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
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 (C
PMP/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）。
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)
4.1.1. Steam sterilisation 蒸汽灭菌 (8)
4.1.2. Dry heat sterilisation 干热灭菌 (14)
4.1.3. Ionization radiation sterilisation 电离辐射灭菌 (15)
4.1.4. Gas sterilisation 气体灭菌 (16)
4.1.5. Sterile filtration 除菌过滤 (18)
4.1.6.
Aseptic processing 无菌加工 ............................................................................................ 21 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)
4.2.1. Active substances 活性物质 (22)
4.2.2. Excipients 辅料 (23)
4.2.3.
Containers 容器 ................................................................................................................. 23 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)
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
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.accepted什么意思中文
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
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。
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 veterin
ary 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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