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Manufacture of Sterile Products 附件1:无菌产品生产 Document map文档目录 | | | | Includes additional areas (other than sterile products) where the general principles of the annex can be applied. （除了无菌产品以外）包括适用该附件一领域的通 | | | General principles as applied to the manufacture of sterile products. 适用于无菌产品生产的一般原则。 | | Pharmaceutical Quality System (PQS) 药品质量体系（PQS） | Highlights the specific requirements of the PQS when applied to sterile products. 强调了无菌药品中PQS的特定要求。 | | | General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of Barrier Technology. 关于设施设计的具体需要和一般指导原则，以及设施确认和屏障技术 的应以指南。 | | | General guidance on the design and operation of equipment. 设备设计和运行的一般指南。 | | | Guidance with regards to the special requirements of utilities such as water, gas and vacuum. 关于公用系统，如水、空气和真空等设施的特殊要求指南。 | | | Guidance on the requirements for specific training, knowledge and skills. Also gives guidance to the qualification of personnel. 关于具体培训、知识和技能要求的指导。还对人员的资格给予指导。 | | Production and specific technologies 生产和特定技术 | Discusses the approaches to be taken with regards to aseptic and terminal sterilization processes. Discusses approaches to sterilization of products, equipment and packaging components. Also discusses different technologies such as lyophilization and Form Fill Seal where specific requirements apply. 讨论了关于无菌和终端灭菌过程应采取的方法。讨论了产品、设备和 包装部件的灭菌方法。还讨论了不同的技术，如BFS设备的具体要求。 | | Viable and non viable environmental and process monitoring 适宜的环境和不适宜的 环境以及过程检测 | This section differs from guidance given in section 4 in that the guidance here applies to ongoing routine monitoring with regards to the design of systems and setting of action limits alert levels and reviewing trend data. 本节与第4节中给出的指导意见不同，因为此处的指导意见适用 于与系统设计和行动限制警报级别设置以及趋势数据审查有关的 持续例行监控。 The section also gives guidance on the requirements of Aseptic Process Simulation (APS). 本节还给出了无菌工艺模拟（APS）要求的指导。 | | Quality control (QC) 质量控制（QC） | Gives guidance on some of the specific Quality Control requirements relating to sterile products. 给出与无菌产品相关的一些具体质量控制要求的指导。 | | 11 | Glossary 术语 | Explanation of specific terminology. 特定术语的解释。 |
1. Scope 范围 1.1. The manufacture of sterile products covers a wide range of sterile product types (active substance,sterile excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units),processes (from highly automated systems to manual processes) and technologies (e.g.biotechnology, classical small molecule manufacturing and closed systems). This Annex provides general guidance that should be used for the manufacture of all sterile products using the principles of Quality Risk Management (QRM), to ensure that microbial,particulateand pyrogen contaminationispreventedin thefinal product. 无菌产品生产涵盖了广泛的无菌产品类型。（活性物质，无菌赋形剂，内包装材料和成品（剂型）、 包装尺寸（从单个单位到多个单位）、流程（从高度自动化系统到手动操作）和技术（例如:生物技 术、小分子制造和封闭系统）。本附件提供了使用质量风险管理原则（QRM）生产所有无菌产品时 应使用的一般指南。以确保能够防止最终产品中的微生物、微粒和热原的污染。 1.2. QRM applies to this document in its entirety andwill not be referredto in specific paragraphs.Wherespecific limits or frequencies are written, these should be considered as a minimum requirement. They are stated due to regulatory historical experience of issues that have previously been identified and have impacted the safety ofpatients. QRM适用于本文档的全部内容，不会在特定段落中提及。如果规定了具体的限值或频率，则应将其 视为最低要求。它们是由于以前发现的问题的监管历史经验而提出的，这些问题影响了患者的安全。 1.3. The intent of the Annex is to provide guidance for the manufacture of sterile products. However,some of theprinciples and guidance, such as contamination control strategy, design of premises,cleanroom classification,qualification, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biologicalintermediates but where the control and reduction of microbial, particulate and pyrogen contamination isconsidered important. Where a manufacturer elects to apply guidance herein to non sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated. 附件的目的是为无菌产品的生产提供指导。然而，一些原则和指导，如污染控制策略、厂房设计、洁 净室分类、环境监测和人员着装，也可用于支持其他非无菌产品的生产，例如如某些液体制剂、乳膏 软膏和低生物负荷的生物中间体，但在控制和减少微生物，微粒和热原污染方面被认为很重要的产品。 如果制造商选择将本指南应用于非无菌产品，制造商应明确记录应用了哪些原则，并承认应遵守这些原则。 2. Principle原则 2.1. The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate andpyrogen contamination. The followingkey areas should be considered: 无菌产品的制造须符合特殊要求，以最大限度地减少微生物、微粒和热原污染。应考虑以下关键领域: 2.1.1. Facility, equipment and process design should be optimized, qualified and validated according to the relevant sections of the Good Manufacturing Practices ( GMP) guide.The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS),isolators, robotic systems, rapidmicrobial testing and monitoring systems) should be considered to increasethe protection of theproduct from potential extraneous sources of particulate and microbial contamination such as personnel, materials and thesurrounding environment, andassist in therapiddetectionof potential contaminants inthe environment andproduct. 应优化设施、设备和工艺设计，根据《药品生产质量管理规范》（GMP）的相关章节进行有 效的确认和验证。应考虑增加对产品的保护（例如限制性屏障技术（RABS)、隔离器、机器 人系统、快速微生物测试和监测系统）使其免受人员、物料和周围环境等可能的外来颗粒物 和微生物污染，并协助快速检测环境和产品中的潜在污染物。 2.1.2. Personnel should have adequate qualifications and experience, training and attitude with aspecificfocus on the principles involved in theprotectionof sterile product during themanufacturing,packaging and distribution processes.
人员应具备足够的资格和经验、培训和态度，人员需要特别关注在生产、包装和分销过程中 保护无菌产品所涉及的原则。 2.1.3. Processes and monitoring systems for sterile product manufacture should be designed,commissioned,qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge. 无菌产品生产的工艺和监控系统应由具有适当工艺、工程和微生物知识的人员设计、使用、 确认和监控。 2.2. Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRMprinciples to provide a proactive means of identifying, scientifically evaluating and controlling potential riskstoquality. Where alternative approaches are used, these should be supported by appropriate rationales andrisk assessment and should meet the intent of this Annex. QRM priorities should include good design of the facility, equipment and process in the first instance,then implementation of well designed procedures, with monitoring systems as the final element that demonstratethat the design and procedures havebeen correctlyimplemented and continue to perform in line with expectations. Exclusively monitoring or testing does not giveassurance of sterility. 工艺、设备、设施及生产活动应根据QRM原则进行管理，科学评估和控制潜在的质量风险。如使用 替代办法，则应以适当的理由和风险评估来作为支持，并应符合本附件的意图。质量风险管理的优先 事项应首先包括设施、设备和工艺的良好设计，然后执行设计良好的工艺，并以监测系统作为最终要 素，证明设计工艺能够正确实施并可以继续执行且符合预期。专门的监测或检测并不能保证产品的无 菌。 2.3. Quality Assuranceisparticularly important,and manufacture ofsterile products must strictlyfollow carefully established and validated methods of manufacture and control. A Contamination Control Strategy (CCS)should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed tomanage risks associated with contamination. The CCS should be actively updated and should drive continuousimprovement of themanufacturingand control methods. 质量保证尤为重要，无菌产品的生产必须严格遵循精心建立并经过验证的生产和控制方法。应在整个 工厂内实施污染控制策略（CCS），以定义所有关键控制点，并评估用于管理与污染相关的风险的所 有控制措施（设计，程序，技术和组织上）的有效性和监控措施。 应积极更新CCS，并应不断改进制造和控制方法。 2.4. Contamination control and steps taken to minimize the risk of contamination from microbial and particulate sources are a series of successively linked events and measures. These are typically assessed,controlled and monitoredindividually buttheir collectiveeffectiveness should be considered altogether. 一系列污染控制和采取措施使微生物和颗粒物污染的风险降至最低，是一系列相继发生的事件和措施。 这些通常是单独评估，控制和监视的，但应综合考虑它们的集体有效性。 2.5. The development of the CCS requires thorough technical and process knowledge. Potential sources ofcontaminationare attributable tomicrobial and cellular debris (e.g.pyrogen, endotoxins) as well as particulate matter (e.g. glass and other visible and sub visible particulates).Elements to be considered within a documented CCS should include (but are not limited to): CCS的开发需要透彻的技术和工艺知识。潜在的污染源可归因于微生物和细胞碎片（例如，热原，内 毒素）以及颗粒物（例如，玻璃碎片以及其他可见的和次要的颗粒）。 CCS文件中应考虑的要素应包括（但不限于）： 2.5.1. Design of boththe plant and processes. 工厂和工艺的设计。 2.5.2. Premises andequipment. 房间和设备。 2.5.3. Personnel. 人员。
2.5.4. Utilities. 公用设施。 2.5.5. Raw material controls – including inprocess controls. 原材料控制 包括过程控制。 2.5.6. Product containers and closures. 产品容器和密封。 2.5.7. Vendor approval – such as keycomponent suppliers, sterilization of components and single use systems (SUS), andservices. 供应商批准–例如关键组件的供应商，组件和一次性系统（SUS）的灭菌服务的供应商。 2.5.8. For outsourced services, such as sterilization, sufficient evidence should be provided to the contract giver toensure the process is operatingcorrectly. 对于灭菌等外包服务，应向要求合同提供方提供充分的证据，以确保流程被正确运行。 2.5.9. Process risk assessment. 工艺风险评估。 2.5.10. Process validation. 工艺验证。 2.5.11. Preventative maintenance – maintaining equipment, utilities and premises (planned and unplannedmaintenance) to a standardthat will not add significant riskof contamination. 预防性维护保养 设备及设施的维护保养（计划性及非计划性维护保养）应有一个标准，使之 不会带来重大的污染风险。 2.5.12. Cleaning anddisinfection. 清洁消毒。 2.5.13. Monitoring systems including an assessment of the feasibility of the introduction of scientifically sound,modern methods that optimize thedetectionof environmental contamination. 监测系统 包括评估引入科学合理的现代方法以优化环境污染检测的可行性。 2.5.14. Prevention – trending, investigation, corrective and preventive actions (CAPA), root cause determination andthe need for more comprehensiveinvestigational tools. 预防 趋势分析、调查、纠正和预防措施（CAPA）、根本原因确定以及对更全面的调查工具 的需求。 2.5.15. Continuous improvement basedon information derivedfrom theabove. 基于上述信息的持续改进。 2.6. The CCS should consider all aspects of contamination control and its life cycle with ongoing and periodicreview resultingin updates within thequalitysystem as appropriate. 2.7. CCS应考虑污染控制及其生命周期的所有方面，进行持续和定期审查，酌情在质量体系内进行更新。 2.8. The manufacturer should take all steps and precautions necessary to assure the sterility of the products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test. 2.9. 制造商应采取所有必要的步骤和预防措施，以确保在其设施内生产的产品的无菌性。无菌或其他质量 方面的唯一依据不应放在任何终端过程或成品测试上。
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发表于 2020-6-29 09:38:59
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