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2 Principle 2.1 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate and endotoxin/pyrogen contamination. The following key areas should be considered: i. Facility, equipment and process should be appropriately designed, qualified and/or validated and where applicable, subjected to ongoing verification according to the relevant sections of the Good Manufacturing Practices (GMP) guidelines. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and the product. 解读：强调了影响无菌产品质量的诸多要素：设施、设备、工艺和新技术。这里面在新技术方面提到了机器人系统和微生物的快检方法，代表对于机器人系统和微生物快检方法，欧洲监管部门是推荐使用的，尤其是提到了对产品的保护以及对污染的快速发现两个方面。 ii. Personnel should have adequate qualifications and experience, training and behaviour with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes. 解读：人员要求的要素：人员的确认、人员的经验、人员的培训以及人员的行为。这是无菌产品生产过程中对于人员方面的基本原则。 iii. Processes and monitoring systems for sterile product manufacture should be designed, commissioned, qualified, monitored and regularly reviewed by personnel with appropriate process, engineering and microbiological knowledge. 解读：工艺和监测系统，需要进行设计、调试、确认、监测和常规的审核。进行这些活动的人员应有适宜的知识。话虽少，但蕴含了大量的信息。 iv. Raw materials and packaging materials should be adequately controlled and tested to ensure that level of bioburden and endotoxin/pyrogen are suitable for use. 解读：物料的控制应遵循的原则，就是控制和检测，确保微生物和热原/内毒素风险可接受。这里为什么没有按照三要素来说，只提了两个要素。为什么没有提到微粒控制的问题？其实内包材和一些耗材中，微粒污染风险也是比较高的，这些微粒都是non-viable，可能是物料生产过程中产生的，应有去除、控制的措施。 2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationale, risk assessment and mitigation, and should meet the intent of this Annex. 解读：表明了QRM的崇高地位，前瞻性的识别、科学的评估及控制。如果不适用QRM，则需要替代的方法和QRM有同等的效果。这也是不可能完成任务，乖乖的使用QRM就是了。 In the first instance, QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems as the element that demonstrates that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility. 解读：最后这句话写得非常好，这才是QbD的原则。首先，必须要有well-designed procedures去确保设施、设备和工艺被良好的设计，最终由监测系统确保这些设施、设备和工艺被按照设计正确的运行和使用。QbT包括过程监测，都无法确保无菌性，必须有合适的设计。 2.3 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 to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods. Its effectiveness should form part of the periodic management review. Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood. 解读：CCS有三个作用：确定关键控制点、评估控制的有效性、监测管理风险的关键数据。CCS的有效性是管理评审的一个部分。对于MAH委托生产和自行生产两种模式，都应进行CCS。其中CCS应与厂房、设施、工艺关联，也就是每个site应有一个CCS，其中不同的工艺和产品，在不同章节分别说明。同时，已存在的控制措施如果是有效的，并不需要被CCS替换掉，在CCS中引用就可以。 2.4 Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together. 解读：这也是CCS存在的意义，就是说，控制策略可以是分散实施的，但是总要有文件和评估过程确保他们之间的关联被认识到。同时，也能确保系统性得评价各个分散的控制策略是否可以在一起起效。 2.5 The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxin) as well as particulate (e.g. glass and other visible and sub-visible particles). Elements to be considered within a CCS should include (but are not limited to): i. Design of both the plant and processes including the associated documentation. ii. Premises and equipment. iii. Personnel. iv. Utilities. v. Raw material controls – including in-process controls. vi. Product containers and closures. vii. Vendor approval – such as key component suppliers, sterilisation of components and single use systems (SUS), and critical service providers. viii. Management of outsourced activities and availability/transfer of critical information between parties, e.g. contract sterilisation services. ix. Process risk management. x. Process validation. xi. Validation of sterilisation processes. xii. Preventative maintenance – maintaining equipment, utilities and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination. xiii. Cleaning and disinfection. xiv. Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, alternative methods that optimize the detection of environmental contamination. xv. Prevention mechanisms – trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools. xvi. Continuous improvement based on information derived from the above. 解读：之前对于CCS，没有什么成型的样式或模板给到工业界。其实根据这一条款的说明，CCS基本上就是把诸多控制措施汇总，形成一个专门的文件，定期进行回顾和修订，同时需要给出结论。类似于关于污染控制的质量回顾，定期完成汇总、分析。 2.6 The CCS should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation. 解读：QMS应该规定CCS的管理要求，这样看来，对于CCS，应有专门的管理文件来进行规定，包括内容、审核周期等等。出现大的变更时，也需要在变更前后，考虑其对CCS的影响。 2.7 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. 解读：对无菌性或其他质量方面的唯一依赖不应放在任何终端过程或成品测试。 |
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