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、辅料和内包材的灭菌指南
Draft agreed by QWP and BWP Adopted by CHMP for release for consultation Adopted by CVMP for release for consultation Start of public consultation End of consultation (deadline for comments) Agreed by BWP Agreed by CAT Agreed by QWP and GMDP IWG Adopted by CHMP for publication Adopted by CVMP for publication Date for coming into effect December 2015 January 2016 February 2016 13 April 2016 13 October 2016 July 2018 September 2018 October 2018 15 November 2018 6 December 2018 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).
本指南取代了灭菌方法选择的决策树文件（CPMP / QWP / 054/98），该文件是药品研发指南说明（CPMP / QWP / 155/96）的附件；以及灭菌方法选择的决策树文件（EMEA / CVMP / 065/99），该文件是指南说明的附件：兽药产品开发药剂学（EMEA / CVMP / 315/98）。
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Keywords 关键词
Active substance, Aseptic processing, Container, Decision trees, Excipients, Filtration, Finished Dosage form, Sterilisation, Sterilisation assurance level, Terminal sterilisation, Post-aseptic processing terminal heat treatment.
活性物质；无菌加工；容器；决策树；辅料；过滤；成品剂型；灭菌；无菌保证水平；终端灭菌；后无菌工艺的终端热处理
Guideline on sterilisation of the medicinal product, active substance, excipient and primary container
药品、活性物质、辅料和内包材的灭菌指南
Table of contents
目录
1. Introduction (background)简介（背景） .............................................................................. 3 2. Scope范围 .................................................................................................................................. 4 3. Legal basis法规依据 ................................................................................................................. 5 4. General requirements一般要求 .............................................................................................. 6
4.1.
Requirements for the manufacture of sterile medicinal products and sterile components无菌
药品和无菌部件的生产要求 .................................................................................................. 6 Steam sterilisation蒸汽灭菌 ............................................................................................... 8 Dry heat sterilisation干热灭菌 ......................................................................................... 14 Ionization radiation sterilisation电离辐射灭菌 ................................................................ 15 Gas sterilisation气体灭菌 ................................................................................................. 16 Sterile filtration除菌过滤 ................................................................................................. 18 Aseptic processing无菌加工 ............................................................................................ 21
4.1.1. 4.1.2. 4.1.3. 4.1.4. 4.1.5. 4.1.6. 4.2.
Good manufacturing practice for sterile active substances, sterile excipients and sterile containers无菌活性物质、辅料和容器的良好生产规范 .................................................. 22 Active substances活性物质 .............................................................................................. 22 Excipients辅料 .................................................................................................................. 23 Containers容器 ................................................................................................................. 23
4.2.1. 4.2.2. 4.2.3. 4.3.
Selection of sterilisation method灭菌方法的选择 ................................................................ 25
5. Decision trees决策树 .............................................................................................................. 29 6. Definitions定义 ....................................................................................................................... 32 7. References文献 ....................................................................................................................... 37
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Executive summary 摘要
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.
本指南提出了无菌产品适当灭菌方法的选择。尽管使用欧洲药典（Ph.Eur）的参考条件进行终端灭菌是可能的选择方法，但本指南提供的有关其他终端灭菌工艺、除菌过滤或无菌工艺的信息（单独的或后无菌工艺终端热处理）也是可以接受的一种选择。
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).
在新的上市许可申请或医药产品的变更申请（整个指南中称为质量档案）中，对无菌成品、无菌活性物质、无菌辅料和无菌内包材（本指南中称为容器）的预期文件提供了指导。 Terminology definitions are included at the end of the document. 术语定义在文见的末段。
1. Introduction (background) 简介（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.
无菌性是所有无菌物质、产品和容器的关键质量属性。通过检测无法确保无菌性，需要通过使用经过适当设计、验证和受控的制造工艺来确保无菌。通过控制若干因素（例如生物负载、灭菌程序、容器封闭系统的完整性以及无菌工艺）使用令人满意的无菌技术来实现无菌。
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.
终端灭菌优于通过过滤和/或无菌工艺进行灭菌，因为它对微生物是致命的，并且可靠的无菌保证水平（SAL）可以进行计算、验证和控制，同时包含安全余量。无菌工艺处理后进行除菌过滤，这是不适用的，因为通过监测和控制不能有效地消除由于技术不足引起的意外污染。因此，终端灭菌提供了最高的无菌保证，尽可能使用这种方法。
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
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controlled conditions can be accepted.
对于高度敏感的产品，例如大多数的生物制品，不可能对成品进行最终灭菌，在有效和受控条件下进行除菌过滤和/或无菌工艺处理是可以接受的。
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. 除菌过滤和无菌工艺处理密切相关，很难单独使用，因为在大多数情况下除菌过滤之后至少要有一个无菌工艺处理步骤，例如灌装。为了聚焦本指南中每个部分的过滤和无菌工艺处理的最重要方面，即使这两个步骤都相关，也只能涉及其中的一个。
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.
除了那些处方本身不允许最终灭菌的成品外，如果患者或使用者获得了其他益处，即使处方本身可以进行最终灭菌，在某些情况下使用无菌工艺也是可以接受的。这些情况在4.3节中详细说明。
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).
在ICH Q8中讨论了容器完整性，（仅用于人用药，但同样的原则也适用于兽药产品与无菌物质的容器）。
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.
该指南适用于人用和兽用的化学和生物医药产品，但不适用于免疫兽药产品。
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.
值得肯定的是，本指南中提供的建议可能需要对人用先进治疗药品（ATMP）的特定特征进行一些调整（例如，在某些情况下难以区分起始物料、活性物质和成品，稀缺起始物料/活性物质/成品（自体产品和配对供体情况下），少量生产）。预计将包含在ATMP的上市授权申请中的文档级别可以进行调整，前提是这在基于风险的方法是合理的。对于基于兽用细胞的新疗法，参考EMA / CVMP / ADVENT / 751229/2016关于用于兽用同种异体干细胞产品的问答：关于无菌的具体问题。
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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.
提供了关于灭菌方法的选择，开发数据和制造数据的指南，以证明所选灭菌工艺的适用性。相同的原则（灭菌方法的选择，开发数据和制造数据）适用于无菌活性物质，辅料和主要容器。仅描述了质量档案中预期的信息，包括与良好生产规范（GMP）证书相关的信息。并非所有GMP要求（例如环境监测，制造设备的灭菌）都参考了指南，只有那些被认为与质量档案特别相关的要求。 The scope of this document includes: 文件的范围包括：
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
使用欧洲药典5.1.1“无菌产品的制备方法”的参考条件或该专论中所述的其他条件，通过蒸汽、干热和电离辐射进行终端灭菌。 Sterilisation by filtration and aseptic processing 通过过滤和无菌工艺进行灭菌 Sterilisation by gas 使用气体进行灭菌
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. 本指南中的概念仅涉及细菌、真菌和细菌内毒素的清除或去除。不考虑可能污染产品的病毒、支原体、朊病毒和其他外来因子的清楚、去除或灭活。对于病毒验证，参考指南病毒验证研究：验证病毒灭活和去除的研究的设计、贡献和解释，CPMP / BWP / 268/95。
3. Legal basis 法规依据
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.
本指南应与法令2001/83 / EC结合阅读，该法令涉及与人用药相关的社会团体准则、法令2001/82 / EC的兽用产品以及现行的欧洲药典。
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
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other documents as linked to or published on the EMA website (www.ema.europa.eu).
此外，本指南应与其他所有相关法令和法规以及所有相关委员会，（V）ICH和CXMP指南，Q＆A文件以及EMA网站（www.ema.europa.eu）公布的文件结合阅读。
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.
该指南涉及与无菌产品和产品组分的无菌、灭菌工艺和无菌加工相关的特定要求。 4.1.
Requirements for the manufacture of sterile medicinal products and sterile components
无菌药品和无菌部件的生产要求
The choice of sterilisation method or aseptic processing should be justified, see section 4.3 Selection of sterilisation method.
灭菌方法或无菌加工的选择应该是合理的，参见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.
所有灭菌工艺均应按照欧洲药典的说明进行，除非有正当理由。
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.
应说明成品、活性物质、辅料或容器的所有灭菌程序以及灭菌场所的名称和地址。应提供灭菌方法和/或无菌处理的描述，包括过程控制和验证数据。
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，实时放行检验指南（以前的参数放行指南），EMA / CHMP / QWP / 811210/2009-Rev1（仅限人用产品），参数放行指南，EMEA / CVMP / QWP / 339588/2005（仅限兽用产品）和应该考虑欧洲药典5.1.1的内容。
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.
应在所有灭菌过程之前指定生物负载控制标准。不应通过灭菌过程或灭菌前的任何生物负载减少的能力来证明高生物负载验收标准。生物负载的验收标准在下面4.1的相关小节中讨论。
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
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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受组分中的生物负载和细菌内毒素（即活性物质，辅料和容器）以及制造过程中引入的微生物污染物的影响。为了确保成品中细菌内毒素的可接受水平，组分的微生物污染物水平应该是最小的。应规定生物负载的验收标准，以及相关的组分和散装溶液中的细菌内毒素。
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.
应描述成品制造过程中与成品接触的所有过滤器，或与成品中所含的任何组分（物质或中间产品）相关的所有过滤器，并且第4.1.5节表3中所述的信息应在质量档案中提供。该信息应符合Eudralex GMP附录1中规定的要求。对于ATMP，应遵循先进治疗药品特有的良好生产规范指南。
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.
如果使用次要容器（例如用于输液袋或泡罩的二级袋以保持容器外部的无菌性）来为药品提供特定保护，则应描述包装过程，包括风险评估，因为它可能影响成品的无菌性；例如，在主要和次要容器之间捕获水分。应提供何时执行包装步骤（灭菌前或灭菌后）以及采用的任何无菌技术的有关信息。从微生物角度来看，既定的工艺应该是合理的。如果使用次要容器意味着对成品应进行额外的灭菌，那么就无菌保证和对成品质量的任何潜在影响而言，这应该是合理的。
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.
有关灭菌和无菌处理的文件将包含在质量档案中，如下所示。如果在第3.2.P.3.3节或第2部分B中提供文件的位置，则出于实际原因，文件可以与待灭菌的项目一起提交。可以提供人用产品的文件，参见3.2.S.2制造、3.2.P.2药物研发、3.2.P.3制造、3.2.P.4辅料的控制，或3.2.P.7容器封闭系统，或用于兽用产品 第2部分A.4药物研发、第2部分B.1制造方法、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。无论工艺是内部开发还是外包，都应提供所有进行灭菌或无菌处理的场地文件。
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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.
在评估质量档案期间评估并同意工艺参数，例如加工和保持时间。这些可在GMP检查期间进一步地审查，因为这可能导致需要更改已登记的档案。 4.1.1.
Steam sterilisation 蒸汽灭菌
All steam sterilisation processes require a minimum lethality of F0 ≥ 8 minutes and a minimum process hold temperature of 110 ℃.
所有蒸汽灭菌工艺都要求F0≥8分钟的最小致死率和110℃的最低工艺保持温度。
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列出了不同杀灭水平的灭菌工艺，以及质量档案中应包含的文件。从上到下看，表中的工艺呈现逐渐降低的致死率，因此应该选择第一个可行的工艺。
For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (≥121 ℃, ≥15 min in all units) validation data for the sterilisation cycle is not required to be submitted in the quality dossier. 使用欧洲药典5.1.1（≥121℃，所有单位≥15分钟）的参考条件进行灭菌，灭菌周期的验证数据不需要在质量档案中提交。
If used as an additional control to measure the process lethality, F0, should be stated, together with the lowest temperature measured by the temperature sensors to determine F0.
如果用作测量过程致死率的附加控制，则应说明F0，以及由温度传感器测量的最低温度来确定F0。
Steam sterilisation performed with finished product temperature below 115 ℃ 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 ℃ are included (during heat-up and cool-down) in the determination of F0, this should be justified.
在保温阶段，成品温度低于115℃进行蒸汽灭菌是一种特殊情况，应该科学合理，并由表1中所述的其他数据支持。如果确定F0包括低于110℃的温度（在加热和冷却期间），这应该是合理的。
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概念和微生物减少的信息在欧洲药典5.1.5 F0概念在水溶性制剂蒸汽灭菌中的应用提供。
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.
生物负载限度应与所有预灭菌生物负载还原过程能力（例如过滤）一致。对于水溶液，表1中列出的限度对于活性物质和药物制剂是可接受的，没有进一步的理由。应该证明在规定水平上控制生物负载的其他测试方案和限度。
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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分钟的湿热工艺可作为无法承受完整终端灭菌周期的配方后无菌工艺终端热处理。此类方法可以进一步确保无菌过滤（或以其他方式灭菌）散装组分的SAL，其已经进行无菌灌装。表1中还列出了后无菌工艺终端热处理。
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，这种额外的后无菌工艺终端热处理不应该作为不良无菌生产实践的补充。对于该工艺无菌部分的相同要求适用于在没有这种额外的后无菌工艺终端热处理的情况下制造的成品。
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Table 1 Cycles for steam sterilisation and post-aseptic processing terminal heat treatment and corresponding data required in the quality 表1蒸汽灭菌和后无菌工艺终端热处理的程序以及质量要求的相应数据 Dossier 档案 Bioburden level before steam sterilisation or terminal heat treatment 灭菌或终端热处理前的生物负载水平 100 CFU/100ml (non-routine) 非常规 100 CFU/100ml (non-routine) 非常规 100 CFU/100ml (routine) 常规 100 CFU/100ml (routine) 常规 100 CFU/100ml (routine) 常规 100 CFU/100ml (routine) 常规 Bioburden Characterised 生物负载鉴定 Process hold temperature 工艺保持温度 2
Cycle 程序 Type of process 工艺类型 Information in dossier* 档案中的信息 Ph. Eur. 5.1.1 Reference Cycle 欧洲药典参考程序 Overkill cycle Fo >12 min 过度杀灭程序 Fo > 8 min Sterilisation 灭菌 Sterilisation 灭菌 Sterilisation 灭菌 Sterilisation 灭菌 Sterilisation 灭菌 Sterilisation 灭菌 1, 6 No ≥ 121 ℃ for ≥15 minutes 1, 2, 3, 4, 7 No ≥ 121 ℃ 1, 2, 3, 4, 7 No > 115 ℃ Fo > 8 min 1, 2, 3, 5, 7, 8 Yes** > 115 ℃ Fo > 8 min 1, 2, 3, 4, 7 Yes > 110 ℃ Fo > 8 min 1, 2, 3, 5, 7, 8 Yes** > 110 ℃
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Fo <8 min Post-aseptic processing terminal heat treatment 后无菌工艺终端热处理 Post-aseptic processing terminal heat treatment 后无菌工艺终端热处理 1, 2, 3, 4, 7, 8 0 CFU/100ml, aseptic filtration and processing prior to terminal heat treatment (routine) 最终热处理之前，使用除菌过滤和无菌工艺（常规） 0 CFU/100ml, aseptic filtration and processing prior to terminal heat treatment (routine) 最终热处理之前，使用除菌过滤和无菌工艺（常规） Yes*** > 110 ℃**** Fo <8 min 1 2, 3, 5, 7, 8 Yes*** > 110 ℃**** 3
* For clarification of the code numbers, see below 有关代码编号的说明，请参见下文
** In-process control demonstrating acceptable heat resistance of bioburden 中间控制证明了生物负载可接受的耐热性
*** The bioburden prior to the sterilisation step (i.e. filtration) should be characterised for heat resistance 灭菌步骤（即过滤）之前的生物负载应具有耐热性的特征
**** Temperatures below 110 ℃ may be used if justified. The requirement for additional documentation for such cycles is evaluated on a case by case basis
如果合理，可以使用低于110℃的温度。根据具体情况评估对此类程序的额外文件要求 Clarification of the information to be presented in the quality dossier 澄清质量档案中提供的信息
1: Sterilisation time, temperature profile 1：灭菌时间，温度曲线
2: Sterilisation method (for instance saturated steam cycle, air/steam-overpressure cycle, vacuum phase) description including SAL
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2：灭菌方法（例如饱和蒸汽循环，空气/蒸汽 – 过压循环，真空阶段）描述，包括SAL
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3： F0Phys和F0Bio验证
11 4: Biological indicator with a D121 ≥ 1.5 minutes used in the validation
4：生物指示剂D121≥1.5分钟用于验证
12 5: Biological indicator with a D121 < 1.5 minutes used in the validation
5：生物指示剂D121 <1.5分钟用于验证
13 6: No validation data requested in the dossier, only a confirmation that validation has been performed.
6：档案中未验证数据，仅确认已执行验证。
14 7: Validation data to be provided in the dossier is presented below
7：档案中提供的验证数据如下所示
15 8: Additional validation data to be provided in the dossier is presented below
8：下面将介绍在档案中提供的附加验证数据
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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):
所有蒸汽灭菌工艺质量档案中提供的验证数据不符合欧洲药典5.1.1标准流程的要求。（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. 腔室的装载分布和腔室中物品的装载分布（包括最慢的加热位置）；性能总结或确认 Physical and biological cycle effect confirmation summary of at least three sterilisation runs demonstrating an SAL ≤10-6, as described in Ph. Eur. 5.1.1 ensuring:
如欧洲药典5.1.1中描述的，至少三次灭菌运行的物理和生物循环效果确认总结证明SAL≤10-6，确保：
Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters, including time, temperature, pressure and F0, if applicable;
证明灭菌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（如果适用）;
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; 装载内可接受的F0变化;
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 Biological indicators and related microbial preparations used in the manufacture of sterile products with a D121-value of ≥1.5 minutes should be used.
对于生物学验证，如欧洲药典第5.1.2章用于无菌产品的生物指示剂和相关的微生物制剂中描述的，生物指示剂应使用D121值≥1.5分钟。
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，其微生物学基础应合理，并在质量档案中提供计算细节。应该根据每个容器的最大生物负载和用于验证的生物指示剂的D值来计算。
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):
在低能蒸汽工艺的质量档案中提供额外的验证数据，或者在灭菌工艺验证中使用D121值<1.5分钟的生物指示剂（表1中的必要信息8）： The following additional data should be provided: 应提供以下附加数据：
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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; 灭菌阶段起点的理由，即温度传感器从工艺开始到结束记录F0时的温度;
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. 生物指示剂在实际温度范围内具有合适的抗性，如欧洲药典5.1.2所描述的，在验证中应包括，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:
要求提供更详细的验证数据，以确保既定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，与工艺温度相关的致死效应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.
在灭菌工艺验证中的SAL取决于用于工艺验证的生物指示剂的耐热性。当在灭菌工艺的验证中使用低D值的生物指示剂时，SAL在数值上更高，但是不提供与使用更耐热的生物指示剂一样高的安全阈值。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载。 Dry heat sterilisation 干热灭菌
4.1.2.
Time and temperature of the sterilisation cycle and a bioburden limit should always be stated. For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (a minimum of 160 ℃ 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 of the sterilisation cycle should be provided to
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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.
应说明灭菌周期的时间和温度以及生物负载限度。使用欧洲药典 5.1.1的参考条件（最低160℃至少2小时）进行灭菌，在质量档案中不需要提交灭菌周期的验证数据。对于灭菌周期的时间和/或温度低于欧洲药典的参考条件，应提供灭菌周期的物理和生物验证数据以证明SAL≤10-6，如欧洲药典 5.1.1中所述。这种灭菌工艺的SAL应根据每个容器的最大生物负载来计算。
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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:
如果需要，应提交足够的验证数据，以证明所有容器的SAL均≤10-6。提交的数据应至少
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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; 腔室的装载分布和腔室中物品的装载分布（包括最慢的加热位置） - 性能的总结或确认;
Physical and biological cycle effect confirmation summary of at least three sterilisation runs ensuring:
物理和生物周期效果至少确认三次灭菌运行的总结，确保：
Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters, including time, temperature, and, lethality;
证明灭菌室中的灭菌负荷达到规定的周期参数，包括时间，温度和致死率; 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; 负载内可接受的致死率变化;
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.
对于生物学验证，应使用欧洲药典第5.1.2章中描述的生物指示剂。
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.
对于肠胃外成品制剂，最大生物负载限度为100CFU / 100g或100CFU / 100ml是可接受的，无需进一步说明。对于非用于肠胃外给药的活性物质和成品，最大总生物负载限度为10 CFU / g或10 CFU / ml是可接受的，无需更多基于风险的理由。应该证明在规定水平上控制生物负载的其他测试方案和限度。还应为空容器建立合理的生物负载限度。
Dry heat at temperatures of greater than 220 ℃ 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.
在大于220℃的温度下进行验证时间的干热灭菌经常用于玻璃器皿和其它耐热容器材料（如铝制材料）的灭菌和去热原。在这种情况下，可以使用耐热内毒素降低3个对数作为验证标准。 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 SAL ≤10−6, if justified and validated.
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对于这种灭菌方法，参考吸收剂量≥25kGy。如果合理且有效，可以使用其他剂量来达到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. “医药产品制造中电离辐射的使用”指南中的数据，符合欧洲药典第5.1.1章。ISO 11137中建立了25 kGy以外辐射剂量。
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或欧洲药典发布的任何指南说明中所述的要求相矛盾，应用欧洲药典和指南说明中的要求。 4.1.4.
Gas sterilisation 气体灭菌
4.1.4.1 General considerations
一般考虑要点
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. 通常，只有在不能使用其他灭菌方法的情况下才会接受气体灭菌。气体灭菌只给材料表面进行灭菌。它主要用于包装材料和设备的灭菌，因此仅包含在容器的决策树中。为了确保足够无菌，必须通过气体和水分充分的渗透，接下来应该进行吹扫，以确保任何残留的气体或相关的转化副产物低于在成品使用过程中可能产生毒性作用的浓度。应证明吹扫过程的有效性。
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.
多孔化合物（如干粉）的气体灭菌是不可接受的，除非其他灭菌方法不可行或者其使用在科学上是合理的。在气体灭菌之前，活性物质或辅料应进行无菌过滤并在无菌条件下结晶，尽量减少生物负载和微生物在晶体内的截留。应提供令人信服的证据，证明待灭菌的材料不易受到压缩，从而防止灭菌过程中的气体和水分渗透。
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
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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.
设备的描述、使用的气体定量数据、灭菌前的生物负载、暴露于气体的时间、灭菌周期的每个步骤之前和期间的温度和湿度，以及，如果适用的话，应提供去除任何有毒气体残留物的条件。用于预处理和/或调节待灭菌材料的湿度应由清洁蒸汽获得。应通过适当的过程控制以及合理的验收标准来监控这些条件。根据欧洲药典5.1.1和5.1.2来开发和验证该工艺。应对残留的有毒杂质进行风险评估，并在适用的情况下提供控制策略。所有要求应符合ICH M7“药物中DNA反应性（诱变性）杂质的评估和控制，限制潜在的致癌风险”的要求。即使相关产品超出了该指南的范围，也可以应用其剧毒杂质的限度。 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).
应定期检查每个批次的工艺有效性，确认工艺参数和生物指示剂均在其验收标准和无菌测试范围内。气体灭菌不接受参数放行（根据欧洲药典第5.1.1章）。 4.1.4.2 Ethylene oxide sterilisation
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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.
环氧乙烷（ETO）灭菌工艺应根据欧洲药典5.1.1和5.1.2进行开发和验证。ISO 11135中提供了建立灭菌工艺周期参数和验证的相关指南。
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。如果没有其他灭菌方法，ETO灭菌通常是可以接受的。风险评估应考虑残留的已知遗传毒性杂质（如ETO和卤代乙烯醇）。应根据ICH M7“药物中DNA反应性（诱变性）杂质的评估和控制，限制潜在的致癌风险”的要求进行评估，除非相关产品超出该指南的范围。对于ICH M7范围以外的产品，申请人应根据ICH M7或表2中规定的验收标准（以最合适的为准）来制定高毒性杂质的限度。
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
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product need to fulfil the requirements of ICH M7, or the limits stated in Table 2 below, as applicable.
对于打算用水溶性产品灌装的空容器（例如预填充注射器），在灌装之前可以忽略使用ETO容器灭菌的合理性，因为ETO在水性介质中的降解动力学已经充分证明。但是，成品中的有毒残留物（ETO和卤代乙烯醇）的含量需要满足ICH M7的要求，或下表2中所述的限度（如适用）。
Table 2 Limits for toxic gas residues from ethylene sterilisation where the ICH M7 limits do not apply
表2环氧乙烷灭菌中有毒气体残留物的限度，其中ICH M7限度不适用 Material 物料 Raw materials 原料 Finished product (when used on the finished product) 成品（用于成品时） Container (based on simulated use) 容器（基于模拟使用） 4.1.5.
Sterile filtration 除菌过滤
The filter data to be provided in the quality dossier is summarised in Table 3. 在表3中总结了质量档案中提供的过滤数据。
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
表3与药品或药品组分接触的过滤器的质量档案中提供的过滤数据 Filter 过滤器 Parameter 参数 Non- Sterilising1 sterilising1 非灭菌 灭菌 General information on filter Comment 评价 Ethylene oxide 环氧乙烷 Ethylene chlorhydrin (or any other halogenated ethylenehydrine) 2-氯乙醇（或任何其他卤代乙烯醇） 50 µg/g 1 µg/g 1 µg/g 50 µg/g 1 µg/ml 50 µg/ml 过滤器的通用信息
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Type of material, nominal pore size 材料类型，标称孔径 Number of filters 过滤数量 Filter area 过滤面积 X X X X - X Filter integrity test 过滤器完整性测试 - 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. 应描述测试原理、测试的详细信息，用于测试的溶液以及过滤前后的验收标准。 Solution used 所用溶液 Filter validation Comment 评价 过滤器验证 Potential sorption of solution components to filter 溶液组分可能吸附到过滤器上 X X Product 产品 Solution Compatibility 溶液相容性 X X Product 产品 Worst case conditions with regards to for instance sterilisation process, contact time, filtration time, pressure, filtered volume. 关于灭菌工艺、接触时间、过滤时间、压力、过滤体积的最差情况。
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Filter retention capacity 过滤保留容量 - X Product 2 产品 Minimum 107 CFU/cm using a justified indicator organism and the actual solution. 使用合理的指示微生物和实际的溶液，最低107 CFU / cm2。 2Filter integrity test limits 过滤器完整性测试限度 Extractable and leachable substances from the filter 过滤器中可提取和可浸出的物质 - X Product 3 产品 X X Product4 产品 Justified surrogate solution may be used. 可以使用合理的替代溶液。 1 As defined in GMP, Annex 1 如GMP附录1中的定义
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.
过滤器保留容量的验证可与溶液相容性结合起来。如果产品溶液对指示微生物产生负面影响，则应在添加微生物之前将其中和。为了验证，应该使用过滤器最差情况挑战试验的合适微生物。
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.
如果在日常生产中使用不同的溶液（例如注射用水）进行测试，则应对这个溶液建立限度。 4 Data on leachables is relevant only if the extractables data indicate that toxic components may leach into the solution to be filtered.
仅当可提取物数据表明有毒成分可能会渗入待过滤的溶液中时，可浸出物的数据才有意义。 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.
灭菌过滤器的完整性应在使用前通过测试进行验证，除非经过特别证明和验证，应在使用后立即通过在线检测进行验证。根据欧洲药典，可以接受标称孔径为0.22μm或更小的，无需进一步证明。
For routine commercial manufacturing, bioburden testing should be performed on the bulk solution immediately before sterile filtration.
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对于常规商业化生产，应在除菌过滤之前立即对溶液进行生物负载检测。
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.
大多数情况下，NMT 10 CFU / 100 ml（TAMC）的限度对于生物负载测试是可接受的。如果仅作为预防措施添加预过滤器而不是因为未过滤溶液具有更高的生物负载，则此限度也适用于预过滤器，并且从GMP的角度强烈推荐。如果由于已知具有固有微生物污染的起始物料，则预过滤前的生物负载限度高于10CFU / 100ml是可接受的。在这种情况下，应该证明第一个过滤器能够在最后一次过滤之前达到NMT 10 CFU / 100ml的生物负载。生物负载应在100 ml的样品中进行测试，以确保该方法的灵敏度。其他在特定浓度控制生物负载的测试方案应该是合理的。
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.
开始溶液制备到除菌过滤之间的最长时间应说明，尽量缩短时间并由数据支持。过滤时间超过24小时应该进行证明。
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.
除非有正当理由，如果除菌过滤的溶液未在24小时内灌装到最终产品的容器中，那么应在灌装前重复无菌过滤过程。在保持时间之后的任何生物负载减少步骤之前，应该进行额外的生物负载测试。保持时间应该是充分合理的。 4.1.6.
Aseptic processing 无菌加工
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).
无菌加工不被认为是一种灭菌工艺，而被认为是使用技术来处理无菌组分，避免添加微生物污染物，例如使用隔离器或限制访问屏障系统（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.
对于无菌加工，应说明灌装前的保存时间和灌装时间的信息，并应有适当支持数据。时间应该最小化。保持时间和灌装时间超过24小时的理由应该充分合理，并有风险评估作支撑。
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应该验证培养基模拟灌装的结果来支持建议的保持和处理时间。培养基模拟的实际结果属于GMP范畴，不需要定期提供，但在某些情况下主管当局可能会要求，因为这些数据对于证明保持时间和灌装时间是合理的非常重要。
Sterile containers should be used for aseptically treated active substances, excipients and finished products.
无菌容器应用于无菌处理的活性物质、辅料和成品。
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
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should, using a biological indicator with a 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 precaution for any possible bioburden enclosed within the material.
如果无菌处理的产品使用吹灌封技术，则应提供验证数据的摘要，以确认所使用的容器是无菌的。验证应使用具有适当抗性的生物指示剂，表明容器表面的SAL≤10-6。应控制用于生产吹灌封容器材料的生物负载。关于经验证的吹灌封工艺的致死率，该限度应该是合理的。生物负载限度还应包括安全余量，作为材料中封闭的任何可能的生物负载预防措施。 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，制造过程应在无菌条件下进行。有关ATMP无菌制造的更多详细信息，请参阅“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、辅料和容器的良好生产规范
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.
“欧盟药品管理条例”第4卷包含对委员会指令91/356 / EEC中规定的人用和兽用药品良好生产规范的原则和指导原则的解释指南，分别通过指令2003/94 / EC和91/412 / EEC进行修订。对于先进治疗药品，应遵循先进治疗药品特有的良好生产规范指南。 4.2.1.
Active substances 活性物质
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.
用作起始物料的活性物质，基本GMP要求（欧盟（EU）GMP指南第II部分）适用于制备无菌活性物质，直至活性物质无菌之前。欧盟GMP第II部分不包括无菌活性物质的灭菌
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和无菌处理，但应按照相关欧盟指令中规定的GMP原则和指南进行，并在GMP指南及其附录1中进行解释。
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处理被认为是医药产品制造中的一个步骤。意味着对于所有活性物质灭菌和无菌后处理的活性物质制造商，必须提交有效的生产授权、EEA的GMP证书、互认协议或其他团体约定。
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).
相同的GMP和数据要求也适用于欧洲药品和医疗保健质量管理局（EDQM）颁发的或活性物质主文件（ASMF）中描述的适用性证书所支持的无菌活性物质。 4.2.2.
Excipients 辅料
All the excipient sterilisation sites should be stated by name and address in the dossier. 所有辅料灭菌场所应在档案中按名称和地址说明。
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.
对于需要无菌处理的辅料（即随后用于无菌生产过程的辅料），辅料灭菌的场所可能未经欧盟当局检查，因此可能未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过程，辅料的无菌性是确保成品无菌的关键质量属性。如果没有GMP证书，则应提供一份声明，确认成品制造商已经评估了所有无菌辅料制造商在其与辅料灭菌相关的质量体系方面情况。对于人用产品，应根据2015年3月19日的（GMP）指南进行评估，以确定适合人用医药产品辅料的良好生产规范，并考虑到人用欧盟GMP指南的附录1的具体要求。 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 consequently may not hold an EU GMP certificate in relation to this activity1. 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:
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对于需要无菌的容器（即随后用于无菌生产过程的容器），容器灭菌的场所可能未经欧盟当局检查，因此可能未持有与此活动相关的欧盟GMP证书。如果没有GMP证书，则认为根据以下ISO标准进行灭菌和验证的认证足以为空容器提供可接受的无菌保证水平： 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;
I.S. EN ISO 20857医疗保健产品的灭菌 - 干热 - 医疗器械灭菌过程的开发、验证和常规控制要求; 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;
I.S. EN ISO 11135医疗保健产品的灭菌 - 环氧乙烷 - 医疗器械灭菌过程的开发、验证和常规控制要求; 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;
I.S. EN ISO 17665-1医疗保健产品的灭菌 - 湿热 - 第1部分：医疗器械灭菌过程的开发、验证和常规控制的要求，以及ISO / TS 17665-2医疗保健产品的灭菌 - 湿热 - 第2部分 ：ISO 17665-1的应用指南; 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;
I.S. EN ISO 11137-1医疗保健产品的灭菌 - 辐射 - 第1部分：医疗器械灭菌过程的开发、验证和常规控制要求; 5.
I.S. EN ISO 11137-2 Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization Dose;
I.S. EN ISO 11137-2医疗保健产品的灭菌 - 辐射 - 第2部分：建立灭菌剂量; 6.
I.S. EN ISO 11137-3 Sterilization of Health Care Products - Radiation - Part 3: Guidance on Dosimetric Aspects.
I.S. EN ISO 11137-3医疗保健产品的灭菌 - 辐射 - 第3部分：剂量学方面的指导。
1 Sites located in the EU which perform sterilisation of primary containers only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities. 位于欧盟的仅对主要容器进行灭菌的工厂不需要持有制造商/进口商的授权（MIA）。位于欧盟的进行药品灭菌的工厂必须持有与这些活动相关的MIA。
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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. 药品制造商有责任确保容器的质量，包括无菌保证。成品的QP认证场所以及负责外包该灭菌活动的其他生产场所应该能够获得必要的信息，以证明该灭菌服务供应商的持续资格状态。这可以在检查成品制造商的过程中进行检查。主管当局还可以根据风险决定在进行灭菌活动的地点进行自检。 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:
有关容器组件灭菌的以下详细信息应包含在质量档案中：
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欧洲药典规定的参考条件，则需验证灭菌周期;
3. The name and address of the site of sterilisation and, where available*, details of GMP
certification of the site.
灭菌场所的名称和地址，以及可用的*场地GMP认证的详细信息。
*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标记的Class Is无菌设备（例如无菌注射器），则设备制造商声明该组件是Class Is无菌设备，以及公告机构的合格证书副本也是可以的。如果没有GMP证书或声明该组件是CE标记的Class Is医疗设备，则应提供成品制造商的确认，说明已根据相关ISO标准进行灭菌并进行验证。 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
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alternative processes may be acceptable when properly designed, validated and controlled. 用于灭菌的成品应尽可能在其最终容器中进行最终灭菌，如欧洲药典第5.1.1章中所述。同样，需要灭菌的活性物质、辅料和容器应尽可能在灭菌前进行包装。当不能通过加热进行最终灭菌时，可以考虑应用除菌过滤和/或无菌处理来替代终端灭菌。考虑利用除欧洲药典以外的条件进行终端灭菌工艺可以开发出令人满意的SAL，并且在适当设计、验证和控制时，这样的替代过程是可接受的。
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.
如果灭菌工艺使用的原理不同于欧洲药典中（蒸汽、干热、电离辐射、气体灭菌和除菌过滤）描述的原则旨在用于活性物质、辅料、容器或成品的灭菌，申请人可考虑寻找该方法的可接受性和所需文件的科学建议。
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.
在制造商评估终端灭菌周期是否可行的过程中，应该做出实质性的努力以实现终端灭菌。如果显示最终产品的活性物质或其他组分显著降解，或者在保质期内即使是最不严苛的最终灭菌条件下杂质超出限度，在开发部分应该介绍努力开发最终灭菌的配方和容器。这些努力可以是最佳pH的选择、辅料的选择（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.
如果医药产品含有高敏感的活性物质（例如蛋白质或其他热不稳定的生物物质），终端灭菌是不可能的，基于科学的原理通常是可以接受的，并进一步证明了选择的合理性。可能不需要在后面4.3节讨论无菌加工。
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.
成品和容器灭菌工艺选择的原则以本指南第5节中的决策树形式呈现。决策树的原理也可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.
对于无法进行最终灭菌并且建议进行无菌处理的成品，决策树应适用于配方中的各个组分或组分的混合物。除非新的储存条件或有效期对用户造成严重问题，否则对终端灭菌工艺
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引起的有效期或储存条件的影响本身并不是排除终端灭菌的理由。
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.
不应仅仅基于ICH Q3A / VICHGL10（活性物质）、ICH Q3B / VICH GL11（成品）或ICH M7产品杂质限度中的降解产物增加超过限定阈值来排除终端灭菌，该指南的范围没有额外的理由。如果杂质是代谢物或在合格的水平产生，那么终端灭菌仍然被认为是可行的。但是，如果降解产物不符合它们产生的水平，则可以选择除菌过滤和无菌处理。对于人用医药产品，应在成品规格中规定高于识别阈值的杂质。
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.
降解引起的风险应该通过引入无菌制造方法的风险来平衡，同时还要考虑成品的性质和降解产物的性质。根据质量档案中的描述，尝试根据活性物质和实际生物负载的降解机理调整最终灭菌条件以提供可接受的杂质水平。
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，如下面的要点所述，即使配方本身可以进行最终灭菌，也可以接受使用无菌处理。该方法应明确记录、解释且科学合理。这种情况可以通过以下方式证明：
User benefit provided by a container that cannot be terminally sterilised such as: 用户利益归于无法进行最终灭菌的容器，例如：
Eye drop containers enabling administration of single drops to the eye; 滴眼液给药方式的滴眼容器;
Containers enabling non parenteral multi-dose preservative free medicinal products for human use;
用于人用非肠外多剂量无防腐剂药品的容器; Enhanced ease of administration; 提高易管理性;
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，例如塑料小瓶代替玻璃小瓶用于细胞毒性药品。
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
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should be included.
选择使用热不稳定容器本身不能成为不采用终端灭菌工艺的唯一原因，应研究替代材料。因此，应该包括关于开发可以进行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.
为有效期不超过一周的放射性药品提供尽可能长的有效期。
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):
无菌处理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处理的合理性，而仅仅为了在评估灭菌或无菌处理的可接受性时所要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; 提出既能增加用户利益又符合预期用途的既定容器的证据;
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形成的毒性杂质; The volume to be administered per dose. 每个剂量给药的体积。
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处理的理由应该包括所有利益的风险评估，并且应该证明已经进行了适当的开发工作。
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). 对于先进治疗药品，当成品不能灭菌时，所有组件的微生物质量、工艺设备和制造过程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。对于ATMP已经预见到基于风险的方法（参见基于风险的方法指南，根据适用于先进治疗药物的指令2001/83 / EC的第IV部分附录I，EMA / CAT / CPWP / 686637/2011）。
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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灭菌方法，同时考虑到各种问题。在向下移动决策树时，这些方法通常表现出无菌保证，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详细阐述，但也可能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CE标记医疗设备的无菌空容器。就生物制品而言，替代方法可能是合适的。
*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相同的无菌保证，但是通过加热灭菌具有较低的风险（例如，辐射会分解杂质），并且比电离辐射灭菌更容易控制。基于这些原因，加热优于决策树中的电离辐射。
Figure 1 Decision tree for sterilisation choices for aqueous products 图1水溶性产品的灭菌选择决策树
产品可以耐受≥121℃，≥15分钟灭菌吗？
产品可以蒸汽灭菌达到F0≥8min，并达到SAL≤10-6？
使用≥121℃，≥15分钟的蒸汽灭菌吗？
产品可以除菌过滤吗？
使用F0≥8min的蒸汽灭菌？
使用预先灭菌的组分并无菌加工
使用除菌过滤、预灭菌容器和无菌加工
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Figure 2 Decision tree for sterilisation choices for dry powder products, non-aqueous liquid or semi-solid products
图2干粉产品、非水溶性液体或半固体产品的灭菌选择决策树
产品可以耐受160℃，120分钟干热灭菌吗？
使用≥160℃，≥120分钟干热灭菌
产品可以在另一种时间和温度条件下干热灭菌达到SAL≤10-6？
产品可以使用电离辐射灭菌吗？最小吸收剂量25kGy的或使用经验证的更低的放射剂量
使用另一种替代时间和温度条件进行干热灭菌达到SAL≤10-6？
产品可以除菌过滤吗？
使用电离辐射灭菌，使用最小吸收剂量≥25kGy或使用经验证的 更低的放射剂量
使用预灭菌的组分并无菌加工
使用除菌过滤，预灭菌容器和无菌加工
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Figure 3 Decision tree for sterilisation choices for containers 图3容器的灭菌选择决策树
该容器是否耐受热力灭菌
该容器是否可以电离辐射灭菌
使用蒸汽或干热灭菌
该容器是否可以使用气体灭菌
使用电离辐射灭菌
使用其他容器
使用气体灭菌
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6. Definitions 定义
Aseptic processing 无菌工艺
Bioburden 生物负载
Biological indicator 生物指示剂
Colony Forming Unit (CFU) 菌落形成单位(CFU)
Critical Quality Attribute 关键质量属性
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. 一种保持产品无菌性的方法，该产品由组分分装而成，每种组分已经通过蒸汽、干热、电离辐射、气体或无菌过滤灭菌。这是通过使用旨在防止微生物污染物的条件和设施来实现的。
The total number of micro-organisms associated with a specific item prior to any sterilisation or bioburden reduction step.
在任何灭菌或生物负载减少步骤之前与特定物品相关的微生物总数。
Biological indicators are test systems containing viable microorganisms (usually spores of bacteria) that provide a defined challenge to verify the required effectiveness of a specified sterilisation process.
生物指示物是含有活微生物（通常是细菌孢子）的测试系统，其提供确定的挑战性以验证特定灭菌过程所需的有效性。
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. One colony forming unit is expressed as 1 CFU.
微生物学术语，将一种或多种微生物引入微生物生长培养基后形成单个可见菌落。一个菌落形成单位表示为1CFU。
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
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Depyrogenation 除热原
D-value (decimal reduction value) D值（指数减少值）
F0 value F0值
Filling time 灌装时间
Holding time 保持时间
Immunological veterinary medicinal product 免疫兽药产品
应在适当的验收标准、范围或分布范围内的物理、化学、生物或微生物性质或特性，以确保所需的产品质量
A process used to destroy or remove pyrogens (e.g. endotoxins).
用于破坏或去除热原（例如内毒素）的方法。
The value of a parameter of sterilisation (duration or absorbed dose) required to reduce the number of viable organisms to 10 per cent of the original number. It is only of significance under precisely defined experimental conditions.
灭菌参数（持续时间或吸收剂量）的值，用于将活菌数量减少到原始数量的10％。它仅在精确定义的实验条件下具有重要意义。
D121 is the D-value of the relevant spores at 121℃. D121是121℃时相关孢子的D值。
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 ℃ delivered by the process to the load in its container with reference to micro-organisms possessing a theoretical Z-value of 10.
饱和蒸汽灭菌工艺的F0值是以相对于具有理论Z值10的微生物通过该过程输送到其容器中负载的121℃温度下的等效时间（以分钟为单位）表示的致死率。
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, until the lyophilisation chamber is closed.
将散装产品填充到容器中直到容器关闭的时间，或者在灌装冻干产品后直到冷冻干燥室关闭的情况下。
The time between two process steps. 两种工艺步骤所间隔的时间
A veterinary medicinal product administered to animals in order to produce active or passive immunity or to diagnose the state of immunity.
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Lethal (process) 致死（过程） Overkill sterilisation 过度杀灭
Ph. Eur. Sterilisation reference conditions 欧洲药典 灭菌参考条件
Post-aseptic processing terminal heat treatment 后无菌工艺的终端热处理SAL
无菌保证水平
Slowest to heat locations
给动物使用的兽药产品，以产生主动或被动免疫或诊断免疫状态。
A process that kills the microorganisms exponentially. 一种以指数方式杀死微生物的过程。
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.
F0BIO > 12分钟的杀灭过程。例如，提供具有最小D值为1分钟的生物指示微生物至少12对数减少的过程。
The reference conditions for sterilisation specified in Ph. Eur. 5.1.1, i.e. terminal steam sterilisation at ≥121 ℃ for 15 min, terminal dry heat sterilisation at ≥160 ℃ for ≥2 h or terminal ionising radiation of 25 kGy.
Ph.Eur 5.1.1中规定的灭菌参考条件，即终端蒸汽灭菌≥121℃ 15分钟，终端干热灭菌≥160℃≥2h或终端电离辐射25 kGy。
A terminal moist heat process employed after aseptic processing which has been demonstrated to provide a SAL ≤10-6, but where the requirements of steam sterilisation (for example, F0≥8 min) are not fulfilled.
在无菌处理之后使用的终端湿热工艺已经证明可提供SAL≤10-6，但是不满足蒸汽灭菌的要求（例如，F0≥8min）。
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 SAL of 10-6, for example, denotes a probability of not more than 1 non-sterile item in 1 × 106 sterilised items of the final product.
无菌保证水平：给定灭菌过程的SAL表示为暴露于该过程后微生物在产品中存活的概率。例如，10-6的SAL表示在最终产品的1×106灭菌物品中不超过1个非无菌物品的概率。
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最慢加热点
Steam sterilisation 蒸汽灭菌
Sterilisation 灭菌
Sterility 无菌性
TAMC
总需氧微生物数量Terminal process
Location in the load that remains coldest or where the temperature is raising slowest during the sterilisation process.
在灭菌过程中保持最冷或温度升高最慢的位置。 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.
它还可以用于其他灭菌方法，以实现最低水平的灭菌能量。
Reference is made to the description in Ph. Eur. 5.1.1. 参考Ph.Eur 5.1.1的描述。
A suitably designed, validated and controlled process that inactivates or removes viable micro- organisms in a product until sterility is obtained.
一种经过适当设计、验证和控制的工艺，可以灭活或去除产品中的活微生物，直至无菌。
Sterility is the absence of viable microorganisms, as defined by a sterility assurance level equal to or less than 10−6. 无菌是指不存在活微生物，如无菌保证水平等于或小于10-6。
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. 通过物理或化学方法灭活微生物遵循指数法则; 因此，总有一个有限的统计概率，即微生物可以在灭菌过程中存活。对于给定的过程，存活的概率取决于存在的微生物的数量、类型和抗性以及处理期间存在的生物体的环境。
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.
总需氧微生物数量：总需氧微生物数量（TAMC）被认为等同于使用酪蛋白大豆消化琼脂发现的CFU数量。
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终端灭菌工艺
Validation 验证
Worst case 最差条件
z-value Z值
A process where a finished product is processed in its primary container, for example terminal sterilisation or post-aseptic processing terminal heat treatment.
成品在其主容器中加工的过程，例如最终灭菌或后无菌工艺的终端热处理。
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.
建立书面证据，高度保证特定过程将始终如一地生产满足其预定规格和质量属性的产品。
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.
包含处理限值的上下限和环境的一系列条件，包括标准操作程序中的那些内容，最有可能导致工艺或产品失效（与理想条件相比）。这些条件不一定会导致产品或工艺失败。
The z-value is the change in temperature required to alter the D-value by a factor of 10.
Z值是通过因子10来改变D值所需的温度变化。
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7. References 文献
Decision trees for the selection of sterilisation methods, CPMP/QWP/054/98; 灭菌方法选择的决策树，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;
指南说明：开发兽药产品制剂：灭菌方法选择的决策树，EMEA / CVMP / 065/99; Note for guidance on manufacture of the finished dosage form, CPMP/QWP/486/95; 关于成品剂型生产的指南说明，CPMP / QWP / 486/95;
Note for Guidance: Manufacture of the finished dosage form, EMEA/CVMP/126/95; 指南说明：成品剂型的制造，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’; ICH Q8（R2）药物研发，EMA / CHMP / ICH / 167058/2004; 欧洲药典通则第5.1.1章“无菌产品的制备方法”;
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;
指南说明：病毒验证研究：验证灭活和清除病毒研究的设计、贡献和解释，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;
欧洲议会和理事会2001年11月6日关于经修正的与人用药品有关的共同体法典的第2001/83 / EC号指令;
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;
欧洲议会和理事会2001年11月6日关于经修正的兽医药品共同体法的第2001/82 / EC号指令;
Guideline on real time release testing (formerly Guideline on parametric release), EMA/CHMP/QWP/811210/2009-Rev1;
实时放行检验指南（以前的参数放行指南），EMA / CHMP / QWP / 811210/2009-Rev1; Guideline on Parametric release, EMEA/CVMP/QWP/339588/2005; 参数放行指南，EMEA / CVMP / QWP / 339588/2005;
EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines; EudraLex - 第4卷良好生产规范（GMP）指南;
European Pharmacopoeia general chapter 5.1.5 ‘Application of the F0 concept to steam
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sterilisation of aqueous preparations’;
欧洲药典通则第5.1.5章“F0概念在水溶性制剂蒸汽灭菌中的应用”;
European Pharmacopoeia general chapter 5.1.2 ‘Biological indicators and related microbial preparations used in the manufacture of sterile products’;
欧洲药典通则第5.1.2章“用于制造无菌产品的生物指示物和相关微生物制剂”; NfG on The use of Ionisation Radiation in the Manufacture of Medicinal products 3AQ4A; NfG关于电离辐射在医药产品3AQ4A制造中的应用; EN/ISO 11137, Sterilisation of health care products – Radiation; EN / ISO 11137，医疗保健产品的灭菌 - 辐射;
ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk (EMA/CHMP/ICH/83812/2013);
ICH指南M7，用于评估和控制药物中的DNA反应性（诱变性）杂质，以限制潜在的致癌风险（EMA / CHMP / ICH / 83812/2013）;
European Pharmacopoeia general chapter 5.1.7 ‘Viral Safety’ 欧洲药典通则第5.1.7章“病毒安全”
Human cell-based medicinal products, EMEA/CHMP/410869/2006 基于人类细胞的医药产品，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
关于兽医用同种异体干细胞产品的问答：关于无菌的具体问题EMA / CVMP / ADVENT / 751229/2016
Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, EMA/CAT/80183/2014
关于基因治疗药品非临床和临床方面的质量指南，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 20857医疗保健产品的灭菌 - 干热 - 医疗器械灭菌过程的开发、验证和常规控制要求
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 11135医疗保健产品的灭菌 - 环氧乙烷 - 医疗器械灭菌过程的开发、验证和常规控制要求
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 I.S. EN ISO 17665-1医疗保健产品灭菌 - 湿热 - 第1部分：医疗器械灭菌过程的开发、验证和常规控制要求
ISO/TS 17665-2 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of ISO 17665-1
ISO / TS 17665-2医疗保健产品的灭菌 - 湿热 - 第2部分：ISO 17665-1的应用指南
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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 11137-1医疗保健产品的灭菌 - 辐射 - 第1部分：医疗器械灭菌过程的开发、验证和常规控制要求
I.S. EN ISO 11137-2 Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose
I.S. EN ISO 11137-2医疗保健产品的灭菌 - 辐射 - 第2部分：确定灭菌剂量
I.S. EN ISO 11137-3 Sterilization of health care products - Radiation - Part 3: Guidance on dosimetric aspects of development, validation and routine control
I.S. EN ISO 11137-3医疗保健产品的灭菌 - 辐射 - 第3部分：开发、验证和常规控制的剂量测定方面指南
ICH Q3A (R2) Impurities in new drug substances, CPMP/ICH/2737/99 ICH Q3A（R2）新原料药中的杂质，CPMP / ICH / 2737/99 ICH Q3B (R2) Impurities in New Drug Products, CPMP/ICH/2738/99; ICH Q3B（R2）新药产品中的杂质，CPMP / ICH / 2738/99;
VICH GL10 Impurities in new veterinary drug substances, CVMP/VICH/837/99 Rev.1 VICH GL10新兽药原料中的杂质，CVMP / VICH / 837/99 Rev.1 VICH GL11 Guideline on impurities EMEA/CVMP/VICH/838/99 Rev.1.
in
new
veterinary
medicinal
products,
VICH GL11新兽药产品的杂质指南，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).
根据用于先进治疗药品的指令2001/83 / EC第IV部分附录I的基于风险的方法指南，EMA / CAT / CPWP / 686637/2011）。
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