should be independent of the
controlling system (e.g. by the use of duplex/double probes).
每次热灭菌应以适当准确度 和精确度的传感器在设备上进行电子记录或纸质记录。
监控和记录系统应独
立于控制系统（例如 ，通过使用双工
/
双探头）。
10
8.50 The position of the temperature probes used for controlling and/or recording should be determined
during the validation which should include heat distribution and penetration studies and, where applicable,
also checked against a second independent temperature probe located at the
same position.
用于控制和
/
或记录的温度探头的位置应在验证期间确定，验证应包括热分布和穿透研究，并且在适用
的情况下，还 应对照位于同一位置的第二个独立温度探头进行检查。
8.51 Sufficient time should be allowed for the whole of the load to reach the required temperature before
measurement of the sterilizing time-period starts. For sterilization cycles controlled by using a reference
probe within the load, specific consideration should be given to ensuring the load probe temperature is
controlled within defined temperature range prior to cycle commencement.
在开始测量灭菌时间之前，
应使整个负载有足够的时 间达到所需的温度。
对于在负载内使用参考探头控
制的灭菌周期，应特别考虑确保在周期开始之 前将负载探头的温度控制在规定的温度范围内。
8.52 After completion of the high temperature phase of a heat sterilization cycle, precautions should be
taken against contamination of a sterilized load during cooling. Any cooling liquid or gas that comes in
contact with the product or sterilized material should be sterilized.
在完成热灭菌周期的高温阶段后，
应采取预防措施，
防止在冷却过程中被灭菌的物品受到污染 。
与产品
或灭菌物品接触的任何冷却液体或气体都应该是无菌的。
8.53 In those cases where parametric release has been authorized, a robust system should be applied to
the product lifecycle validation and the routine monitoring of the manufacturing process. This system
should be periodically reviewed. Further guidance regarding parametric release is provided in Annex 17.
在已批准参数放行 的情况下，
应将稳定的系统应用于产品生命周期验证和制造过程的常规监视。
该系统
应 定期审查。附件
17
提供了有关参数释放的更多指南。
Moist heat sterilization
湿热灭菌
8.54 Moist heat sterilization utilises steam or superheated water, typically at lower temperatures and
shorter duration than dry heat processes, in order to sterilize a product or article. Moist heat sterilization
of hard goods or porous loads is primarily effected by latent heat of condensation of clean steam and the
quality of steam is therefore important to provide consistent results. For aqueous
1
liquid-filled containers,
energy from moist heat is transferred through conduction and/or convection to the content of the
container without direct contact with the autoclave steam. In these cases, time and temperature are the key
parameters and steam quality does not have the same impact to the process. Moist heat sterilization
processes may be utilized to sterilize or control bioburden (for non
sterile applications) of thermally
stable materials, articles or products and is the preferred method of sterilization, where possible. Moist
heat sterilization can be achieved using steam, (direct or indirect contact), but also includes other systems
such as superheated water systems. Superheated systems are typically used for the terminal sterilization
of product in flexible containers where the pressure differentials associated with the steam would cause
damage to the primary container.
湿热灭菌利用蒸汽或过热水对产品 或物品进行灭菌，
通常比干热灭菌温度低，
持续时间短。
硬质物品或
多孔物品 的湿热灭菌主要受纯蒸汽的冷凝潜热和蒸汽质量的影响。
因此提供一致的结果很重要。
对于水< br>填充的容器，来自湿热的能量通过传导和
/
或对流传递到容器的内容物，而不与高压釜直 接接触蒸汽。
在这些情况下，
时间和温度是关键参数，
而蒸汽品质对过程的影响并不相 同。
湿热灭菌过程可用于灭菌
或控制生物限度（对于非无菌应用）。对热稳定的材料、物品或产 品进行灭菌，并在可能的情况下作为
首选的灭菌方法。可使用蒸汽（直接或间接接触）进行湿热灭菌，还 包括过热水系统等其他系统。过热
系统通常用于对柔性容器中的产品进行终端灭菌，其中压力差蒸汽会对 主容器造成损坏。
8.55 For porous cycles (hard goods) time, temperature and pressure should be used to monitor the process.
Each item sterilized should be inspected for damage, packaging material integrity and moisture on
removal from the autoclave. Any item found not to be fit for purpose should be removed from the
manufacturing area and an investigation performed.
对于多孔物品（硬的物品）的灭菌，应使用时间、温度和压力来监控 过程。在从高压灭菌器中取出时，
应检查灭菌的每个物品是否损坏、
包装材料是否完整以及是否 受潮。
任何发现不适合使用的物品都应从
11
生产区域移走，并进行调查。
8.56 For autoclaves fitted with a drain at the bottom of the chamber, the temperature should be recorded
at this position throughout the sterilization period. For steam in place systems, the temperature should be
recorded at condensate drain locations throughout the sterilization period.
对于在灭 菌室底部装有排水管的高压灭菌器，
应在整个灭菌期间记录该位置的温度。
对于在线蒸汽系统，
在整个灭菌期间，应记录冷凝水排放位置的温度。
8.57 Validation of porous cycles should include a calculation of equilibration time, exposure time,
correlation of pressure and temperature and maximum temperature range during exposure. Validation of
fluid cycles should include temperature, time and/or F
0
. These critical processing parameters should be
subject to defined limits (including appropriate tolerances) and be confirmed as part of the sterilization
validation and routine cycle acceptance criteria.
多孔物品灭菌验证应包括平衡时 间、
暴露时间、
压力和温度的相关性，
以及暴露期间最大温度范围的计
算。液 体物品灭菌验证应包括温度、时间和
/
或
F
0
值。这些关键工艺参数 应符合规定的限值（包括适当
的公差），作为灭菌验证和常规灭菌接受标准的一部分进行确认。
8.58 Leak tests on the sterilizing system should be carried out periodically (normally weekly) when a
vacuum phase is part of the cycle or the system is returned, post- sterilization, to a pressure lower than the
environment surrounding the sterilized system.
当真空阶段是灭菌的一部分或灭菌后系统回到低于灭菌系统周围环境的压力时，
应定 期
（通常每周）
对
灭菌系统进行泄漏测试。
8.59 There should be adequate assurance of air removal prior to and during sterilization when the
sterilization process includes air purging (e.g. porous autoclave loads, lyophilizer chambers). For
autoclaves, this should include an air removal test cycle (normally performed on a daily basis) or an air
detector system. Loads to be sterilized should be designed to support effective air removal and be free
draining to prevent the build-up of condensate.
当灭菌过程 包括空气吹扫
（如多孔物品装载、
冻干器室）
时，
应充分保证灭菌前和灭菌期 间的空气去除。
对于高压灭菌器，
这应包括空气去除测试
（通常每天进行）
或 空气检测系统。
灭菌负载应设计为支持有
效的空气去除，并可自由排放，以防止冷凝水的积聚。
8.60 The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a
material which allows removal of air and penetration of steam and prevents recontamination after
sterilization. All loaded items should be dry upon removal from the sterilizer. Load dryness should be
confirmed by visual inspection as a part of the sterilization process acceptance.
除密封 容器中的产品外，
待消毒的物品应干燥，
并用一种可排除空气和蒸汽渗透的材料包裹，
以防止灭
菌后再次污染。
所有装载的物品从灭菌器中取出后应保持干燥。
作为灭菌过程 验收的一部分，
应通过目
视检查来确认负载的干燥度。
8.61 If it is necessary to wet equipment using WFI (e.g. ultrafiltration membrane) prior to the sterilization
process, then a risk-based assessment should be carried out to demonstrate the acceptable dryness level
that will not impact the sterility of the equipment sterilized and the product sterility assurance level. The
hold time between the wetting phase and sterilization should be justified and validated.
如果有必要在灭菌过程之前使用
WFI
（如超滤膜）湿润设备，应进行基于 风险的评估，以证明可接受的
干燥水平不会影响灭菌设备的无菌和产品的无菌保证水平。
润湿阶 段和灭菌之间的保持时间应合理并应
经过验证。
8.62 Distortion and damage of non-rigid containers that are terminally sterilized, such as containers
produced by Blow-Fill-Seal or Form-Fill-Seal technologies, should be prevented by appropriate cycle
design and control (for instance setting correct pressure, heating and cooling rates and loading patterns).
应通过适当的循环设计和控制
（例如设定 正确的压力、
加热和冷却速率以及装载模式）
来防止最终灭菌
的非刚性容器（如吹填密 封或模装密封技术生产的容器）的变形和损坏。
8.63 Where steam in place systems are used (e.g. for fixed pipework, vessels and lyophilizer chambers),
the system should be appropriately designed and validated to assure all parts of the system are subjected
12
to the required treatment. The system should be monitored for temperature, pressure and time at
appropriate locations during routine use to ensure all areas are effectively and reproducibly sterilized.
These locations should be demonstrated as being representative of, and correlated with, the slowest to
heat locations during initial and routine validation. Once a system has been sterilized by steam in place it
should remain integral and held under positive pressure prior to use.
使用在线蒸汽系统（例如用于固定管道、容器和冻干器室）以外，应对系统进行适 当的设计和验证，以
确保系统的所有部件都经过所需的处理。
应监测系统的温度，
在常 规使用过程中，
在适当的位置施加压
力和时间，
以确保所有区域都得到有效和可重复的 灭菌。
应证明这些关键位置具有代表性，
且和首次和
日常验证中升温最慢的位置相关的 。一旦系统被蒸汽在线灭菌，在使用前应保持完整并保持正压。
8.64 For systems using superheated water rather than steam, as the sterilizing agent, the heated water
should consistently reach all of the required contact points. Initial qualification studies should include
temperature mapping of the entire load. There should be routine checks on the equipment to ensure that
nozzles (where the water is introduced) are not blocked and drains remain free from debris.
对于使用过热水而不是蒸 汽的灭菌系统，
热水应始终达到所有要求的接触点。
初始确认研究应包括整个
载荷的温 度图。应对设备进行常规检查，以确保喷嘴（水引入处）未堵塞，排水管无杂物。
8.65 For the qualification of superheated systems it should be demonstrated that all parts of the load meet
the minimum required temperature and that routine monitoring probes are located in the worst case
positions identified during the qualification process.
对于过热灭菌系 统的确认，
应证明负荷的所有部分均满足最低要求温度，
且常规监测探头位于确认过程
中确定的最坏位置。
Dry heat sterilization
干热灭菌
8.66 Dry heat sterilization is of particular use in the removal of thermally robust contaminants such as
pyrogens and is often used in the preparation of components for aseptic filling. The combination of time
and temperature to which product, components and equipment are exposed should produce an adequate
and reproducible level of lethality and/or pyrogen (endotoxin) inactivation/removal when operated
routinely within the established limits.
干热灭菌特别用于去除敏的污染物，
例如热原，
并且通常 用于制备无菌灌装的组件。
在规定的范围内常
规操作时，
暴露于产品，
组件和 设备的时间和温度的组合应产生足够的和可再现的致死率和
/
或热原
（内
毒素 ）灭活
/
去除水平。
8.67 Dry heat sterilization/depyrogenation tunnels should be configured to ensure that airflow protects
the integrity and performance of the Grade A sterilizing zone by maintaining pressure differentials and
airflow through the tunnel from the higher grade area to the lower grade area. Airflow patterns should be
visualised and correlated with temperature studies. The impact of any airflow change should be assessed
to ensure the heating profile is maintained. All air supplied to the tunnel should pass through at least a
HEPA filter and periodic tests should be performed to demonstrate air filter integrity (at least biannually).
Any tunnel parts that come into contact with sterilized components should be appropriately sterilized or
disinfected. Critical process parameters that should be considered during validation and/or routine
processing should include, but may not be limited to:
干热灭菌
/
去热隧道烘箱应配置成通过维 持从较等级区域到较低等级区域的压差和气流来确保
A
级灭菌
区的完整性和性能。气流流型应可视化，
并与温度研究相关联。
应评估任何气流变化的影响，
以确保维
持加热曲线。供给隧道的所有空气均应至少通过
HEPA
过滤器，并应进行定期测试以 证明空气过滤
器的完整性（至少每半年一次）。与灭菌物品接触的任何隧道部件都应进行适当的灭菌或消 毒。
验证和
/
或日常操作期间应考虑的关键控制参数应包括但不限于：
i.
Belt speed or dwell time within the sterilizing zone.
传送带速度或灭菌区的滞留时间。
ii.
Temperature
–
minimum and maximum temperatures.
温度
最低和最高温度。
iii.
Heat penetration of the material/article.
13
物料
/
物品的热穿透
iv.
Heat distribution/uniformity.
热分布
/
均匀度。
v.
Airflows
–
correlated with the heat distribution and penetration studies.
气流
–
与热分布和热穿透研究相关
8.68 When a thermal depyrogenation process is used for any component or product contact equipment,
validation studies should be performed to demonstrate that the process provides a suitable F
h
value and
results in a minimum 3 log reduction in endotoxins concentration.
当去热源工艺用于任何部件或与产品接触的设备时，应进行 验证研究，以证明该工艺可提供合适的
F
H
值，并可使内毒素浓度至少降低
3
个对数级。
8.69 Containers inoculated with endotoxin should be used during validation and should be carefully
managed with a full reconciliation performed. Containers should be representative of the materials
normally processed. Endotoxin quantification and recovery efficiency should also be demonstrated
through biological measurement.
在验证期间应使用添加内毒素的容器，
并应进行仔细管理，
完整的物料平衡计算。
容器应代表正常加工
的材料。内毒 素定量和回收效率也应通过生物测量来证明。
8.70 Dry heat ovens are typically employed to sterilize or depyrogenate primary packaging components,
finished materials or active substances but may be used for other processes. They should be maintained at
a positive pressure relative to lower grade areas throughout the sterilization and post sterilization hold
process. All air entering the oven should pass through a sterilizing filter. Critical process parameters that
should be considered in qualification and/or routine processing should include, but may not be limited to:
干热烘箱通常用于对初级包装、
成品材料 或活性物质进行灭菌或去热源，
但也可用于其他用途。
在整个
灭菌和灭菌后保持过程中 ，
它们应保持相对于较低等级区域的正压。
所有进入烤箱的空气都应经过灭菌
过滤器。 在确认和
/
或日常操作中应考虑的关键工艺参数应包括但不限于
:
i.
Temperature.
温度
ii.
Exposure period/time.
暴露周期
/
时间
iii.
Chamber pressure (for maintenance of over pressure).
腔室压力（用于维持过压）
。
iv.
Air speed.
空气风速
v.
Air quality within the oven.
腔室内的空气质量。
vi.
Heat penetration of material/article (slow to heat spots).
物料
/
物品的热穿透（加热较慢的点和不同的装载方式）
。
vii.
Heat distribution/uniformity.
热分布
/
均匀度
8.71
For
dry
heat
sterilization
of
starting
materials
and
intermediates,
the
same
principles
should
be
1349
applied. Consideration should also be given to factors affecting heat penetration such as the container 1350
type, size and packing matrix.
对 于起始原料和中间体的干热灭菌，
应采用相同的原则。
还应考虑影响热渗透的因素，
如 容器类型、
尺
寸和包装基质。
14
Sterilization by radiation
辐射灭菌
8.72 Guidance regarding ionising radiation sterilization can be found within Annex 12.
关于离子化辐射灭菌法的指南参见
EU GMP
附录
12
。
8.73
Sterilization
by
radiation
is
used
mainly
for
the
sterilization
of
heat
sensitive
materials
and
products.
Ultraviolet irradiation is not an acceptable method of sterilization.
辐射灭菌主要用于热敏性物料和产品的灭菌。紫外线照射不是一种可接受的灭菌方法。
8.74 Validation procedures should ensure that the effects of variations in density of the product and packages
are considered.
验证程序应确保考虑到产品和不同包装密度的影响。
Sterilization with ethylene oxide
环氧乙烷灭菌
8.75
This
method
should
only
be
used
when
no
other
method
is
practicable.
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
result
in
the
reduction
of
any
residual
ethylene
oxide
(EO)
gas
and
reaction
products
to
defined
acceptable limits for the given product or material.
只有在没有其他方法可行的情况下，
才应使用这种方法。
在工艺 验证期间，
应表明对产品没有损害，
且
排气的条件和时间允许将任何残留的环氧乙烷（
EO
）气体和反应产物减少到给定产品或材料的规定的
可接受限度。
8.76
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, porosity
and quantity of packaging materials can significantly affect the process.
气体和微生物细 胞之间的直接接触是至关重要的，
应采取预防措施，
应采取预防措施避免容易包裹在物
料（如晶体和干燥的蛋白质）中的微生物出现。包装材料的性质、孔隙率和数量会显著影响工艺。
8.77
Before
exposure
to
the
gas,
materials
should
be
brought
into
equilibrium
with
the
humidity
and
temperature required by the process. The time required for this should be balanced against the opposing need
to minimize the time before sterilization.
在暴露于气体之前，
应使物料与工艺所需的湿度和温度达到平衡。
此过程所 需时间应尽可能与缩短灭菌
前时间的相对需求相平衡。
8.78 Each sterilization cycle should be monitored with suitable BIs, using the appropriate number of test units
distributed throughout the load at defined locations that have been shown to be worst case during validation.
每个灭菌周期应使用适当的
B Is
进行监控，应将适当数量的生物指示剂分布在装载物中，这些位置在验
证期间已被证明为最 差点。
8.79
Critical
process
variables
that
could
be
considered
as
part
of
the
sterilization
process
validation
and
routine monitoring include, but are not limited to:
灭菌工艺验证和日常监控中应考虑的关键工艺变量包括，但不限于：
i.
EO gas concentration.
EO
气体浓度
ii.
EO gas pressure.
EO
气体压力
iii.
Amount of EO gas used.
EO
气体用量
iv.
Relative humidity.
相对湿度
v.
Temperature.
温度
vi.
Exposure time.
暴露时间
8.80 After sterilization, the load should be aerated to allow EO gas and/or its reaction products to desorb from
the
packaged
product
to
predetermined
levels.
Aeration
can
occur
within
a
sterilizer
chamber
and/or
in
a
15
separate aeration chamber or aeration room. The aeration phase should be 1399 validated as part of the overall
EO sterilization process validation.
灭菌完成后，应 对装载物进行通气，以使
EO
气体和
/
或其反应产物从包装产品中释放出来， 并达到预
期水平。通气可在灭菌柜和
/
或独立的曝气柜或曝气室中进行。通气阶段应作 为整个
EO
灭菌工艺验证
的一个部分来进行验证。
Filter sterilization of products which cannot be sterilized in their final container
非最终灭菌药品的无菌
过滤
8.81
If
the
product
cannot
be
sterilized
in
the
final
container,
solutions
or
liquids
should
be
sterilized
by
filtration through a sterile sterilizing grade filter (with a nominal pore size of 0.22 ?
m (or less) that has been
appropriately
validated
to
obtain
a
sterile
filtrate)
and
subsequently
aseptically
filled
into
a
previously
sterilized container. The selection of the filter used should ensure that it is compatible with the product and as
described in the marketing authorization (refer to paragraph 8.125).
如果产品不能最终灭菌，溶液 或液体应通过
用无菌的除菌级过滤器
（公称孔径为
0.22μm
（或更小）< br>，
已适当的验证可获得无菌滤液）
进行无菌过滤，
随后无菌灌装到预先灭菌的容 器中。
所用过滤器的选择
应确保与产品兼容，并符合市场许可规定（参见
8.125< br>章节
)
。
8.82
Suitable
bioburden
reduction
prefilters
and/or
sterilizing
grade
filters
may
be
used
at
multiple
points
during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the primary
sterilizing
grade
filter.
Due
to
the
potential
additional
risks
of
a
sterile
filtration
process,
as
compared
with
other
sterilization
processes,
a
second
filtration
through a
sterile
sterilizinggrade
filter,
immediately
prior
to
filling, should be considered as part of an overall CCS.
在生产过程中，可在多个点处使 用适当的降低生物负荷的预滤器和
/
或无菌级过滤器，以确保在初级无
菌级滤器之前液 体的生物负荷降低至受控水平。
由于与其他灭菌工艺相比，
无菌过滤工艺存在潜在的额
外风险，因此在灌装之前，通过无菌级过滤器进行的第二次过滤器应被视为整个
CCS
的一部分 。
8.83 The selection of components for the filtration system and their interconnection and arrangement within
the
filtration
system,
including
pre- filters,
should
be
based
on
the
critical
quality
attributes
of
the
product,
justified and documented. The filtration system should minimize the generation of fibres and particulates, not
cause
or
contribute
to
unacceptable
levels
of
impurities,
or
possess
characteristics
that
otherwise
alter
the
quality and efficacy of the product. Similarly, the filter characteristics should be compatible with the fluid and
not
be
adversely
affected
by
the
product
to
be
filtered.
Adsorption
of
product
components
and
extraction/leaching of filter components should be evaluated (refer to paragraph 8.125). 过滤系统部件的选择，
及其在过滤系统内的相互连接和布置，
包括预过滤器，
应以 产品的关键质量属性
为基础，
证明合理并记录在案。
过滤系统应最大限度地减少纤维和 微粒的产生，
不会导致或促成不可接
受的杂质水平，
或具有以其他方式改变产品质量和 功效的特性。
同样，
过滤器特性应与液体相容，
不受
待过滤产品的不利影响。 应评估对产品组分的吸附和过滤组分的溶出
/
析出（参见第
8.125
章节）
。
8.84 The filtration system should be designed to:
过滤系统应被设计为
i.
Allow operation within validated process parameters.
允许在经验证的工艺参数范围内进行操作。
ii.
Maintain the sterility of the filtrate.
维持滤液的无菌度。
iii.
Minimize the number of aseptic connections required between the sterilizing filter and the final filling
of the product.
最大程度降低除菌过滤器和产品最终灌装之间的无菌连接的次数。
iv.
Allow cleaning procedures to be conducted as necessary.
允许在必要时进行清洁操作
v.
Allow sterilization procedures, including sterilization in place, to be conducted as necessary.
允许在必要时进行灭菌，包括在线灭菌。
16
vi.
Permit in-place integrity testing, of the 0.22 ?
m sterilizing filter, preferably as a closed system, prior
to filtration as necessary. In-place integrity testing methods should be selected to avoid any adverse
impact on the quality of the product.
必要时，在过滤之前， 允许对
0.22
微米的灭菌过滤器（最好作为封闭系统）进行完整性测试。
应选择适当 的完整性测试方法，以避免对产品质量产生任何不利影响。
8.85
Sterile
filtration
of
liquids
should
be
validated
in
accordance
with
European
(or
other
relevant)
Pharmacopeia
requirements.
Validation
can
be grouped by
different
strengths
or
variations
of
a
product
but
should be done under worst case conditions. The rationale for grouping should be justified and documented.
液体的无菌过滤应根据欧洲
（或其他相关）
药典 要求进行验证。
验证可以按产品的不同规格或变化进行
分组，但应在最坏的情况下进行。分组的 理由应该是合理的，并应记录在案。
8.86 During filter validation, wherever possible, the product to be filtered should be used for bacterial retention
testing
of
the
sterilizing
filter.
Where
the
product
to
be
filtered
is
not
suitable
for
use
in
bacterial
retention
testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the
bacterial retention test should be justified.
在过滤器验证过程中，
只要有可能，
应将待过滤的产品用于灭菌过滤器的细菌保留测试。
如果要过滤的
产品不适合用于细菌 保留试验，
则应证明合适的替代产品可用于该试验。
在细菌保留试验中使用的挑战
生物 应该是合理的。
8.87 Filtration parameters that should be considered and established in validation and monitored in
routine
processing should include, but are not limited to:
在验证中应考虑和建立的过滤参数以及在日常操作中应监控的过滤参数应包括但不限于
:
i.
The
wetting
fluid
used
for
filter
integrity
testing
should
be
based
on
th
e
filter
manufacturer’s
recommendation or the fluid to be filtered. The appropriate integrity test value specification should be
established.
用于过滤器完整性测试的润湿液 应基于过滤器制造商的建议或要过滤的液体。应建立适当的完
整性测试值标准。
ii.
If
the
system
is
flushed
or
integrity
tested
in-situ
with
a
fluid
other
than
the
product,
appropriate
actions are taken to avoid any deleterious effect on product quality.
如果使用产品以外的液体对系统 进行现场冲洗或完整性测试，则应采取适当措施以避免对产品
质量造成任何有害影响。
iii.
Filtration process conditions including:
过滤工艺条件包括
:
?
Fluid pre-filtration holding time and effect on bioburden.
预过滤液体的保存时间和对生物负载的影响。
?
Filter conditioning, with fluid if necessary.
如有必要，用液体对过滤器进行润湿。
?
Maximum filtration time/total time filter is in contact with fluid.
最大过滤时间
/
过滤器与流体接触的总时间。
?
Maximum operating pressure.
最大工作压力。
?
Flow rate.
滤速
?
Maximum filtration volume.
最大的过滤体积
?
Temperature.
温度
17
?
The time taken to filter a known volume of bulk solution and the pressure difference to be used
across the filter.
过滤已知体积的溶液所需的时间和过滤器所用的压差。
Note: Results of these checks should be included in the batch record. Any significant difference in parameters
from those validated to those observed during routine manufacturing should be noted and investigated.
应关注并调查任何在日常生产中观察到 的数值与验证过的数值之间的明显差异。
这些检查结果应包含在
批记录中。
8.88 The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check
for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is
used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior to removal of the
filter from its housing. Test results should correlate to the microbial retention capability of the filter established
during
validation.
Examples
of
tests
that
are
used
include
bubble
point,
diffusive
flow,
water
intrusion
or
pressure hold test. It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be
possible after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In
these
cases,
an
alternative
approach
may
be
taken
providing
that
a
thorough
risk
assessment
has
been
performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of
non-sterility. Points to consider in such a risk assessment should include but are not be limited to:
灭菌后的过滤器组件的完整性在 使用前应通过完整性测试进行验证，
在使用前应检查过滤器准备工作造
成的完整性损坏和损失。
用于对液体进行除菌的灭菌级过滤器在使用后应进行无损完整性测试，
然后再
将过滤器 从外壳中取出。
测试结果应与验证期间建立的过滤器的微生物保留能力相关。
使用的测试方法< br>包括起泡点、扩散流、水侵入或压力保持测试。使用前和灭菌后完整性测试（
PUPSIT
）由于工艺的限
制（例如过滤极少量的溶液）
，在灭菌后可能不总是可行的。在这些情况下， 如果已经进行了彻底的风
险评估，
并且通过实施以下措施实现了合规性，
则可以采用另 一种方法适当的控制措施，
以减轻任何不
育的风险。此类风险评估中要考虑的要点应包括但不限 于
:
i.
In depth knowledge and control of the sterilization process to ensure that the potential for damage to the
filter is minimized.
深入了解和控制除菌过程，以确保将损坏过滤器的可能性降至最低。
ii.
In depth knowledge and control of the supply chain to include:
对供应链的深入了解和控制包括
:
?
Contract sterilization facilities.
委托灭菌设施。
?
Defined transport mechanisms.
指定的运输设备。
?
Packaging of the sterilized filter, to prevent damage to the filter during transportation and storage.
灭菌过滤器的包装，以防止在运输和储存过程中损坏过滤器。
iii.
In depth process knowledge such as:
深入的工艺知识，如
:
?
The specific product type, including particulate burden and whether there exists any risk of impact
on filter integrity values, such as the potential to alter integrity testing values and therefore prevent
the detection of a non-integral filter during a post-use filter integrity test.
具体的产品类型，包括颗粒负荷，以及是否存在影响过滤 器完整性值的任何风险，例如改变
完整性测试值的可能性，从而防止在使用后过滤器完整性测试期间检测 到非完整的过滤器。
?
Pre-filtration
and
processing
steps,
prior
to
the
sterilizing
filter,
which
would
remove
particulate
burden and clarify the product prior to the sterile filtration.
在除菌过滤器之前的预过滤和处理步骤，这将在除菌过滤之前去除颗粒负载并滤清产品。
8.89 The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product)
should be verified by testing after use, with the filter remaining in the filter assembly.
关键的无菌气体 和排气过滤器
（直接与产品的无菌性相关）
的完整性应通过使用后的测试进行确认，
且
18
过滤器应保留在过滤器组件中。
8.90
The
integrity
of
non-critical
air
or
gas
vent
filters
should
be
confirmed
and
recorded
at
appropriate
intervals. Where gas filters are in place for extended periods such as vent filters, integrity testing should be
carried out pre and post-use. The maximum duration of use should be specified and monitored based on risk
(e.g. considering the maximum number of uses and sterilization cycles permitted).
应在适当的时间间隔内确认和记录非关键性空气或排气过滤器的完 整性。
如果气体过滤器
（如排风过滤
器）
安装时间较长，
则应在使用 前和使用后进行完整性测试。
应根据风险
（例如考虑允许的最大使用次
数和灭菌周期） 规定和监测最长使用期限。
8.91 For gas filtration, attention should be paid to avoiding unintended moistening or wetting of the filter or
filter equipment. This can be achieved by the use of hydrophobic filters.
对于气体过滤，应注意避免过滤器或过滤设备 被意外弄潮或湿。这可以通过使用疏水过滤器来实现。
8.92 If the sterilizing filtration process has been validated as a system consisting of multiple filters to achieve
the sterility for a given fluid, the filtration system is considered to be a single sterilizing unit and all filters
within the system should satisfactorily pass integrity testing after use.
如果除菌过滤过程已被验证为一个由多个过滤器组 成的系统，
以实现对特定液体的无菌过滤，
则该过滤
系统被认为是一个单一的灭菌单元 ，
且该系统中的所有过滤器在使用后均应令人满意地通过完整性测试。
8.93 In a redundant filtration system (where a second filter is present as a backup but the sterilizing process is
validated
as
only
requiring
one
filter),
post-use
integrity
test
of
the
primary
sterilizing
filter
should
be
performed
and
if
demonstrated
to
be
integral,
then
a
post-use
integrity
test
of
the
secondary
filter
is
not
necessary.
However,
in
the
event
of
a
failure
of
the
post-use
integrity
test
on
the
primary
filter,
a
risk
assessment should be carried out to determine the acceptability of performing a post-use integrity test on the
secondary (redundant) filter.
在冗余过滤系统中（有第二个过滤器作为备用，但灭菌过程经验证只需要一 个过滤器）
，应对初级无菌
过滤器进行使用后的完整性测试，
如果证明是完整的，则无需对次级过滤器进行使用后完整性测试。
但
是，如果主过滤器的后使用完整性测试失败 ，应进行风险评估，以确定对二级（冗余）进行使用后完整
性测试的可接受性。
8.94
Bioburden
samples
should
be
taken
from
the
bulk
product
and
immediately
prior
to
the
final
sterile
filtration. Systems for taking samples should be designed so as not to introduce contamination.
应在最终无菌过滤之前立即从产品中进行微生物取样。取样系统的设计应避免引入污染。
8.95 Liquid sterilizing filters should be discarded after the processing of a single lot and the same filter should
not be used for more than one working day unless such use has been validated.
液体除菌过滤器应在处理完一批后丢弃，
且同一过滤器不应 使用超过一个工作日，
除非这种使用已得到
验证。
8.96 Where campaign manufacture of a product has been appropriately justified in the CCS and
validated,
the filter user should:
如果在
CCS
中对产品的生产活动进行了适当的论证并进行了验证，则过滤器用户应
:
i.
Assess and document the risks associated with the duration of filter use for the sterile filtration process
for a given fluid.
评估并记录与特定流体的无菌过滤过程中使用过滤器的持续时间相关的风险。
ii.
Conduct and document effective validation and qualification studies to demonstrate that the duration of
filter use for a given sterile filtration process and for a given fluid does not compromise performance of
the sterilizing filter or filtrate quality.
进行并记录有效的验证和确认研究，
以证明用于特定无菌过滤过程和特定流体的过滤 器使用时间
不会影响除菌过滤器的性能或滤液质量。
iii.
Document the maximum validated duration of use for the filter and implement controls to ensure that
filters
are
not
used
beyond
the
validated
maximum
duration.
Records
of
these
controls
should
be
maintained.
记录过滤器的最长确认使用期限，并实施控制以确保过滤器的使用不超过确认的最长期限。应 保
19
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