标准编号:	YY/T 0567.1-2013
中文名称:	医疗保健产品的无菌加工 第1部分：通用要求
英文名称:	Aseptic processing of health care products - Part 1: General requirements
中标分类:	C47    公共医疗设备
行业分类:	YY    医药行业标准
ICS分类:	11.080.01 11.080.01    消毒和灭菌综合 11.080.01
发布机构:	国家食品药品监督管理总局
发布日期:	2013-10-21
实施日期:	2014-10-1
标准状态:	valid
替代旧标准:	YY/T 0567.1-2005 医疗产品的无菌加工 第1部分：通用要求
翻译语言:	英文
文件格式:	PDF
中文字符数:	40000 字
翻译价格(元):	2400.0
交付时间:	付款后 1 个工作日

Aseptic processing of health care products -Part 1: General requirements 1 Scope This part of YY/T 0567 specifies the general requirements for, and offers guidance on, processes, programmes and procedures for development, validation and routine control of the manufacturing process for aseptically-processed health care products. This part includes requirements and guidance relative to the overall topic of aseptic processing. Specific requirements and guidance on various specialized processes and methods related to filtration, lyophilization, clean-in place (CIP) technologies, sterilization in place (SIP) and isolator systems are given in other parts. Note: This part of YY/T 0567 does not supersede or replace national regulatory requirements, such as Good Manufacturing Practices (GMPs) and/or pharmacopoeial requirements that pertain in particular national or regional jurisdictions. 2 Normative references The following referenced documents are indispensable for the application of this document. For dated reference, only the edition cited applies. For undated references, the latest edition (including any amendments) applies. ISO 9001 Quality management systems - Requirements ISO 11135-1 Sterilization of health care products - Ethylene oxide - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices ISO11137-1 Sterilization of health care products - Radiation - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices ISO 11137-2 Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose ISO 13408-2 Aseptic processing of health care products - Part 2: Filtration ISO 13408-3 Aseptic processing of health care products - Part 3: Lyophilization ISO 13408-4:2005 Aseptic processing of health care products - Part 4: Clean-in-place technologies ISO 13408-5 Aseptic processing of health care products - Part 5: Sterilization in place ISO 13408-6 Aseptic processing of health care products - Part 6: Isolator systems ISO 13485 Medical devices - Quality management systems - Requirements for regulatory purposes ISO 14160 Sterilization of single-use medical devices incorporating materials of animal origin - Validation and routine control of sterilization by liquid chemical sterilants ISO 14644-1 Cleanrooms and associated controlled environments - Part 1: Classification of air cleanliness ISO 14644-2 Cleanrooms and associated controlled environments - Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1 ISO 14644-3 Cleanrooms and associated controlled environments - Part 3: Test methods ISO 14644-4 Cleanrooms and associated controlled environments - Part 4: Design, construction and startup ISO 14644-5 Cleanrooms and associated controlled environments - Part 5: Operations ISO 14644-7 Cleanrooms and associated controlled environments - Part 7: Speparative devices ( clean air hoods, gloveboxes, isolators and mini-environments) ISO 14698-1 Cleanrooms and associated controlled environments - Biocontamination control - Part 1: General principles and methods ISO 14698-2 Cleanrooms and associated controlled environments - Biocontamination control - Part 2: Evaluation and interpretation of biocontamination data ISO 14937 Sterilization of health care products - General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices ISO 14971 Medical - Devices - Application of risk management to medical devices 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 20857 Sterilization of health care products - Dry heat - Requirements for the development, validation and routine control of a sterilization process for medical devices ICH Guidance for Industry - Q9 Quality Risk Management ) 3 Terms and definitions For the purpose of this document, the following terms and definitions apply. 3.1 action level established microbial or particulate monitoring results requiring immediate follow-up and corrective action 3.2 airlock room with interlocked doors designed to maintain pressure control between adjacent rooms of different cleanliness class 3.3 alert level established microbial or particulate monitoring results giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which could require follow-up investigation 3.4 aseptic processing handling of sterile product, containers and/or devices in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to maintain sterility Note: This includes sterilization by membrane filtration which cannot be separated from the subsequent aseptic process. 3.5 aseptic processing area(APA) facilities for aseptic processing (3.4), consisting of several zones 3.6 bioburden population of viable microorganisms on or in product and/or sterile barrier system [ISO/TS 11139:2006, 2.2] Note: For the purposes of aseptic processing, the bioburden of concern is that on or in the product including all factors affecting it such as raw material, intermediates, other components and equipment. 3.7 bio-decontamination removal of microbiological contamination or its reduction to an acceptable level [ISO 13408-6:2005, 3.1] 3.8 cleaning removal of contamination from an item to the extent necessary for further processing or for intended use [ISO/TS 11139:2006, 2.7] 3.9 combination product product comprised of drug/device, biologic/device, drug/biologic or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity 3.10 correction action to eliminate a detected non-conformity Note: correction may be made in conjunction with corrective action. [ISO 9000:2005, 3.6.6] 3.11 corrective action action to eliminate the cause of a detected non-conformity or other undesirable situation [ISO 9000:2005, 3.6.5] Note 1: There may be more than one cause for a nonconformity. Note 2: Corrective action is taken to prevent recurrence whereas preventive action (3.29) is taken to prevent occurrence. Note 3: There is a distinction between correction and corrective action. Note 4: Corrective actions might be subject to change control. 3.12 critical processing zone location within the aseptic processing area in which product and critical surfaces are exposed to the environment 3.13 critical surface surface that may come into contact with or directly affect a product or its containers or closures 3.14 depyrogentation validated process designed to remove or deactivate endotoxins 3.15 design qualification verification that the proposed specification for the facility, equipment or system is suitable for the intended use [ISO/TS 11139:2006, 2.12] 3.16 direct support zone protective area directly surrounding a critical processing zone 3.17 disinfectant chemical agent that is able to reduce the number of viable microorganisms 3.18 disinfection removal, destruction or de-activation of microorganisms on objects or surfaces [ISO 14644-5:2004, 3.1.4] 3.19 endotoxin lipopolysaccharide component of the cell wall of Gram-negative bacteria which is heat stable and elicits a variety of inflammatory responses in animals and humans 3.20 environmental isolates microorganisms present in and/or isolated from processing or manufacturing environments

Foreword I Introduction IV 1 Scope 2 Normative references 3 Terms and definitions 4 Quality system elements 5 Aseptic process definition 6 Manufacturing environment 7 Equipment 8 Personnel 9 Manufacture of the product 10 Process simulation 11 Test for sterility Annex A (Informative) Example of a flow chart Annex B (Informative) Typical elements of an aseptic process definition Annex C (Informative) Examples of specific risks Annex D (Informative) Comparison of classification of cleanrooms Annex E (Informative) Specification for water used in the process Annex F (Informative) Aseptic processing area Bibliography

3 术语和定义 下列术语和定义适用于本文件。 3.1 措施限 action level 需要立即采取跟踪和纠正措施的微生物或微粒监测结果的限度。 3.2 气闸 airlock 用于维持不同洁净度级别的相邻房间之间的压力控制，且装有互锁门的房间。 3.3 警戒限 alert level 警示操作条件可能已经偏离正常范围的微生物或者微粒监测结果的限度。达到警戒限并非应采取相应的纠正措施，但可能需要跟进调查。 3.4 无菌加工 aseptic processing 在受控环境中对无菌的产品、容器及器械进行处理。受控环境中的气源、材料、设备和人员均不得破坏环境的无菌状态。 注：无菌加工包括过滤除菌，因为过滤除菌是后续无菌加工不可分割的一部分。 3.5 无菌加工区(APA) aseptic processing area 由若干个区域组成的，用于无菌加工(3.4)的厂房设施。 3.6 生物负载 bioburden 产品和／或包装及内部存活微生物的总数。 [ISO／TS 1139：2006，定义2.2] 注：对于无菌加工的目的，所关注的生物负载除产品的表面及内部的微生物数量外，还包括影响产品生物负载的所有因素，如：原料、中间体、部件和设备等。 3.7 生物去污 bio-decontamination 去除微生物污染或者使其减少到可接受水平。 [ISO 13408-6：2005，定义3.1] 3.8 清洁 cleaning 除去物品上的污染，使之达到预定用途或为进一步加工所需的程度。 [ISO／TS 1139：2006，定义2.7] 3.9 复合型产品 combination product 通过物理、化学或其他方式将药物-器械或生物制品-器械或药物-生物制品或者药物-器械-生物制品组合或混合而生产出来的完整产品。 3.10 纠正 correction 为消除已发现的不合格所采取的措施。 注：纠正可连同纠正措施一起实施， [ISO 9000 ：2005，定义3.6.6] 3.11 纠正措施 corrective action 为消除已发现的不合格或其他不期望情况的原因所采取的措施。 [ISO 9000：2005，定义3.6.5] 注1：一个不合格可以有若干个原因。 注2：采取纠正措施是为了防止再发生；而采取预防措施(3.29)是为了防止发生。 注3：纠正和纠正措施是有区别的。 注4：变更控制可能导致相关纠正措施的采用。 3.12 关键加工区域 critical processing zone 无菌生产区域内，产品和关键表面暴露在环境中的位置。 3.13 关键表面 critical surface 与产品或其容器、盖子接触的表面或对其产生直接影响的表面。 3.14 去热原 depyrogenatation 经过确认的用于去除或者灭活内毒素的过程。 3.15 设计鉴定 design qualification 确认为设施、设备或者系统所拟定的各项技术规范适合预期用途的验证过程。 [ISO／TS 1139：2006，定义2.12] 3.16 直接支持区 direct support zone 与关键生产区直接相连的保护区域。 3.17 消毒剂 disinfectant 能够减少可存活微生物数量的化学药剂。 3.18 消毒 disinfection 去除、破坏或者灭活物体或者表面上的微生物的过程。 [ISO 14644-5：2004，定义3.1.4] 3.19 内毒素 endotoxin 革兰阴性菌的细胞璧中具有热稳定性，并且能引发动物和人类各种炎症反应的脂多糖成分。 3.20 环境分离自然菌 environmental isolates 存在于加工、制造环境中的微生物和／或从中分离出来的微生物。 3.21 更衣程序 gowning procedure 在进入无菌加工区(APA)(3.5)时，为减少污染风险而规定的防护服穿着步骤。 3.22 医疗保健产品 health care product 医疗器械(包括体外诊断器械)或医药产品(包括生物制剂)。 [ISO／TS 11139：2006，定义2.20] 3.23 高效空气微粒过滤器(HEPA过滤器) high efficiency particulate air filter，HEPA filter 微粒截获效率至少达99.97％(即0.3μm的微粒的最高穿透率为0.03％)的截留过滤器。 3.24 间接支持区 indirect support zone 位于无菌加工区内，对直接支持区起保护作用的区域。 注：间接支持区所需的洁净度级别取决于在该区城进行的无菌生产活动。 3.25 安装鉴定 installation qualification；IQ 验证设备规格正确，安装符合技术规范，并将验证形成记录的过程。 [ISO／TS 11139：2006，定义2.22] 3.26 隔离器 isolator 通过内、外部物理隔离，从而能够防止污染物进入的密闭体。隔离器能够承受反复的内部生物去污。 注：隔离器可小至一个盒子，大至一个房间。 3.27 运行鉴定 operational qualification；OQ 验证当按照操作规程使用时，设备可在预定的范围内运行，并将验证形成记录的过程。 [ISO／TS 11139：2006，定义2.27] 3.28 性能鉴定 performance qualification；PQ 验证当设备安装、运行符合操作规程的情况下，设备性能持续符合预定标准，生产出的产品能满足其技术规范要求，并将验证形成记录的过程。 [ISO／TS 1139：2006，定义2.30] 3.29 预防措施 preventive action 为消除潜在不合格或其他潜在不期望情况的原因所采取的措施。 [ISO 9000：2005，定义3.6.4] 注1：一个潜在不合格可以有若干个原因。 注2：采取预防措施是为了防止发生；而采取纠正措施(3.11)是为了防止再发生。 3.30 鉴定 qualification 医疗保健产品制造商，在设备和／或工艺批准用于正式生产之前，为保证设备和／或工艺的可靠性和性能而进行的形成记录的验证过程。 注：设备和／或工艺的鉴定通常包括安装鉴定(3.25)、运行鉴定(3.27)和性能鉴定(3.28)。 3.31 风险控制 risk control 将估计的风险和给定的风险准则进行比较，以决定风险可接受性的过程。 [ISO 14971：2007，定义2.19] 3.32 隔离装置 separative device 利用结构和动态方式保证一定容积空间的内外之间达到一定隔离保证水平的设备。 注：用于特定行业的隔离装置有：洁净空气罩、污染物包裹体、手套箱、隔离器和微环境等。 [ISO 14644-7：2004，定义3.17] 3.33 班次 shift 由指定的一组工人进行规定时间的工作或完成规定产量的生产。 注：一个班次通常不超过12h。 3.34 无菌 sterile 没有可存活的微生物。 [ISO／TS 11139：2006，定义2.43] 注：实际上，这种关于微生物不存在的绝对说法还没能得到证实。参见灭菌(3.35)。 3.35 灭菌 sterilization 经过确认的用于获得不含可存活微生物产品的过程。 [ISO／TS 11139 ：2006，定义2.47] 3.36 最终灭菌 terminal sterilization 在无菌屏障系统内对产品进行灭菌的过程。 [ISO／TS 11139：2006，定义2.52] 3.37 超低穿透率的空气过滤器(ULPA过滤器) ultra low penetration air filter 0.3μm的微粒最低截留率达99.999％的过滤器。 3.38 单向气流 unidirectional airflow 具有一个限定方向的气流。 3.39 单元操作 unit operation 在生产过程中所定义的一个化学或者物理步骤。 注：参见“附录A”的流程图举例。 3.40 确认 validation 为设定某可持续生产出符合预定技术规格的产品的工艺，获得、记录和解释结果的文件化程序。 [ISO／TS 11139：2006，定义2.55] 3.41 最坏情况 worst case 在常规生产期间将可接受的对产品完整性和安全性具有最大挑战的一系列条件。 4 质量管理体系要素 4.1 概述 4.1.1 应执行适合于操作运行特性的质量管理体系，确保影响无菌处理的所有活动得到控制。除非采用国家、地区或者国际的生产质量管理规范(例如：世界卫生组织GMPs)，否则，质量管理体系应符合ISO 9001和／或ISO 13485的要求。 注：ISO 9004标准和ISO／TR 14969标准给出了选择合适模型的指引。 4.1.2 应制定并实施无菌加工中的开发、确认、常规监测和控制的各个阶段的文件化程序。 4.1.3 本部分所要求的文件应由指定的人员进行审查和批准。 4.1.4 为了提供符合本部分要求的证据，应保存开发、确认、常规控制和监测的记录。 4.2 职责分配 4.2.1 实施、执行和监控标准本部分标准中所描述的程序的职责和权限应依照标准ISO 13485分配给主管人员的指定职责。 4.2.2 管理层应负责确保有足够数量的有资格的工作人员执行所要求的工作，而且管理层负责监督他们的执行情况。为了评估任何需要改进的方面，管理层应定期审查质量管理体系的执行情况。 4.2.3 如果是由具有独立质量管理体系的组织来保证本部分要求，那么，应规定每一方的职责和权限。 4.3 校准 4.3.1 应规定所有测量仪器校准或者测量系统校准的形成文件的程序。 4.3.2 所有测量仪器的精度和公差应适合待测量的程序。 5 无菌加工定义 5.1 概述 5.1.1 无菌加工是由多个单元操作组成的活动，各单元操作应有效组合方可维持无菌状态。 定义无菌加工的目的是为了全面理解不同要素的整合。典型的要素参见“附录B”。 5.1.2 应使用文件证明使用无菌加工的合理性。 注：最终容器中的最终灭菌是优先选择。