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3 Pharmaceutical Quality System (PQS) 3.1 The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMP guidelines (Part I - Basic Requirements for Medicinal Products), the PQS for sterile product manufacture should also ensure that: i. An effective risk management system is integrated into all areas of the product life cycle with the aim to minimize microbial contamination and to ensure the quality of sterile products manufactured. ii. The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the equipment, engineering and manufacturing methods employed that have an impact on product quality. iii. Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood so that suitable corrective and preventive actions (CAPA) are implemented. iv. Risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk. Senior management should effectively oversee the state of control throughout the facility and product lifecycle. Risk management outcome should be reviewed regularly as part of the on-going quality management, during change, in the event of a significant emerging problem, and during the periodic product quality review. vi. Processes associated with the finishing, storage and transport of sterile products should not compromise the sterile product. Aspects that should be considered include: container integrity, risks of contamination and avoidance of degradation by ensuring that products are stored and maintained in accordance with the registered storage conditions. vii. Persons responsible for the certification/release of sterile products have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile products and the associated critical quality attributes. This is in order to allow such persons to determine if the sterile products have been manufactured in accordance with the registered specifications and approved process and are of the required quality. 3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation should be clearly justified and recorded. 解读：这个章节的要求，其实是很基本的。3.1中有意义的几个点：风险管理系统的要求，可见对于风险管理是否能够有效实施，越来越被关注；关键人员对于工艺、产品、设施、设备的经验和知识，是做好无菌产品的关键；RCA和CAPA必须是强大的；CCS应该考虑风险评估的工具，并且风险评估的文件化和技术原理应被关注；包装、储运不应带来额外的风险；对于放行人对于无菌工艺，CQA都应当有足够的知识和经验。3.2感觉上更像是对于很多检查缺陷的提前预警，就是对于不符合事件的调查应覆盖对于本产品的工艺和产品质量的潜在影响，以及其它可能有潜在影响的产品和批次。相关的批次和产品，均应当被证明和记录。也就是说，对于无菌产品的不符合事件的调查和评估，应做较为充分的扩大的延伸，因为通常无菌产品的不符合事件，具有一些通行的RC和“雨露均沾”的风险。 4 Premises 4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through change rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms and change rooms should be maintained to an appropriate cleanliness standard and supplied with air that has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and should effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches. 解读：洁净室、人物流的airlock（其中人流的airlock可以是更衣室，是否不用单独设置更衣室前后的bufferroom？）、洁净要求、过滤器（没说一定要用HEPA，只提到过滤器的效率是合适的）、有效的评估洁净室、airlocks和传递舱的环境条件（仅有控制和监测是不够的，控制和监测的目的是为了评估）。对洁净室的控制、监测和评估，可能需要对环境的趋势进行一定的管理和监督。对于传递舱，算是比较明确的提出了管理要求，需要考虑验证怎么做。这东西其实是一个设备，不应该按照洁净室的测试逻辑来进行。关于传递舱的验证，我有惨痛的教训，可以作为一个主题来自准备一个培训。 4.2 The various operations of component preparation, product preparation and filling should be carried out with appropriate technical and operational separation measures within the cleanroom or facility to prevent mix up and contamination. 解读：说到了控制混淆和污染的基本原则、方法，就是技术性或操作性的隔离（也可理解为硬件和软件）。 4.3 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified. 解读：很重要的观点，就是说RABS和Isolator是标准配置，如果没有使用的话，就属于替代方法了。使用的目的是确保需要的环境并减少人员在关键区域的直接干预所带来的微生物污染风险。这里有一个问题出来，对于RABS和Isolator的准确定义，以前是没有的。这一版Annex，最大的进步在于给出了定义。 Restricted Access Barrier System (RABS) – System that provides an enclosed, but not fully sealed, environment meeting defined air quality conditions (for aseptic processing grade A), and using a rigid-wall enclosure and integrated gloves to separate its interior from the surrounding cleanroom environment. The inner surfaces of the RABS are disinfected and decontaminated with a sporicidal agent. Operators use gloves, half suits, RTPs and other integrated transfer ports to perform manipulations or convey materials to the interior of the RABS. Depending on the design, doors are rarely opened, and only under strictly pre-defined conditions. Isolator – An enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (e.g. surrounding cleanroom air and personnel). There are two major types of isolators: i. Closed isolator systems exclude external contamination of the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations. ii. Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g. using continuous overpressure) to exclude the entry of external contaminant into the isolator. 解读：1. RABS不是sealed，但是closed isolator在使用过程中是sealed，对于open isolator应该在把opening关上后，也是sealed；2. 内部消毒的方式不一样，同时，isolator强调了自我净化的能力；3. open isolator强调了高压力对出入口的保护；4. 动态下，RABS很少开门，Isolator就没提开门的事情；5. RABS内部可以是A级，Isolator内部必须是A级。. |
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