6 March 2019

EMA/CHMP/CVMP/QWP/850374/2015
Committee for Medicinal Products for Human use (CHMP)
Committee for Medicinal Products for Veterinary use (CVMP)

Guideline on the sterilisation of the medicinal product, active

substance, excipient and primary container
药品、活性物质、辅料和内包材灭菌指南

翻译：晕晕、流浪的沙子
校对：Owen

GMP 办公室翻译组

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• 国内外（FDA、EMA、MHRA、CFDA、WHO、PIC/S 等）GMP 法规解读；
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• GMP 技术指南（ISPE、PDA、ISO、ASTM 等）分享

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Draft agreed by QWP and BWP December 2015

Adopted by CHMP for release for consultation January 2016

Adopted by CVMP for release for consultation February 2016

Start of public consultation 13 April 2016

End of consultation (deadline for comments) 13 October 2016

Agreed by BWP July 2018

Agreed by CAT September 2018

Agreed by QWP and GMDP IWG October 2018

Adopted by CHMP for publication 15 November 2018

Adopted by CVMP for publication 6 December 2018

Date for coming into effect 1 October 2019

This guideline replaces the document Decision trees for the selection of sterilisation methods
(CPMP/QWP/054/98), which is an annex to the note for guidance on development pharmaceutics
(CPMP/QWP/155/96); and the document Decision trees for the selection of sterilisation methods
(EMEA/CVMP/065/99) which is an annex to the note for guidance: Development pharmaceutics for veterinary
medicinal products (EMEA/CVMP/315/98).

Keywords Active substance, Aseptic processing, Container, Decision trees, Excipients,

Filtration, Finished Dosage form, Sterilisation, Sterilisation assurance level,
Terminal sterilisation, Post-aseptic processing terminal heat treatment.
Executive summary
综述
Guidance is provided on the selection of appropriate methods of sterilisation for sterile products. Although, terminal
sterilisation using a reference condition of the European Pharmacopoeia (Ph. Eur.) is the method of choice whenever
possible, this guideline provides information on when other terminal sterilisation processes, sterilising filtration or
aseptic processing, (either alone or when combined with an additional post-aseptic processing terminal heat
treatment), could be accepted as an alternative.

Guidance is provided on the documentation expected for sterile finished products, sterile active substances, sterile
excipients and sterile primary containers (referred to as container in this guideline) in a new marketing authorisation
application or a variation application for a medicinal product, (called quality dossier throughout the guideline).

Terminology definitions are included at the end of the document.

1. Introduction (background)
介绍（背景）

Sterility is a critical quality attribute for all sterile substances, products and containers. Sterility cannot be assured by
testing, it needs to be assured by the use of a suitably designed, validated and controlled manufacturing process.
Sterility is achieved by controlling several factors such as the bioburden, the sterilisation procedure, the integrity of
the container closure system and in the case of aseptic processing, the use of satisfactory aseptic technique.

Terminal sterilisation is preferred to sterilisation by filtration and/or aseptic processing because it is lethal to micro-
organisms and a reliable sterility assurance level (SAL) is possible to calculate, validate and control, and thus
incorporates a safety margin. For sterile filtration followed by aseptic processing, this is not applicable as accidental
contamination caused by inadequate technique cannot be reliably eliminated by monitoring and control. Therefore,
terminal sterilisation provides the highest assurance of sterility and should be used whenever possible.

For highly sensitive products, such as most biological products, where terminal sterilisation of the finished
product is not possible, sterile filtration and/or aseptic processing under validated and controlled conditions can
be accepted.

Sterile filtration and aseptic processing are closely related and difficult to consider separately, since sterile filtration
in most cases is followed by at least one aseptic processing step such as filling. In order to focus on the most
important aspect of filtration and aseptic processing at each section of this guideline, only one of the two steps may
be mentioned, even if both steps are related.

In addition to those finished products where the formulation itself prohibits the possibility of terminal sterilisation, the
use of aseptic processing can be accepted in certain situations, even if the formulation itself can be terminally
sterilised, if other benefits are gained for patients or users of the product. These situations are specified below in
section 4.3.

Container integrity is discussed in ICH Q8, (adopted for human medicinal products only, nevertheless the same
principles are also applicable to veterinary medicinal products and containers of sterile substances and containers).

2. Scope
范围
The guideline applies to chemical and biological medicinal products for human and veterinary use but is not applicable
to immunological veterinary medicinal products.
It is acknowledged that the recommendations provided for in this guideline may require some adaptation to the
specific characteristics of Advanced Therapy Medicinal Products (ATMPs) for human use (e.g. difficulties to
differentiate between starting material, active substance and finished product in some cases, scarcity of starting
materials/active substance/finished product (autologous products and matched-donor scenario), small volumes of
production). The level of documentation that is expected to be included in marketing authorisation applications for
ATMPs may be adapted provided that this is justified under a risk-based approach. For veterinary cell based novel
therapies, cross reference is made to EMA/CVMP/ADVENT/751229/2016 Questions and Answers on allogenic stem
cell-based products for veterinary use: specific questions on sterility.

Guidance is provided on the choice of sterilisation method, the development data and manufacturing data required
to demonstrate the suitability of the selected sterilisation process. The same principles (choice of method of
sterilisation, development data and manufacturing data) apply to sterile active substances, excipients and primary
containers. Only the information expected in the quality dossier, including information related to Good Manufacturing
Practice (GMP) certificates, is described. Not all GMP requirements (e.g. environmental monitoring, sterilisation of
manufacturing equipment) are referenced in the guideline, only those that are considered specifically relevant for the
quality dossier.

The scope of this document includes:

Terminal sterilisation by steam, dry heat and ionising irradiation using the reference conditions of Ph. Eur.
5.1.1 “Methods of preparation of sterile products” or other conditions stated in that monograph

Sterilisation by filtration and aseptic processing

Sterilisation by gas

The concepts in this guideline refer only to absence or removal of bacteria, fungi and bacterial endotoxins. The
absence, removal or inactivation of viruses, mycoplasma, prions and other adventitious agents, which could
contaminate a product, are not considered. For virus validation reference is made to the Guideline Virus validation
studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses,
CPMP/BWP/268/95.

3. Legal basis
法律基础
This guideline should be read in conjunction with Directive 2001/83/EC on the community code relating to medicinal
products for human use, Directive 2001/82/EC on medicinal products for veterinary use as amended and also the
current Ph. Eur.

In addition, this guideline should be read in conjunction with all other relevant directives and regulations, and all
relevant Commission, (V)ICH and CXMP guidelines, Q&A documents and other documents as linked to or
published on the EMA website (www.ema.europa.eu).

4. General requirements
一般要求
The guideline concerns specific requirements related to sterility, sterilisation processes and aseptic processing
of sterile products and product components.
本指南包含与灭菌、灭菌工艺以及无菌产品和产品组份的无菌工艺相关的具体要求。

4.1. Requirements for the manufacture of sterile medicinal products and sterile
components
无菌药品和无菌组分生产的要求

The choice of sterilisation method or aseptic processing should be justified, see section 4.3 Selection of sterilisation
method.
灭菌方法或无菌工艺的选择应合理, 见第 4.3 节灭菌方法的选择。

All sterilisation processes should be carried out according to the instructions of the Ph. Eur. unless justified.
除经过论证，否则所有灭菌工艺都应按照 Ph. Eur.的规定进行。

All sterilisation procedures for the finished product, active substance, the excipient(s) or the containers and the name
and address of the sterilisation site should be stated. A description of the sterilisation method and/or aseptic
processing, including in-process controls and validation data should be provided.
应说明所有成品、活性物质、辅料或容器的灭菌工艺，以及灭菌地点的名称和地址。应提供灭菌方法和/或无菌工艺的
说明, 包括中控和验证数据。

When parametric release of sterility is proposed, the Guideline on real time release testing (formerly Guideline on
parametric release), EMA/CHMP/QWP/811210/2009-Rev1 (human products only), the Guideline on Parametric
release, EMEA/CVMP/QWP/339588/2005 (veterinary products only) and the text of Ph. Eur. Chapter 5.1.1 should
be taken into account.
当提出无菌参数放行时, 应考虑 EMA/CHMP/QWP/811210/2009-Rev1《实时放行检验指南(仅适用于人用产品)》
(原《参数放行指南》)、EMEA/CVMP/QWP/339588/2005《参数放行指南(仅适用于兽药产品)》和 Ph. Eur. 5.1.1 章
节的要求。

The bioburden control criteria should be specified prior to all sterilisation processes. High bioburden acceptance
criteria should not be justified by the capacity of the sterilisation process or any bioburden reducing step before
sterilisation. Acceptance criteria for bioburden are discussed under the relevant sub-sections of 4.1 below.
应明确灭菌前的生物负荷控制标准。高生物负荷接受标准不应依赖灭菌工艺的能力或灭菌前的任何生物清除步骤。以
下章节 4.1 的相关小节讨论了生物负荷的接受标准。

The levels of bacterial endotoxins in the finished product can be impacted by the bioburden and bacterial endotoxins
in the components (i.e. active substance, excipients and containers), and by microbiological contaminants introduced
during manufacture. To ensure an acceptable level of bacterial endotoxins in the finished product, the level of
microbiological contaminants of the components should be minimal. Acceptance criteria for bioburden and, where
relevant, bacterial endotoxins in components and bulk solutions should be specified.
成品中细菌内毒素的水平可能会受到组件 (即活性物质、辅料和容器)中生物负荷和细菌内毒素的影响, 也会受到生产过
程中引入的微生物污染物的影响。为确保成品中细菌内毒素的可接受水平, 各组件的微生物污染物水平应最低。应规定
组件和待灌装溶液的生物负荷和细菌内毒素（如适用）的接受标准。

All filters used in the manufacture of the finished product that come in contact with the finished product, or with any
component (substance or intermediate product) incorporated in the finished product should be described and the
information stated in Table3, section 4.1.5 should be provided in the quality dossier. The information should be in
line with the requirements stated in Eudralex GMP Annex 1. For ATMPs, the Guidelines on Good Manufacturing
Practice specific to Advanced Therapy Medicinal Products should be followed.
应描述所有与成品接触或与成品中任何组分 (活性成分或中间产品) 接触的用于成品生产的过滤器，并在其质量档案中
提供章节 4.1.5 表 3 中要求的信息。这些资料应符合 Eudralex GMP 附录 1 的要求。对于 ATMP, 应遵循《ATMP 良好
生产规范指南》。

If a secondary container (e.g. secondary pouch for infusion bags or blisters intended to keep the outside of the
container sterile) is used to provide a specific protection to the medicinal product, the packaging process should be
described, including a risk assessment, since it may affect the sterility of the finished product; for example, trapping
moisture between the primary and secondary containers. Information should be provided as to when the packaging
step is performed (before or after sterilisation) and any aseptic techniques employed. The proposed processes
should be justified from a microbiological perspective. If the use of a secondary container means additional
sterilisation of the finished product is performed, this should be justified with regard to sterility assurance and any
potential impact on finished product quality.
如果使用二级容器 (例如用于保持输液袋或泡罩外部无菌的外袋) 为医药产品提供特定保护, 则应说明包装过程, 包括风
险评估, 因为它可能会影响成品的无菌性;例如, 在内包装容器和二级容器之间残留水分。应提供关于何时 (灭菌前或灭
菌后) 进行包装步骤以及所采用的任何无菌技术的信息。工艺应从微生物的角度加以证明。如果使用二级容器意味着需
要对成品进行额外的灭菌, 则应在无菌保证和对成品质量的任何潜在影响方面进行论证。

Documentation regarding sterilisation and aseptic processing to be included in the quality dossier is presented below. The
documentation could, for practical reasons, be presented in connection with the item which is to be sterilised if a reference
to the location of the documents is provided in section 3.2.P.3.3 or in Part 2 B. The documents may be provided for human
products in sections 3.2.S.2 Manufacture, 3.2.P.2 Pharmaceutical development, 3.2.P.3 Manufacture, 3.2.P.4 Control of
excipients, or 3.2.P.7 Container closure system, or for veterinary products in Part 2 A.4 Development pharmaceutics,
Part 2 B.1 Manufacturing method, Part 2 C.1 Active substance, Part 2 C.2 Excipients or Part 2 C.3 Container closure
systems. The documentation should be provided for all sites performing sterilisation or aseptic processing,
regardless of whether the processes are performed in-house or outsourced.
需包含在质量档案中的关于灭菌和无菌工艺的文件罗列如下。出于实际原因, 如果 3.2.P.3.3 节或第 2 b 部分提到文件
的位置, 则文件可和待灭菌的物品放在一起。这些文件可在人用药品的 3.2.S.2 生产、3.2.P.2 药品研发、3.2.P.3 生
产、3.2.P.4 辅料控制，或 3.2.P.7 容器封闭系统中提供；或兽药第 2 部分 A.4 药品研发, 第 2 部分 B.1 生产方法, 第 2
部分 C.1 活性物质, 第 2 部分 C.2 辅料或第 2 部分 C.3 容器封闭系统中提供。所有进行灭菌或无菌工艺的场所都应提供
文件, 无论操作是本厂执行或是外包。

Process parameters such as processing and holding times are assessed and agreed during the evaluation of the
quality dossier. These may be further reviewed during GMP inspections, which may result in changes to the
registered dossier being required.
在质量档案的评估过程中, 会对工艺参数,例如工艺和保留时间进行评估和商定。这些可能会在 GMP 检查期间进一步
审查, 并可能导致需要变更注册档案资料。

4.1.1. Steam sterilisation

蒸汽灭菌

All steam sterilisation processes require a minimum lethality of F 0 ≥ 8 minutes and a minimum process hold
temperature of 110 °C.
所有蒸汽灭菌工艺都要求最低杀灭力为 f0≥8 分钟, 最低工艺温度为 110°c。

Sterilisation processes of different levels of lethality are presented in Table 1, along with the documentation to be included
in the quality dossier. The processes in the table are presented with decreasing lethality when read from top to bottom,
thus the first feasible process should be selected.
表 1 列出了不同水平的杀灭力的灭菌过程, 以及需要列入质量档案的文件。表中的工艺从上到下杀死力逐渐降低, 因
此应优先选择上一个可行的工艺。

For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (≥121 °C, ≥15 min in all units) validation data
for the sterilisation cycle is not required to be submitted in the quality dossier.
对于使用 ph. eur. 5.1.1 的参考条件进行灭菌 (所有位置≥121°c,≥15 分钟), 则无需在质量档案中提交灭菌周期的
验证数据。

If used as an additional control to measure the process lethality, F 0, should be stated, together with the lowest
temperature measured by the temperature sensors to determine F 0.
如果使用 f0 作为监测工艺杀灭力的额外控制, 则应说明 f0, 并由温度传感器测得的最低温度来确定 f0。

Steam sterilisation performed with finished product temperature below 115 °C during the holding phase is an
exceptional case and should be scientifically justified and supported by additional data as described in Table 1. If
temperatures below 110 °C are included (during heat-up and cool-down) in the determination of F0, this should be
justified.
成品温度低于 115°c 的蒸汽灭菌保持阶段是一种特殊情况, 应进行论证, 并有表 1 所述的其他数据的支持。如果 f0 的测
定中包括低于 110°c 的温度 (在加热和冷却过程中), 则应进行论证。

Information regarding the F0 concept and microbial reduction is provided in Ph. Eur. 5.1.5 Application of the F0
concept to steam sterilisation of aqueous preparations.
关于 f0 概念和微生物降低的信息载于 ph. eur. 5.1.5 f0 概念在水制剂蒸汽灭菌中的应用。
The bioburden limit should be in line with any pre-sterilisation bioburden reduction process capability (e.g. filtration).
For aqueous solutions, the limits stated in Table 1 are acceptable for active substances and drug product
formulations without further justification. Other testing regimes and limits to control bioburden at the defined level
should be justified.
生物负荷限度应与任何预灭菌生物负荷降低工艺能力 (如过滤) 一致。在没有特殊说的情况下，对于水溶液， 表 1 所述
的限度对于活性物质和药物产品制剂是可以接受的。其他控制生物负荷在既定水平的测试方法和限度应进行论证。

Moist heat processes with an F0 < 8 min may be suitable as a post-aseptic processing terminal heat treatment for
formulations that cannot withstand a complete terminal sterilisation cycle. Such processes may further ensure a SAL
of sterile filtered (or otherwise sterilised) bulk components, which have been aseptically filled. Post-aseptic
processing terminal heat treatments are also presented in Table 1.
f0 < 8 分钟的湿热处理工艺可作为无菌处理后的终端热处理, 适用于无法承受完整的终端灭菌程序的情况。此类工艺可
进一步确保无菌过滤 (或以其他方式灭菌) 的散装组件经无菌分装后的 SAL。无菌处理后终端热处理也见表 1。

It is emphasised that this additional post-aseptic processing terminal heat treatment should not compensate for poor
aseptic manufacturing practice. The same requirements for the aseptic part of the process apply as for finished
products manufactured without such an additional post-aseptic processing terminal heat treatment.
需要强调的是, 这种额外的无菌加工终端热处理不应作为不良无菌生产操作的补偿。这与没有额外无菌加工终端热处理
在无菌工艺部分的要求是一样的。
Validation data to be provided in the quality dossier for all steam sterilisation processes that do not fulfil the
requirements of Ph. Eur. 5.1.1 standard process (required information 7 in Table 1):
对于不符合 ph. eur. 标准工艺要求的所有蒸汽灭菌工艺, 需在质量档案中提供的验证数据 (表 1 中所需信息 7):

Load mapping of the chamber and load mapping distribution of the items in the chamber (including the slowest to
heat locations); summary or confirmation of performance.
腔体的装载布置和腔体中物品的装载热分布（包括加热最慢的位置）; 性能确认总结。

Physical and biological cycle effect confirmation summary of at least three sterilisation runs
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demonstrating an SAL ≤10 , as described in Ph. Eur. 5.1.1 ensuring:
至少三次灭菌程序的物理和生物效果确认总结, 显示 SAL≤10-6, 如 ph. Eur 第 5.1.1 章节的要求:

Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters,
including time, temperature, pressure and F0, if applicable;
显示灭菌腔室中的灭菌负荷达到规定的循环参数, 包括时间、温度、压力和 f0 (如适用);

Acceptable temperature differences between temperature sensors in the load;

装载中温度传感器之间可接受的温差;

Acceptable F0 variability within the load;

负载内可接受的 f0 波动;

Relationship between physical and biological validation.

物理验证和生物验证之间的关系。
 For the biological validation, a biological indicator as described in Ph. Eur. chapter 5.1.2 Biological indicators
and related microbial preparations used in the manufacture of sterile products with a D121-value of ≥1.5
minutes should be used.
对于生物验证, 应使用 Ph.Eur. 5.1.2 章节 “用于无菌产品生产的生物指示剂和相关微生物制品无菌产品的相关微
生物制剂”中规定的 D121℃≥1.5 分钟的生物指示剂。

The SAL should be determined, its microbiological basis should be justified and details of calculations provided
in the quality dossier. Preferably it should be calculated from the maximum bioburden per container and the D-
value of the biological indicator used in the validation.
应确定 SAL，其微生物基础应合理，并在质量档案中提供计算细节。最好是根据每个容器的最大生物负荷和验
证中使用的生物指示剂的 D 值计算。

Additional validation data to be provided in the quality dossier for low energy steam processes or
where a bio-indicator with a D121-value of <1.5 minutes is used in the validation of the sterilisation
process (required information 8 in Table 1):
在低杀灭率蒸汽灭菌工艺的质量档案中提供的补充验证数据,或在灭菌过程的验证中使用 D121 值<1.5 分钟
的生物指示剂的情况下需提供的补充验证数据(表 1 中所需信息 8):

The following additional data should be provided:

应提供以下补充数据:

A justification for the start point of the sterilisation phase, that is the temperature when the temperature
sensors record the F0 from the start to end of the process;
论证灭菌阶段的起点，即灭菌开始至结束温度探头用于记录 f0 的温度;

Biological indicators with suitable resistance at the actual temperature range as described in Ph. Eur. 5.1.2
should be included in the validation to demonstrate sensitivity to the process.
验证应包括在 Ph.Eur.第 5.1.2 章中所述的实际温度范围内具有适当阻力的生物指示剂，以证明对工艺的敏感
性。

More detailed validation data is requested to ensure that the proposed sterilisation process is suitable for low
temperature processes and for processes using biological indicators of low heat resistance because:
需要更详细的验证数据, 以确保建议的灭菌工艺适用于低温工艺和使用低耐热性生物指示剂的工艺, 因为:

The change in lethal effect in relation to the process temperature may not be log linear at lower
sterilisation temperatures.
在较低的灭菌温度下, 杀灭效率与工艺温度的变化可能不是对数线性的。

The SAL demonstrated in the validation of a sterilisation process is dependent on the heat resistance of
the biological indicator used in the validation of the process. When a biological indicator of low D-value is
used in the validation of the sterilisation process, the SAL demonstrated becomes numerically higher, but
does not provide as high a safety margin as where a more resistant biological indicator is used. The SAL
should always be established in relation to a D-value that is higher than that of the normal bioburden at
routine production.
在灭菌工艺的验证中显示的 SAL 取决于在验证过程中使用的生物指示剂的耐热性。当在灭菌过程的验证中
使用低 D 值的生物指示剂时， 所显示的 SAL 会变得更高，但不能提供与使用更耐热的生物指示剂那样高
的安全系数。SAL 应该始终与 D 值相关，D 值高于常规生产中的正常生物负荷。

4.1.2. Dry heat sterilisation

干热灭菌

Time and temperature of the sterilisation cycle and a bioburden limit should always be stated.
通常应说明灭菌周期的时间和温度以及生物负荷限度。
For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (a minimum of 160 °C for at least 2 h), the
validation data for the sterilisation cycle is not required to be submitted in the quality dossier. For sterilisation cycles
with time and/or temperature lower than the reference conditions of the Ph. Eur., physical and biological validation
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of the sterilisation cycle should be provided to demonstrate an SAL of ≤10 , as described in Ph. Eur. 5.1.1. The
SAL of such a sterilisation process should be calculated from the maximum bioburden per container.
对于使用 ph. eur. 5.1.1 的参考条件 ( ≥160℃至少 2 小时 ) 进行灭菌, 灭菌周期的验证数据不需要在质量档案中提
交。对于时间和温度低于药典参考条件的灭菌周期，应提供灭菌周期的物理和生物验证, 以证明 SAL≤10-6。这种灭
菌工艺的 SAL 应根据每个容器的最大生物负荷计算。
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Where required, sufficient validation data should be submitted to demonstrate that an SAL of ≤10 is obtained for
all containers. The data submitted should include at least, but is not limited to:
必要时，应提交足够的验证数据, 以证明所有容器都能获得≤10-6 的 sal。提交的数据至少应包括但不限于:

 Load mapping of the chamber and load mapping distribution of the items in the chamber (including the
slowest to heat locations) – summary or confirmation of performance;
腔体负载分布和箱体中物品负载的分布 (包括最慢加热位置)--性能的总结或确认;

 Physical and biological cycle effect confirmation summary of at least three sterilisation runs
ensuring:
至少 3 次的物理和生物性能确认总结, 以确保:

 Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle
parameters, including time, temperature, and, lethality;
证实灭菌器腔体中的灭菌负载达到规定的循环参数, 包括时间、温度、杀灭力等;

 Acceptable temperature differences between temperature sensors in the load;

负载中温度传感器之间可接受的温差;

 Acceptable lethality variability within the load;

负载内杀灭率的可接受波动范围;

 Relationship between physical and biological validation.

物理和生物验证之间的关系。

For the biological validation, a biological indicator as described in Ph. Eur. chapter 5.1.2 should be used.
对于生物验证, 应使用 5.1.2 所述的生物指示剂。

A maximum bioburden limit of 100 CFU/100 g or 100 CFU/100 ml would be acceptable for parenteral finished product
formulations without further justification. For active substances and finished products that are not used for parenteral
administration, a maximum total bioburden limit of 10 CFU/g or 10 CFU/ml is acceptable without further risk based
justification. Other testing regimes and limits to control bioburden at the defined level should be justified. A justified
bioburden limit should also be established for empty containers.
对于肠外成品配方, 在没有进一步说明的情况下, 最大生物负荷限制为 100 cfu/100 g 或 100 cfu/100 毫升是可以接受
的。对于不用于肠外给药的活性物质和成品, 最大总生物量限制为 10 cfu/g 或 10 cfu/ml 是可以接受的, 没有进一步基于
风险说明。其他用以控制生物负荷在规定水平内的方法和限度应进行论证。对于空的容器，也应建立合理的生物负荷限
度。

Dry heat at temperatures of greater than 220 °C for a validated time is frequently used for both sterilisation and
depyrogenation of glassware and other heat-resistant container materials e.g. aluminium crimps. In this case,
demonstration of a 3 log reduction in heat-resistant endotoxins can be used as validation criteria.
在温度大于 220°c 的情况下, 在经过验证的时间内进行干热, 通常用于玻璃器皿和其他耐热容器材料的灭菌和去热原。
在这种情况下, 可将耐热内毒素下降 3 个 log 作为验证标准。

4.1.3. Ionization radiation sterilisation

电离辐射灭菌
For this method of sterilisation, the reference absorbed dose is ≥25 kGy. Other doses may be used to achieve an
−6
SAL ≤10 , if justified and validated.
对于这种灭菌方法, 参考吸收剂量≥25 kGy。如经论证和验证，也可以使用其他剂量以达到 sal≤10-6。

Data as requested in Note for Guidance “The use of Ionization Radiation in the Manufacture for Medicinal
Products” and in compliance with Ph. Eur. chapter 5.1.1 should be provided. Relevant guidance in establishing
the radiation dose other than 25 kGy is available in ISO standard 11137.
应提供指南《药品生产中使用电离辐射》中要求的数据, 并符合 ph. eur 5.1.1 章的要求。ISO 标准 11137 提供了
确定 25 kgy 以外的辐射剂量的相关指导。

Where any requirements in ISO 11137 are in contradiction to requirements stated in any Note for Guidance issued
by the EMA or Ph. Eur. monograph, the requirements of the Ph. Eur. and the Note for guidance apply.
如果 ISO 11137 中的任何要求与 ema 或 ph. eur. 专论发布的任何指导说明中的要求相抵触, 则应使用 ph. eur. 和指南
的要求。

4.1.4. Gas sterilisation

气体灭菌

4.1.4.1 General considerations

一般考虑

Generally, gas sterilisation is only acceptable if no other method of sterilisation is possible. Gas sterilisation
provides sterilisation of the surface of materials. It is mainly employed for sterilising packaging materials and
equipment, and has therefore only been included in the decision tree for containers. To ensure adequate sterility,
sufficient penetration by gas and moisture is essential. This should be followed by a purging process to ensure that
any residues of gas or related transformation by-products are below concentrations that could give rise to toxic
effects during use of the finished product. The effectiveness of the purging process should be demonstrated.
一般来说, 只有在没有其他灭菌方法的情况下, 气体灭菌才是可以接受的。气体灭菌可对材料表面进行灭菌。它主要
用于对包装材料和设备进行灭菌, 因此只包括在容器的决策树中。为了确保足够的无菌性, 气体和水分的充分渗透是
必不可少的。气体灭菌结束后应采取清除工艺, 以确保气体或相关转化副产品的任何残留物低于可能导致成品使用过
程中产生毒性影响的浓度。应证明清除过程的有效性。

Gas sterilisation of porous compounds, such as dry powders, is not acceptable unless other methods of sterilisation
are not feasible and its use is scientifically justified. Prior to the gas sterilisation, the active substance or excipient
should be sterile filtered and crystallised under aseptic conditions to minimise bioburden and entrapment of micro-
organisms within the crystals. Convincing evidence should be provided demonstrating that the material to be sterilised
is not susceptible to compression preventing gas and moisture penetration during sterilisation.
对多孔化合物 (如干粉体) 进行气体灭菌是不可接受的, 除非其他灭菌方法不可行且使用该方法经科学论证。在气体灭菌
之前, 活性物质或辅料应在无菌条件下进行无菌过滤和结晶, 以最大限度地减少微生物在晶体中的吸收和包裹。应提供
令人信服的证据, 证明待灭菌的材料在灭菌过程中不易挤压，防止气体和水分渗透。

A description of the apparatus, quantitative data on gas(es) to be used, the bioburden prior to sterilisation, the time of
exposure to the gas, the temperature and humidity prior to and during each step of the sterilisation cycle, and, if
applicable, the conditions for the removal of any toxic gas residues should be provided. Humidity used for the
preconditioning and/or conditioning of the material to be sterilised shall be generated by clean steam. These
conditions should be monitored by appropriate in-process controls with justified acceptance criteria. The process
should be developed and validated in compliance with Ph. Eur. 5.1.1 and 5.1.2. A risk assessment with regards to
residual toxic impurities should be conducted and a control strategy should be provided where applicable. The
requirements should be in accordance with the requirements of ICH M7 “Assessment and control of DNA reactive
(mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”. Even if the relevant product is outside
the scope of that guideline, its limits for highly toxic impurities could be applied.
应提供设备说明、要使用的气体的定量数据、灭菌前的生物负荷、接触气体的时间、灭菌周期每一步开始前和期间的温
度和湿度, 以及，适当时，清除任何有毒气体残留的条件。用于对待灭菌材料进行预处理和/或调节的湿度应通过清洁蒸
汽产生。这些条件应通过适当的过程控制和合理的接受标准进行监测。应按照 ph. eur. 5.1.1 和 5.1.2 制定和验证这一程
序。应对残留有毒杂质进行风险评估, 并酌情提供控制战略。这些要求应符合 ich m7 “评估和控制药品中的 dna 反应
性 (诱变) 杂质以限制潜在致癌风险”。即使相关产品超出了该准则的适用范围, 也可以使用其对剧毒杂质的限度。
-6
Results of the process validation should demonstrate an SAL of ≤10 .
工艺验证的结果应证明 sal ≤10-6。
The effectiveness of the process should be routinely checked for every batch confirming that the process parameters
and biological indicators are all within their acceptance criteria and by sterility testing. Parametric release is not
acceptable for gas sterilisation (according to Ph. Eur. chapter 5.1.1).
应检查每一批工艺的有效性, 确认工艺参数和生物指示剂都在其接受标准范围内, 并通过无菌测试。参数放行对于气体
灭菌是不可接受的 (根据 5.1.1 页)。

4.1.4.2 Ethylene oxide sterilisation

环氧乙烷灭菌

Ethylene oxide (ETO) sterilisation processes should be developed and validated in compliance with Ph. Eur. 5.1.1
and 5.1.2. Relevant guidance in establishing the sterilisation process cycle parameters and validation is available in
ISO standard 11135.
应按照 ph. eur 5.1.1 和 5.1.2 开发和验证环氧乙烷 (eto) 灭菌工艺。iso 标准 11135 提供了在确定灭菌工艺循环参数和
验证方面的相关指导。

ETO is a gas which is highly toxic. ETO sterilisation is generally only acceptable if no other method of sterilisation is
possible. The risk assessment should consider the residual known genotoxic impurities (such as ETO and
halogenated ethylenehydrines). This should be evaluated in accordance with the requirements of ICH M7
“Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic
risk”, unless the relevant product is outside the scope of that guideline. For products outside the scope of ICH M7, the
applicant should apply limits for highly toxic impurities in accordance with ICH M7, or the acceptance criteria stated in
Table 2, whichever is most appropriate.
eto 是一种剧毒气体。eto 灭菌通常只有在没有其他灭菌方法的情况下才可接受。风险评估应考虑已知的残留遗传毒性
杂质 (如 eto 和卤化乙二氢)。应根据 ich m7 "评估和控制药品中的 dna 反应性 (诱变) 杂质以限制潜在致癌风险" 的要
求对此进行评估, 除非相关产品不在该指南的范围之内。对于 ich m7 范围以外的产品, 申请人应根据 ich m7 或表 2 中
规定的接受标准对剧毒杂质实施限制, 以最适当者为准。

For empty containers intended to be filled with aqueous products, (e.g. prefilled syringes), the need to justify the
use of ETO in the sterilisation of the container prior to filling can be waived, as the degradation kinetics of ETO in
an aqueous medium have been sufficiently demonstrated. However, the levels of toxic residues (ETO and
halogenated ethylenehydrines) in the finished product need to fulfil the requirements of ICH M7, or the limits stated
in Table 2 below, as applicable.
对于打算装满水性产品的空容器 (例如预填充注射器), 可以免除对灌装前使用 ETO 对容器灭菌的论证，因为 ETO 在
水介质中的降解动力学已经充分证明。但是, 成品中毒性残留物 (ETO 和卤化乙基氢) 的含量需要满足 ich m7 的要
求，或者适当时，满足下文表 2 所述的限度。

Table 2 Limits for toxic gas residues from ethylene sterilisation where the ICH M7 limits do not apply
在不适用 ich m7 限度的情况下, 乙烯灭菌产生的有毒气体残留限值
Material
物料 Ethylene Ethylene chlorhydrin (or any other
Oxide halogenated ethylenehydrine)
环氧乙烷 2-氯乙醇或其他卤化乙烯醇

Raw materials
原料 1 µg/g 50 µg/g

Finished product (when used on 1 µg/g 50 µg/g

the finished product)
成品

Container (based on simulated 1 µg/ml 50 µg/ml

use)
容器
4.1.5. Sterile filtration
除菌过滤

The filter data to be provided in the quality dossier is summarised in Table 3.

质量档案中需要提供的过滤数据摘要见表 3。

Table 3 Filter data to be provided in the quality dossier for filters in contact with the drug product or
components of the drug product
与药品或药品组件接触的过滤器的质量档案中提供的过滤器数据

Parameter Filter Comment

1
Non- Sterilising
1
sterilising
General information on filter

Type of material, X X
nominal pore size
Number of filters X X
Filter area - X
Filter integrity test - X Principle of the test, details on when the tests are
performed, solution(s) used in the test and
acceptance criteria before and after filtration
should be described.
Filter validation Solution Comment
used
Potential sorption of X X Product
solution components
to filter
Solution X X Product Worst case conditions with regards
Compatibility to for instance sterilisation process,
contact time, filtration time,
pressure, filtered volume.
2 7 2
Filter retention - X Product Minimum 10 CFU/cm using a
capacity justified indicator organism and the
actual solution.
3
Filter integrity test - X Product
limits
4
Extractable and X X Product Justified surrogate solution may be
leachable used.
substances from the
filter
1
As defined in GMP, Annex 1
2
Validation of filter retention capacity may be combined with solution compatibility. If the product solution affects
the indicator organisms negatively, it should be neutralised before adding the organisms. For validation, a suitable
challenge microorganism representing the worst-case challenge to the filter should be used.
3
If the test is performed using a different solution in routine manufacture (for instance water for injections),
the limits should be established in this solution.
4
Data on leachables is relevant only if the extractables data indicate that toxic components may leach into the
solution to be filtered.

The integrity of the sterilised filter should be verified by testing before use unless specifically justified and
validated, and should be verified by on line testing immediately after use. Nominal pore sizes of 0.22 µm or less
are acceptable without further justification, in accordance with Ph. Eur.
除非有明确的证明和验证，除菌过滤器的完整性应在使用前通过测试进行确认, 并应在使用后立即通过在线测试进
行确认。根据 ph. eur., 在没有进一步理由的情况下, 可以接受 0.22μm 或以下的公称孔径。

For routine commercial manufacturing, bioburden testing should be performed on the bulk solution
immediately before sterile filtration.
对于日常的商业生产, 应在除菌过滤前立即对溶液进行生物负荷测试。
 In most situations, a limit of NMT 10 CFU/100 ml (TAMC) would be acceptable for bioburden testing. If a pre-filter is
added as a precaution only and not because the unfiltered bulk solution has a higher bioburden, this limit is
applicable also before the pre-filter and is strongly recommended from a GMP point of view. A bioburden limit of
higher than 10 CFU/100 ml before pre-filtration may be acceptable if this is due to starting material known to have
inherent microbial contamination. In such cases, it should be demonstrated that the first filter is capable of
achieving a bioburden of NMT 10 CFU/100 ml prior to the last filtration. Bioburden should be tested in a bulk
sample of 100 ml in order to ensure the sensitivity of the method. Other testing regimes to control bioburden at the
defined level should be justified.
在大多数情况下, 生物负荷测试可以接受 ≤ 10 cfu/100 ml (总需氧菌计数) 的限度。如果添加预过滤器仅为预防措
施, 而不是因为待过滤溶液生物负荷过高， 则此限度也适用于预过滤器之前，并且从 GMP 角度考虑也是强烈建议
如此。如果由于起始材料已知具有固有微生物污染, 在预过滤前生物负荷限度高于 10 cfu/100 ml 可能是可以接受
的。在这种情况下, 应证明第一个过滤器能够达到在后一个过滤器之前达到≤10 cfu/100 ml 的生物负荷。生物负荷
应该在 100 毫升的溶液中进行测试, 以确保该方法的敏感性。其他用以控制生物负荷在规定水平的测试方法应进行
论证。

The maximum time between the start of bulk solution preparation and sterile filtration should be stated, minimised and
appropriately supported by data. Filtration times longer than 24 hours should be justified.
应说明和最大限度减少从溶液配制到除菌过滤之间的最长时间间隔，并有数据支持。过滤时间超过 24 小时应进行论
证。

If a sterile filtered bulk solution is not filled into the final product containers within 24 hours, the sterile filtration should,
unless justified, be repeated immediately before filling. An additional bioburden test should be performed before any
further bioburden reduction step after the holding time. The holding time should be adequately justified.
如果无菌过滤溶液未在 24 小时内灌入最终产品容器, 除非经论证, 否则应立即重新进行无菌过滤才能灌装。一旦超出保
持时间，在任何进一步减少生物负荷的步骤之前， 应进行额外的生物负荷检验。保持时间应进行充分论证。

4.1.6. Aseptic processing

无菌工艺

Aseptic processing is not considered to be a sterilisation process but concerns the usage of technologies to process
sterile components avoiding addition of microbiological contaminants, e.g. use of an isolator or Restricted Access
Barrier System (RABS).
无菌处理不被认为是灭菌过程, 但涉及使用无菌部件进行加工的技术，需要避免引入微生物污染，例如使用隔离器或受
限进入屏障系统 (rabs)。

For aseptic processing, information on the bulk holding time before filling and on the filling time should be stated and
appropriately supported by data. The times should be minimised. The grounds for holding and filling times longer than
24 hours should be justified and supported by a risk assessment. It should be verified that the results of the media
simulations support the proposed holding and processing times. The actual results of media simulations fall within the
field of GMP and need not be presented routinely, but may be requested by the competent authorities in certain
circumstances since such data are important to justify proposed holding and filling times.
对于无菌处理, 应说明灌装前的保持时间和灌装时长的信息, 并有适当的数据支持。时间应尽量减少。保持时间和灌装
时长超过 24 小时的理由应得到风险评估的论证和支持。应当核实的是, 培养基模拟灌装的结果支持了拟议的保持时间
和处理（灌装）时长。培养基模拟灌装的实际结果属于 GMP 领域， 不需要例行提出，但在某些情况下, 主管当局可能
会提出要求, 因为这类数据对于证明拟议的保持时间和灌装时长的合理性是很重要的。

Sterile containers should be used for aseptically treated active substances, excipients and finished products.
经无菌处理的活性物质、辅料和成品应使用无菌容器。

Where blow-fill-seal technology is used for aseptically treated products, a summary of the validation data should be
provided to confirm that the container produced is sterile. The validation should, using a biological indicator with a
-6
suitable resistance, demonstrate a SAL of ≤10 for the surface of the container. The bioburden of the material(s)
used for the manufacture of the blow-fill-seal container should be controlled. The limit should be justified in relation
to the lethality of the validated blow-fill-seal process. The bioburden limit should also include a safety margin as a for
any possible bioburden enclosed within the material.
当吹-灌-封技术用于在无菌处理产品时，应提供验证数据总结, 以确认所生产的容器是无菌的。验证应使用具有适当耐
受性的生物指示剂, 证明容器表面的 SAL≤10-6。应控制用于制造吹-灌-封容器的材料的生物负荷。生物负荷的限度应
结合吹-灌-封工艺的杀灭力进行论证。生物负荷限度还应包括安全系数，以防止材料中包含的任何可能的生物负荷。

The majority of ATMPs cannot be terminally sterilised. In such cases, the manufacturing process should be conducted
aseptically. Further details on aseptic manufacturing for ATMPs can be found in the Guidelines on Good
Manufacturing Practice for Advanced Therapy Medicinal Products.
大多数 ATMP 不能进行最终灭菌。在这种情况下, 生产过程应无菌。有关 ATMP 无菌生产的更多详细信息，请参见《先
进治疗药品良好生产规范指南》。

4.2. Good manufacturing practice for sterile active substances, sterile excipients
and sterile containers
无菌活性物质、无菌辅料和无菌容器 GMP

Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation
of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use
laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC
respectively. For Advanced Therapy Medicinal Products, the Guidelines on Good Manufacturing Practice specific to
Advanced Therapy Medicinal Products should be followed.
《欧盟药品管理法》第 4 卷载有解释委员会规定的人用和兽用医药产品 GMP 的原则的指南。对于高级治疗药品, 应遵
循《高级治疗药品的良好生产规范指南》。

4.2.1. Active substances

活性成分

The basic GMP requirements for active substances used as starting materials (European Union (EU) GMP guide
part II) apply to the manufacture of sterile active substances up to the point immediately prior to the active
substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not
covered by EU GMP Part II but should be performed in accordance with the principles and guidelines of GMP as
laid out in the relevant EU Directive and interpreted in the GMP Guide including its Annex 1.
作为起始物料的活性物质的基本 GMP 要求 (欧盟 (EU) GMP 指南 第二部分 ) 适用于无菌活性物质在进入无菌步骤之
前的生产。无菌活性成分的灭菌和无菌处理不在欧盟 GMP 第二部分的范围内, 但应按照欧盟相关指令中的规定和
GMP 指南中 解释的 GMP 原则和指南进行, 包括其附录 1。

The sterilisation and aseptic processing of active substances is considered to be a step in the manufacture of the
medicinal product. This implies that for any active substance manufacturer who performs sterilisation and
subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an
EEA authority or from an authority of countries where mutual recognition or other Community arrangements apply
has to be submitted.
活性物质的灭菌和无菌加工被认为是药品生产的一个步骤。这意味着，对活性物质进行灭菌及随后无菌处理的任何活
性物质生产商，需要提交 EEA 药监局，或 MRA 国家药监局颁发的有效的生产许可或 GMP 证书。

The same GMP and data requirements also apply to sterile active substances supported by a Certificate of Suitability
issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM) or described in an Active
Substance Master File (ASMF).
同样的 GMP 和数据要求也适用于由 EDQM 颁发的符合性证书支持的无菌活性物质, 或在活性物质主文件 (ASMF) 中描
述的无菌活性物质。

4.2.2. Excipients
辅料

All the excipient sterilisation sites should be stated by name and address in the dossier.
所有的辅料灭菌工厂都应在档案中注明名称和地址。
For excipients required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site
where sterilisation of the excipients takes place may not have undergone inspection by an EU authority and
consequently may not hold an EU GMP certificate in relation to this activity. Nevertheless the sterilisation of an
excipient is a critical process and the sterility of the excipient is a critical quality attribute to ensure the sterility of the
finished product. When a GMP certificate is not available, a statement should be provided confirming that the
finished product manufacturer has evaluated all the manufacturers of sterile excipients with regards to their quality
system related to the sterilisation of the excipient. For products for human use this evaluation should be conducted in
line with the (GMP) Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate
good manufacturing practice for excipients of medicinal products for human use by taking into account the specific
requirements of Annex 1 of EU GMP-Guidelines.
对于需要无菌的辅料 (例如，直接用于无菌生产过程的辅料)， 对辅料进行灭菌的工厂可能没有经过欧盟当局的检查, 因
此可能无法持有与此活动相关的欧盟 GMP 证书。然而, 辅料的灭菌是一个关键的过程, 辅料的无菌性是确保成品无菌
的一个关键的质量属性。在没有 GMP 证书的情况下, 应提供一份声明, 确认成品生产商已对所有无菌辅料生产商进行
了与辅料灭菌相关的质量体系评价。对于人用药品，这一评价应按照 2015 年 3 月 19 日发布的关于正式风险评估的
(GMP) 指南进行，考虑欧盟 GMP 附录 1 的具体要求，以确定所适用的人用药品辅料的 GMP。

4.2.3. Containers
容器

For containers required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site
where sterilisation of the containers takes place may not have undergone inspection by an EU authority and
1
consequently may not hold an EU GMP certificate in relation to this activity . When a GMP certificate is not available,
certification that the sterilisation has been conducted and validated in accordance with the following ISO standards
would be considered sufficient to provide an acceptable level of sterility assurance for the empty container:
对于需要无菌的容器 (例如直接用于无菌生产过程容器)， 对容器进行灭菌的工厂可能没有经过欧盟当局的检查, 因此
可能没有持有与此活动相关的欧盟 GMP 证书。在没有 GMP 证书的情况下, 证明已按照以下 ISO 标准进行灭菌和验
证，将被视为足以提供适当无菌保证水平的容器：

1. I.S. EN ISO 20857 Sterilization of Health Care Products - dry Heat - Requirements for the Development,
Validation and Routine Control of a Sterilization Process for Medical Devices;

2. I.S. EN ISO 11135 Sterilization of Health-care Products - Ethylene Oxide - Requirements for the Development,
Validation and Routine Control of a Sterilization Process for Medical Devices;

3. I.S. EN ISO 17665-1 Sterilization of Health Care Products - Moist Heat - Part 1: Requirements for the
Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS
17665-2 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of ISO
17665-1;

4. I.S. EN ISO 11137-1 Sterilization of Health Care Products - Radiation - Part 1: Requirements for Development,
Validation and Routine Control of a Sterilization Process for Medical Devices;

5. I.S. EN ISO 11137-2 Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization
Dose;

6. I.S. EN ISO 11137-3 Sterilization of Health Care Products - Radiation - Part 3: Guidance on Dosimetric
Aspects.

It is the responsibility of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance,
of containers. The site where QP certification of the finished product takes place, and other manufacturing sites which
are responsible for outsourcing this sterilisation activity, should have access to the necessary information to
demonstrate the ongoing qualification status of suppliers of this sterilisation service. This may be checked during
inspections of the manufacturer of the finished product. The Competent Authorities may also decide, based on risk, to
carry out their own inspections at the sites where such sterilisation activities take place.
药品生产商有责任确保容器的质量，包括无菌保证。对成品进行 QP 的工厂，以及负责将这一灭菌活动外包的其他制造
工厂, 应能获得必要的信息, 以证明此灭菌服务供应商的持续确认状态。这可能会在成品生产商的检查过程中进行检
查。主管当局还可根据风险决定对进行此类灭菌活动的工厂进行自己的检查。
Quality Dossier requirements
质量档案要求

The following details regarding the sterilisation of the container components should be included in the quality
dossier:
关于容器部件灭菌的以下细节应包括在质量档案中:

1. The sterilisation method and sterilisation cycle;

灭菌方法和灭菌周期

2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions
stated in the Ph. Eur.;
如果灭菌周期不使用 ph. Eur 中规定的参考条件, 则验证灭菌周期;

3. The name and address of the site of sterilisation and, where available*, details of GMP certification
of the site.
灭菌现场的名称和地址, 以及现场 GMP 认证的详细信息（如适用） *。

*Where the container component is a CE-marked Class Is sterile device (e.g. sterile syringe), a declaration from the
device manufacturer that the component is a Class Is sterile device, together with a copy of the certificate of
conformity from the Notified Body will suffice. In the absence of a GMP certificate or declaration that the component is
a CE-marked Class Is medical device, confirmation by finished product manufacturer that the sterilisation process
has been conducted and validated in accordance with the relevant ISO standards should be provided.
* 如果容器组件是 CE 标志等级 I 的无菌器械 (例如无菌注射器)，则一份来自该器械生产商声明该组件是等级 I 无菌器械
的声明，以及认证机构提供的符合性证书副本，足够。在没有 GMP 证书或声明组件是 CE 标志等级 I 医疗器械的情况
下, 应提供成品制造商确认已按照相关 ISO 标准灭菌和验证的证明。

4.3. Selection of sterilisation method

灭菌方法的选择

Finished products intended to be sterile should be terminally sterilised in their final container whenever possible, as
clearly stated in the Ph. Eur., general chapter 5.1.1. Similarly, active substances, excipients and containers when
required to be sterile should be packed before they are sterilised whenever possible. When terminal sterilisation by
heat is not possible, the application of an alternative method of terminal sterilisation, sterilising filtration and/or aseptic
processing may be considered. It is recognised that terminal sterilisation processes utilising conditions other than the
Ph. Eur. reference conditions may be developed to provide satisfactory SALs and such alternative processes may be
acceptable when properly designed, validated and controlled.
欧洲药典通论 5.1.1 中明确指出, 无菌成品应尽可能在其最终容器中进行最终灭菌。同样, 需要无菌时, 活性物质、辅料
和容器应包装好，然后尽可能进行灭菌。当不可能用热进行终端灭菌时, 可以考虑采用一种替代的方法，如终端灭菌、
除菌过滤和/或无菌处理。应认识到可以开发欧洲药典参考条件以外的其他终端灭菌工艺，以提供令人满意的 SAL，这
种替代工艺如经适当设计、验证和使用，是可以接受的。

If a sterilisation process using principles other than those described in the Ph. Eur. (steam, dry heat, ionising radiation,
gas sterilisation and sterilising filtration) is intended to be used for the sterilisation of an active substance, excipient,
container or finished product, the applicant may consider seeking scientific advice regarding the acceptability of the
method and the documentation required.
如果使用欧洲药典中(蒸汽、干热、电离辐射、气体灭菌和除菌过滤)以外的其他灭菌方法对活性物质、辅料、容器或成品进
行灭菌，申请人可考虑就该方法的可接受性和所需文件寻求科学意见。

During the manufacturer’s evaluation of whether a terminal sterilisation cycle is possible, substantial efforts should
be made to enable terminal sterilisation. If the active substance or another component of the finished product is
shown to degrade significantly or an impurity limit is exceeded during shelf-life under even the least stressful
terminal sterilisation conditions, the efforts made to develop a formulation and container capable of undergoing
terminal sterilisation should be presented in the development section. Such efforts could be selection of optimal pH,
choice of excipients (qualitative and quantitative), container, optimisation of sterilisation method and manufacturing
conditions.
在生产商评估是否有可能进行最终灭菌的过程中，应尽可能使用终端灭菌。如果即使在最缓和的最终灭菌条件下, 活
性物质或成品的其他成分在其有效期内仍会明显下降或杂质超标，则应在开发部分展示为开发耐受最终灭菌配方和容
器所做的努力。这些努力可以包括选择最佳 ph 值、选择辅料 (定性和定量)、容器、优化灭菌方法和生产条件。

In case of medicinal products containing highly sensitive active substances, (e.g. proteins or other heat labile
biological substance), where it is well known that terminal sterilisation is not possible, a justification based on a
scientific rationale is generally acceptable and further justification of the choice of aseptic processing discussed later
in section 4.3 may not be needed.
如果是含有高敏感性的活性物质 (如蛋白质或其他热不稳定的生物物质) 的医药产品, 众所周知, 不可能进行最终灭菌, 基
于科学合理的论证通常是可以接受的，不需要进一步论证选择第 4.3 节无菌加工的理由。

The principles for the choice of sterilisation process for finished products and containers are presented in the form of
decision trees in section 5 of this guideline. The principles of the decision trees may also be applied for the
sterilisation of active substances and excipients.
本指南第 5 节以决策树的形式介绍了成品和容器灭菌工艺选择的原则。决策树的原则也可适用于活性物质和辅料的灭
菌。

For finished products where terminal sterilisation is not possible and aseptic processing is proposed, the decision
trees should be applied to individual components or mixtures of components in the formulation. An impact on the
shelf-life or storage conditions caused by a terminal sterilisation process is not in itself a reason to exclude terminal
sterilisation, unless the new storage condition or shelf-life would cause significant problems for the user.
对于不可能进行最终灭菌并拟进行无菌处理的成品，决策树应应用于配方中的单个组件或组件组合。最终灭菌过程对有
效期或储存条件造成的影响本身并不是排除最终灭菌的理由, 除非新的储存条件或有效期会给用户带来重大问题。

Terminal sterilisation should not be ruled out purely on the basis of an increase in degradation products above the
qualification thresholds in ICH Q3A/VICHGL10 (active substances), ICH Q3B/ VICH GL11 (finished products) or the
impurity limits in ICH M7 for products in the scope of that guideline without additional justification. If impurities are
either metabolites or are generated at levels already qualified, then terminal sterilisation is still considered feasible.
However, if the degradation products are not qualified at the level at which they occur, then sterile filtration and
aseptic processing may be selected. For medicinal products for human use impurities which occur above the
identification threshold should be specified in the finished product specification.
不应仅仅因为降解产物增加超过 ICH Q3A/VICHGL10 (活性物质)、ICH Q3B/VICH GL11 (成品) 中的限度或 ICH M7
指导范围中的产品的杂质限度，就排除最终灭菌而不进行论证。如果杂质都是代谢产物或是其产生水平经确认, 那么最
终灭菌仍然被认为是可行的。然而, 如果降解产物在发生的水平上不合格, 则可以选择除菌过滤和无菌工艺。对于人用
药产品, 超过识别阈值的杂质应在成品标准中明确规定。

The risk induced by the degradation should be balanced by the risk induced with an aseptic manufacturing method,
also taking in account the posology of the finished product and the nature of the degradation products. Attempts to
find terminal sterilisation conditions adjusted to give acceptable impurity levels based on degradation mechanisms of
the active substance and the actual bioburden should be described in the quality dossier.
降解引入的风险应与无菌生产方法引入的风险相平衡, 同时考虑到成品的剂量和降解产物的性质。在质量档案中, 应说
明试图根据活性物质的降解机制和实际生物负荷，找到最终灭菌条件，调整到可接受的杂质水平。

In certain cases, as described in the bullet points below, the use of aseptic processing may be accepted, even if
the formulation itself can be terminally sterilised. The approach should be clearly documented, explained and
scientifically justified. Such cases could be justified by:
在某些情况下, 如下文要点所述, 即使工艺本身可以最终灭菌, 也可以使用无菌工艺。应明确记录、解释和科学论证
这一方法。这种情况的通过以下方式论证：

User benefit provided by a container that cannot be terminally sterilised such as:

不能最终灭菌的容器有利于用户利益, 例如:

Eye drop containers enabling administration of single drops to the eye;

能实现单滴液滴滴到眼睛里的滴眼容器；
 Containers enabling non parenteral multi-dose preservative free medicinal products for

human use;

能实现人用注射剂无防腐剂的容器;

Enhanced ease of administration;

增强易管理性;

Safer handling of toxic products, for instance plastic vials instead of glass vials for cytotoxic medicinal products.
更安全地处理有毒产品，例如使用塑料瓶而不是玻璃瓶至细胞毒性药品。

The choice to use a heat-labile container cannot in itself be the sole reason for not applying a terminal
sterilisation process and alternative materials should be investigated. Thus, a discussion regarding the efforts
made to develop a container that may be terminally sterilised should be included.
选择使用热不稳定容器本身不能成为不采用最终灭菌工艺的唯一理由，应研究替代材料。因此，应包含关于努力
研究可以最终灭菌的容器的讨论。

Enabling as long a shelf-life as possible for radiopharmaceutical medicinal products with a shelf-life of less than
one week.
为放射性药物医药产品提供不超过一周的尽可能长的保质期。

The acceptability of aseptic processing should be based on the application of the decision tree and a risk
assessment. The bullet points below are not intended to be used to justify aseptic processing as such, but are only
intended to provide guidance on issues that are considered when evaluating the acceptability of a sterilisation or
aseptic processing. Considerations include (but are not limited to):
无菌工艺的可接受性应基于决策树的应用和风险评估。下面的要点并非旨在用于证明无菌工艺的合理性，而仅旨在
为评估灭菌或无菌工艺的可接受性时需考虑的问题提供指导。考虑因素包括（但不限于）：

Evidence that the proposed container with enhanced user benefits is fit for purpose;
提出具有增强的用户利益的推荐容器符合目的的证据;

Stability of the active substance, the degradation mechanism(s) and the toxicity of impurities formed during the
sterilisation process;
活性物质的稳定性，降解机理和灭菌过程中产生的杂质的毒性;

The volume to be administered per dose.

每剂给药的体积

In conclusion, the justification for the chosen sterilisation or aseptic processing should include a thorough benefit risk
evaluation and it should be demonstrated that suitable development efforts have been made.
总之，所选择的灭菌或无菌工艺的理由应包括彻底的利益风险评估，并且应该证明已经进行了适当的研发工作。

For advanced therapy medicinal products, the microbiological quality of all components, process equipment and the
aseptic techniques of the manufacturing processes are of utmost importance when the finished product cannot be
sterilised. For those medicinal products that cannot be sterilised, such as cell based medicinal products, a detailed
risk assessment with regards to microbial contamination should be provided. A risk based approach is already
foreseen for these ATMP (see Guideline on the risk-based approach according to annex I, part IV of Directive
2001/83/EC applied to Advanced therapy medicinal products, EMA/CAT/CPWP/686637/2011).
对于先进的治疗药品，当成品不能灭菌时，所有组分的微生物质量，工艺设备和生产工艺的无菌技术都是至关重要
的。 对于那些不能灭菌的药品，如基于细胞的药品，应提供有关微生物污染的详细风险评估。已经预见到这些 ATMP
的基于风险的方法（参见基于风险的方法指南，根据适用于高级治疗药物的指令 2001/83 / EC 的第 IV 部分附录 I，
EMA / CAT / CPWP / 686637/2011）。

5. Decision trees
决策树
The decision trees in Figures 1 and 2 are intended to assist in the selection of the optimal sterilisation method taking
into account the various issues to be considered. When moving down the decision trees, the methods generally show
a decreasing assurance of sterility and therefore, the first feasible option should normally be chosen.* The decision
trees have been elaborated primarily for finished products containing chemical active substances, but may be
applicable also to other types of products (including active substance and excipients). Figure 3 provides the
corresponding information for empty containers. The decision tree is not applicable to sterile empty containers that are
CE marked medical devices. In the case of biological products, an alternative approach may be appropriate.
图 1 和图 2 中的决策树旨在帮助选择最佳的灭菌方法,同时考虑到需要考虑的各种问题。决策树越向下的方法，无菌性
保证越低, 因此, 通常应选择第一个可行的选择. 决策树主要针对含有化学活性物质的成品进行了详细阐述，但也可适用
于其他类型的产品（包括活性物质和辅料）。图 3 提供了空容器的相应信息。决策树不适用于有 CE 标记的医疗器械的
无菌空容器。对于生物产品,可采用替代办法。

*While sterilisation by heat and sterilisation by ionising irradiation provide the same assurance of sterility,
sterilisation by heat has lower risk (e.g. radiolysis impurities) and is more easily controlled than sterilisation by
ionising irradiation. For these reasons, heat is given priority over ionising irradiation in the decision trees.
虽然通过加热灭菌和通过电离辐射灭菌提供了同样的无菌保证, 但加热灭菌的风险较低(例如辐射杂质)，也比电离辐
射灭菌更容易控制。因此, 在决策树中, 加热灭菌优先于电离辐射灭菌。

Figure 1 Decision tree for sterilisation choices for aqueous products

对于溶液剂型产品灭菌方法选择的决策树：
Figure 2 Decision tree for sterilisation choices for dry powder products, non-aqueous liquid or semi-solid
products
非溶液剂型、半固体或干粉产品灭菌方法选择的决策树：
Figure 3 Decision tree for sterilisation choices for containers
容器灭菌工艺选择的决策树
6. Definitions 定义
Aseptic processing A process performed maintaining the sterility of a
product that is assembled from components, each of
which has been sterilised by steam, dry heat, ionizing
radiation, gas or sterile filtration. This is achieved by
using conditions and facilities designed to prevent
microbiological contaminants.

The total number of micro-organisms associated with a

specific item prior to any sterilisation or bioburden
Bioburden
reduction step.

Biological indicators are test systems containing viable

microorganisms (usually spores of bacteria) that
Biological indicator
provide a defined challenge to verify the required
effectiveness of a specified sterilisation process.

A microbiological term that describes the formation of a

single macroscopic colony after the introduction of one or
more micro-organisms to microbiological growth media.
Colony Forming Unit (CFU) One colony forming unit is expressed as 1 CFU.

A physical, chemical, biological or microbiological

property or characteristic that should be within an
appropriate acceptance criteria, range, or distribution to
ensure the desired product quality
Critical Quality Attribute
A process used to destroy or remove pyrogens (e.g.
endotoxins).

The value of a parameter of sterilisation (duration or

absorbed dose) required to reduce the number of viable
Depyrogenation organisms to 10 per cent of the original number. It is only
of significance under precisely defined experimental
conditions.
D-value (decimal reduction value)
D121 is the D-value of the relevant spores at 121 C.

The F0 value of a saturated steam sterilisation process

is the lethality expressed in terms of the equivalent time
in minutes at a temperature of 121 °C delivered by the
process to the load in its container with reference to
micro-organisms possessing a theoretical Z-value of 10.

F0 value The time used to fill a bulk product into containers until
the container is closed or, in the case of a product
which is lyophilized after the

Filling time
 filling, until the lyophilisation chamber is closed.

Holding time The time between two process steps.

Immunological veterinary medicinal product A veterinary medicinal product administered to

animals in order to produce active or passive
immunity or to diagnose the state of immunity.

Lethal (process) A process that kills the microorganisms

exponentially.

Overkill sterilisation
A process with a lethality of F0BIO > 12 minutes.
For example a process that provides at least a 12
log reduction of biological indicator micro-
organisms having a minimum D value of 1
minute.

Ph. Eur. sterilisation reference conditions The reference conditions for sterilisation specified
in Ph. Eur. 5.1.1, i.e. terminal steam sterilisation
at ≥121 °C for 15 min, terminal dry heat
sterilisation at ≥160 °C for ≥2 h or terminal
ionising radiation of 25 kGy.

Post-aseptic processing terminal heat treatment A terminal moist heat process employed after
aseptic processing which has been demonstrated
-6
to provide a SAL ≤10 , but where the
requirements of steam sterilisation (for example,
F0≥8 min) are not fulfilled.

SAL Sterility Assurance Level. The SAL for a given

sterilisation process is expressed as the
probability of micro-organisms surviving in a
product item after exposure to the process. An
-6
SAL of 10 , for example, denotes a probability of
6
not more than 1 non-sterile item in 1 × 10
sterilised items of the final product.

Slowest to heat locations Location in the load that remains coldest or where
the temperature is raising slowest during the
sterilisation process.

It could, in a figurative sense, also be used for

other sterilisation methods for the location in the
load achieving the lowest level of sterilising
energy.

Steam sterilisation Reference is made to the description in Ph. Eur.

5.1.1.

Sterilisation A suitably designed, validated and controlled

process that inactivates or removes viable micro-
organisms in a product until sterility is obtained.
Sterility Sterility is the absence of viable microorganisms,
as defined by a sterility assurance level equal to
−6
or less than 10 .
The inactivation of microorganisms by physical or
chemical means follows an exponential law; thus
there is always a finite statistical probability that
a micro-organism may survive the sterilising
process. For a given process, the probability of
survival is determined by the number, types and
resistance of the microorganisms present and by
the environment in which the organisms exist
during treatment.

TAMC Total aerobic microbial count: The total aerobic

microbial count (TAMC) is considered to be equal
to the number of CFU found using casein soya
bean digest agar.

Terminal process A process where a finished product is processed

in its primary container, for example terminal
sterilisation or post-aseptic processing terminal
heat treatment.

Validation Establishing documented evidence that provides a

high degree of assurance that a specific process
will consistently produce a product meeting its
predetermined specifications and quality
attributes.

Worst case A set of conditions encompassing upper and lower

processing limits and circumstances, including
those within standard operating procedures, that
pose the greatest chance of process or product
failure (when compared to ideal conditions). Such
conditions do not necessarily induce product or
process failure.

z-value The z-value is the change in temperature

required to alter the D-value by a factor of 10.
7. References 参考文献
Decision trees for the selection of sterilisation methods, CPMP/QWP/054/98;

Note for Guidance: Development Pharmaceutics for veterinary medicinal products: Decision tree for the selection
of sterilisation methods, EMEA/CVMP/065/99;

Note for guidance on manufacture of the finished dosage form, CPMP/QWP/486/95; Note for Guidance:

Manufacture of the finished dosage form, EMEA/CVMP/126/95; ICH guideline Q8 (R2) on

pharmaceutical development, EMA/CHMP/ICH/167058/2004; European Pharmacopoeia general chapter

5.1.1 ‘Methods of preparation of sterile products’;

Note for Guidance: Virus validation studies: the design, contribution and interpretation of studies validating the
inactivation and removal of viruses, EMA/CPMP/BWP/268/95;

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community
code relating to medicinal products for human use, as amended;

Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community
code relating to veterinary medicinal products, as amended;

Guideline on real time release testing (formerly Guideline on parametric release),

EMA/CHMP/QWP/811210/2009-Rev1;

Guideline on Parametric release, EMEA/CVMP/QWP/339588/2005; EudraLex

- Volume 4 Good manufacturing practice (GMP) Guidelines;

European Pharmacopoeia general chapter 5.1.5 ‘Application of the F0 concept to steam sterilisation of aqueous
preparations’;
European Pharmacopoeia general chapter 5.1.2 ‘Biological indicators and related microbial preparations used in the
manufacture of sterile products’;

NfG on The use of Ionisation Radiation in the Manufacture of Medicinal products 3AQ4A; EN/ISO

11137, Sterilisation of health care products – Radiation;

ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit
potential carcinogenic risk (EMA/CHMP/ICH/83812/2013);

European Pharmacopoeia general chapter 5.1.7 ‘Viral Safety’ Human cell-

based medicinal products, EMEA/CHMP/410869/2006

Questions and Answers on allogenic stem cell-based products for veterinary use: specific questions on sterility
EMA/CVMP/ADVENT/751229/2016

Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products,
EMA/CAT/80183/2014

I.S. EN ISO 20857 Sterilization of health care products - dry Heat - Requirements for the development, validation and
routine control of a sterilization process for medical devices

I.S. EN ISO 11135 Sterilization of health-care products - Ethylene Oxide - Requirements for the development, validation
and routine control of a sterilization process for medical devices I.S. EN ISO
17665-1 Sterilization of health care products - Moist heat - Part 1: Requirements for the development, validation and
routine control of a sterilization process for medical devices

ISO/TS 17665-2 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of
ISO 17665-1

I.S. EN ISO 11137-1 Sterilization of health care products - Radiation - Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices

I.S. EN ISO 11137-2 Sterilization of health care products - Radiation - Part 2: Establishing the sterilization
dose

I.S. EN ISO 11137-3 Sterilization of health care products - Radiation - Part 3: Guidance on dosimetric aspects of
development, validation and routine control

ICH Q3A (R2) Impurities in new drug substances, CPMP/ICH/2737/99

ICH Q3B (R2) Impurities in New Drug Products, CPMP/ICH/2738/99;

VICH GL10 Impurities in new veterinary drug substances, CVMP/VICH/837/99 Rev.1

VICH GL11 Guideline on impurities in new veterinary medicinal products, EMEA/CVMP/VICH/838/99 Rev.1.

Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced
therapy medicinal products, EMA/CAT/CPWP/686637/2011).