Introduction 简介
The pharmaceutical industry is encountering an increase in regulatory scrutiny related to sterile manufacturing, this is in part due to the update to Eudralex and PIC/S issuance of the updated Annex 1 for the manufacture of sterile medicinal products partly due to events such as the Pseudomonas aeruginosa contamination of eye drops of 2023. Inspection observations highlight gaps in alignment with the current state of manufacturing science, particularly in aseptic processing and contamination prevention. These gaps often stem from legacy equipment and facility designs, inadequate or misapplied risk assessments, and incomplete execution or documentation of process validation and monitoring that does not align with expectations described in Eudralex and PIC/S GMP Annex 1 (2022) or the Code of Federal regulations, such as 21 CFR 210 and 211 as interpreted in the USFDA Guidance for Industry - sterile drug products produced by aseptic processing (September 2004). Despite the identified challenges, industry remains committed to supplying patients with high-quality medicines that meet evolving standards and best practices, even as expectations evolve with the progression of technology and scientific understanding.
制药行业正面临着与无菌生产相关的日益严格的监管审查。这部分是由于《欧盟药品管理法》（Eudralex）的更新以及 PIC/S 发布的无菌药品生产新版附录 1，部分原因则是 2023 年发生的铜绿假单胞菌滴眼液污染事件。检查发现，当前的生产活动与制造科学的现状存在差距，特别是在无菌工艺和污染预防方面。这些差距通常源于老旧的设备和设施设计、不充分或误用的风险评估，以及不符合《欧盟药品管理法》和 PIC/S GMP 附录 1（2022）或《联邦法规》（如美国 FDA 工业指南《无菌工艺生产的无菌药品》（2004 年 9 月）中解释的 21 CFR 210 和 211）所描述期望的工艺验证与监测的执行或记录。尽管面临这些挑战，随着技术进步和科学认知的提升，行业仍致力于为患者提供符合不断发展的标准和最佳实践的高质量药品。
To safeguard patient supply while strengthening compliance, a practical, risk-based path is needed — one that recognizes changing expectations and provides actionable principles to mitigate risk during transitions to new equipment, facilities, and controls. This white paper responds to that need by consolidating contemporary expectations across contamination control strategy, aseptic process validation, equipment and facility design, and personnel practices. These propose a harmonized approach across industry which will ensure consistency during the development of aseptic processes and regulatory oversight. It explains how risk management supports sterility assurance and supply continuity, emphasizing that monitoring and aseptic process simulations should guide evaluations of control measures and inform future strategies, rather than justify inadequate designs or practices.
为了在加强合规性的同时保障患者供应，需要一条切实可行的、基于风险的路径 —— 一条能够识别不断变化的期望，并在向新设备、新设施和新控制手段过渡期间提供可操作的风险缓解原则的路径。本白皮书通过整合污染控制策略、无菌工艺验证、设备与设施设计以及人员实践方面的当代期望，来回应这一需求。这些内容提出了一种全行业的协调方法，将确保无菌工艺开发和监管监督的一致性。它解释了风险管理如何支持无菌保证和供应连续性，并强调监测和无菌工艺模拟应指导控制措施的评估并为未来策略提供信息，而不是为设计或实践的不足找借口。
The white paper is intended to bridge near-term operational realities with longer-term investments in robust sterile and contamination-controlled operations. It outlines how manufacturers can prioritize control and monitoring of critical activities while adopting facility and equipment strategies aligned with current expectations. It also reinforces the essential role of qualified personnel, proper gowning, and disciplined behaviors in maintaining controlled environments and preventing contamination.
本白皮书旨在将短期运营现实与对稳健的无菌和污染控制运营的长期投资联系起来。它概述了制造商如何在优先控制和监测关键活动的同时，采用符合当前期望的设施和设备策略。它还强调了合格人员、正确更衣和严谨行为在维持受控环境和防止污染方面的重要作用。
Scope 范围
This whitepaper provides principles and practical expectations for manufacturing operations within the scope of GMP Annex 1, focusing on four areas: environmental monitoring and control; aseptic process validation; equipment and facility design; and personnel practices. Each subject area was drafted as an individual chapter to the whitepaper by multiccompany and multidisciplinary teams with oversight from the GPMLF committee to ensure consistency of messaging. Informal feedback was also obtained from regulatory agencies to ensure that the principles expounded are in line with regulatory expectations and do not have significant gaps or contradictions. This does not imply regulatory approval or endorsement.
本白皮书为 GMP 附录 1 范围内的生产运营提供原则和实际期望，重点关注四个领域：环境监测与控制；无菌工艺验证；设备与设施设计；以及人员实践。每个主题领域均由多公司、多学科团队起草为本白皮书的独立章节，并由 GPMLF 委员会进行监督，以确保信息的一致性。还从监管机构获得了非正式反馈，以确保阐述的原则符合监管期望，且没有重大差距或矛盾。这并不意味着监管部门的批准或背书。
Recognizing the need for alignment with current regulatory interpretations promotes risk-mitigating approaches that enable continuity of supply and approval of innovative treatments while the design, execution, and qualification of equipment and facility upgrades proceed. This whitepaper does not replace applicable laws or regulations; rather, it offers industry-oriented guidance to support compliance and sterility assurance during periods of change. It should be noted that the paper is written with the current state of available technology in mind and is not intended to prevent innovative practices being adopted. Companies should consider new and emerging technologies such as gloveless isolators, rapid microbiology methods and automated cleaning and disinfection systems, and the use of Artificial intelligence as next steps for the industry to move forward and further enhance current Contamination Control Strategies.
认识到需要与当前监管解释保持一致，这推动了风险缓解方法的采用，这些方法能够在设备和设施升级的设计、执行和确认过程中，实现供应的连续性和创新疗法的批准。本白皮书不取代适用的法律或法规；相反，它提供了面向行业的指导，以支持变革时期的合规性和无菌保证。应当指出，本文是基于现有技术水平编写的，无意阻止采用创新实践。公司应考虑新出现的技术，如无手套隔离器、快速微生物方法和自动化清洁消毒系统，以及人工智能的使用，作为行业向前发展并进一步增强当前污染控制策略的下一步措施。
Group 1: Strategic Approach for Maximizing Use of CCS in GMP Facilities
第一组：在 GMP 设施中最大化利用 CCS 的战略方法
Aim 目标：
The 2022 revision of EU / PIC/S GMP Annex 1 introduces the concept of a Contamination Control Strategy to define critical control points and assess the effectiveness of controls and monitoring measures used to manage contamination risks.
欧盟 / PIC/S GMP 附录 1 的 2022 年修订版引入了污染控制策略（CCS）的概念，旨在定义关键控制点，并评估用于管理污染风险的控制和监测措施的有效性。
This document provides strategic guidance to enable effective use of the Contamination Control Strategy (CCS) in quality governance for GMP-compliant manufacturing, with the overall aim of ensuring high quality product and protecting the patient. Strategies outlined are also applicable to facilitate consistent and effective communication of the organization’s holistic approach to contamination prevention (e.g. during internal communication and regulatory inspections) and to illustrate quality, compliance and operational benefits associated with capital expenditure and other strategic business decisions relating to contamination control in a facility.
本文件提供战略指导，以实现在 GMP 合规生产的质量治理中有效使用污染控制策略（CCS），总体目标是确保高质量产品并保护患者。概述的策略也适用于促进组织整体污染预防方法的一致和有效沟通（例如在内部沟通和监管检查期间），并说明与设施污染控制相关的资本支出和其他战略业务决策带来的质量、合规性和运营效益。
The scope of this document includes sterile, low bioburden and other areas of GMP activity (e.g. sterility testing) where contamination control is a requirement. When developing a CCS for products not intended to be sterile, the manufacturing site should understand those parts of Annex 1 and CCS that are applicable to their product and process. The CCS owner must be able to articulate the risk-based justification for excluding aspects of Annex 1 content that are not applicable.
本文件的范围包括无菌、低生物负荷和其他需要污染控制的 GMP 活动领域（例如无菌测试）。在为非无菌产品制定 CCS 时，生产现场应了解附录 1 和 CCS 中适用于其产品和工艺的部分。CCS 负责人必须能够阐明基于风险的理由，以排除附录 1 中不适用的内容。
Background背景：
Several publications are available that provide guidance on the technical content and structure of a contamination control strategy. Examples include:
有若干出版物提供了关于污染控制策略的技术内容和结构的指导。例子包括：
Parenteral Drug Association (PDA) 注射剂药物协会 (PDA) BioPhorum (CCS guidance for low bioburden drug substance) BioPhorum（低生物负荷原料药的 CCS 指南） European Compliance Academy ECA 欧洲合规学院 (ECA)
However, a technically comprehensive CCS will only achieve the regulatory expectation if implemented effectively and integrated into a manufacturer’s pharmaceutical quality system (PQS). This guidance aims to show how CCS can be (i) embedded in routine operations and (ii) inform quality and strategic decision-making by facilitating robust communication of how contamination hazards are identified, mitigated, and reviewed throughout the organization.
然而，只有当技术全面的 CCS 得到有效实施并整合到制造商的药品质量体系（PQS）中时，才能达到监管期望。本指南旨在展示 CCS 如何（i）嵌入日常运营中，以及（ii）通过促进关于如何在整个组织内识别、缓解和审查污染危害的强有力沟通，为质量和战略决策提供信息。
This guidance will outline how the CCS can be integrated to maximize impact in manufacturing operations, quality system oversight and strategic decision-making, using illustrative examples of how this can be achieved in practice.
本指南将概述如何整合 CCS，以最大化其在生产运营、质量体系监督和战略决策中的影响，并通过实际案例说明如何实现这一点。
Implementing a CCS in multi-site organizations:
在多站点组织中实施 CCS：
Implementing a CCS across a multi-site organization can enable efficiency and ensure consistency across an organization by working to global procedures and standards, while recognizing local specifics.
在多站点组织中实施 CCS 可以通过遵循全球程序和标准来提高效率并确保整个组织的一致性，同时兼顾本地特点。
A global CCS SOP and template is recommended to describe rationale, design and implementation of global systems that contribute to contamination control and/or monitoring. This provides a tool for education across the organization’s network to understand the rationales for facility design, equipment selection, process design, maintenance, environmental monitoring, training, qualification, and material sourcing, etc. and how these contribute to contamination control individually and collectively. It also serves as a standard against which compliance may be verified (e.g. during self-inspection or audit).
建议制定全球 CCS 标准操作规程（SOP）和模板，以描述有助于污染控制和 / 或监测的全球系统的基本原理、设计和实施。这为整个组织网络提供了一个教育工具，以了解设施设计、设备选择、工艺设计、维护、环境监测、培训、确认和材料采购等的基本原理，以及这些因素如何单独和共同促进污染控制。它还可作为验证合规性的标准（例如在自检或审计期间）。
Global approach can enable 60−70% of the CCS content be provided without duplication of effort at each site, while allowing local fine-tuning dependent on products, manufacturing processes, equipment, and facility layout specifics. The final document comprising a common summary that is augmented by site description/interpretation, forms the final document to integrate into the site’s pharmaceutical quality system. It is important not to force-fit a global description of contamination control measures into site CCS documents without the ability to explain local modifications. This risks compliance failures when global descriptions mis-align with local practice.
全球方法可以提供 60% 至 70% 的 CCS 内容，而无需在每个站点重复工作，同时允许根据产品、制造工艺、设备和设施布局的具体情况进行本地微调。最终文件包括一个通用摘要，并辅以站点描述 / 解释，形成整合到站点药品质量体系中的最终文件。重要的是，不要在无法解释本地修改的情况下，将全球污染控制措施的描述强行套用到站点 CCS 文件中。如果全球描述与本地实践不一致，这将面临合规失败的风险。
Integrating the CCS into the Pharmaceutical Quality System (PQS):
将 CCS 整合到药品质量体系（PQS）中：
CCS integration into the PQS ensures continued review of contamination risks and mitigations through routine QMS activities such as investigations, deviations, changes, and periodic review of data. (e.g., environmental, personnel, and utilities monitoring This ensures that changes in risk, improvements in process knowledge and revisions to control measures or monitoring strategies can be considered on an ongoing basis. The CCS is utilized daily, as a strategic tool to ensure a state of control.
将 CCS 整合到 PQS 中，可通过调查、偏差、变更和数据定期审查等常规 QMS 活动，确保持续审查污染风险和缓解措施。（例如环境、人员和公用设施监测）这确保了风险的变化、工艺知识的改进以及对控制措施或监测策略的修订可以持续得到考虑。CCS 作为一种战略工具，每天都在使用，以确保持续的受控状态。
The CCS may inform quality impact decisions during investigations (e.g. assessing opportunities to minimise introduction or proliferation of contamination in a facility, containment, and detection opportunities), or the PQS investigation may lead to actions to improve the CCS itself. Where relevant, the CCS changes may form part of GMP update training.
CCS 可以在调查期间为质量影响决策提供信息（例如评估最大限度减少设施内污染引入或扩散的机会、遏制和检测机会），或者 PQS 调查可能导致改进 CCS 本身的行动。如相关，CCS 的变更可能构成 GMP 更新培训的一部分。
In addition to this event-driven review, there should be a periodic review of risks, mitigations and monitoring activities described in the CCS as part of the routine Quality Risk Management review cycle or in association with a site master plan review or annual product quality reviews. This may form part of Management Review or other quality system oversight, and it should be visible to senior leadership.
除了这种事件驱动的审查外，还应作为常规质量风险管理审查周期的一部分，或结合场地主计划审查或年度产品质量审查，对 CCS 中描述的风险、缓解措施和监测活动进行定期审查。这可能构成管理评审或其他质量体系监督的一部分，并且应向高层领导展示。
Use of the CCS as a training tool:将 CCS 用作培训工具：
The CCS may serve as a training and educational tool across the organization. The interaction of contamination control and monitoring activities, including the assessment of effectiveness and residual risk described in the CCS, enables personnel to understand the impact of their work on critical quality attributes at other stages of manufacture or control. This understanding highlights their individual contribution to protecting the patient and positively impacts Quality Culture.
CCS 可以作为整个组织的培训和教育工具。污染控制和监测活动的相互作用，包括 CCS 中描述的有效性和残留风险评估，使人员能够理解他们的工作对制造或控制其他阶段关键质量属性的影响。这种理解突出了他们个人在保护患者方面的贡献，并对质量文化产生积极影响。
For example 例如：
Enabling personnel responsible for aseptic processing to understand the importance of procedural compliance in protecting the patient from product contamination due to: 终末无菌测试的统计学弱点，即受污染的批次可能通过无菌测试。 The limited capability to remove viable contamination introduced during processing, particularly at final steps of finished product manufacturing (e.g. fill-finish). 去除加工过程中引入的活污染的能力有限，特别是在成品制造的最后步骤（如灌装）。 The statistical weakness of end-stage sterility testing, where a contaminated batch may pass a sterility test. 使负责无菌工艺的人员理解程序合规性在保护患者免受产品污染方面的重要性，原因如下：
Enabling support functions, e.g. purchasing teams, to understand the impact of supplier selection decisions on material inputs or process controls. This includes appropriate balancing of cost while ensuring robust with supplier quality management, which can affect product or process contamination control and monitoring. 使支持职能部门（如采购团队）了解供应商选择决策对材料输入或工艺控制的影响。这包括在确保强有力的供应商质量管理的同时进行适当的成本平衡，这可能影响产品或工艺的污染控制和监测。
Use of CCS in Inspection and Audit 在检查和审计中使用 CCS：
The CCS enables communication of risks and mitigations to internal and external stakeholders as a single, holistic review of risks and control measures. The CCS process owner should be able to explain the general CCS approach and bringing in other SMEs as needed. Suitable summary materials (diagrams or other tools that provide an overview of relationship between control measures) may be useful for this purpose.
CCS 能够作为对风险和控制措施的单一、整体审查，向内部和外部利益相关者传达风险和缓解措施。CCS 流程负责人应能够解释 CCS 的总体方法，并根据需要引入其他主题专家（SME）。适当的摘要材料（提供控制措施之间关系概述的图表或其他工具）可能对此有用。
The CCS is recommended for review as early as possible in any external assessment audit or inspection. This enables the organization to clearly explain the identification of risk, together with cumulative impact of the control strategy in good facility and process design, minimizing potential for contamination ingress hazards from materials, environment and personnel, and monitoring environment and process for failure. Demonstration of the CCS as a strategic tool, utilized daily, within PQMS highlights a proactive culture to regulators.
建议在任何外部评估审计或检查中尽早审查 CCS。这使组织能够清楚地解释风险的识别，以及控制策略在良好设施和工艺设计中的累积影响，最大限度地减少来自材料、环境和人员的污染进入危害，并监测环境和工艺是否存在故障。向监管机构展示 CCS 作为 PQMS 内日常使用的战略工具，突显了积极主动的文化。
Using the CCS as a tool in strategic business decision making
将 CCS 用作战略业务决策工具：
The CCS typically does not include information relating to productivity, avoidance of waste or resource utilization. However, improved quality assurance leads to many long term cost benefits. Effective implementation of a harmonized CCS drives down Cost of Goods, reduces waste from duplicative drafting and maintenance of individual CCS documents and enables organization-wide planning for Continuous Improvement and capital expenditure.
CCS 通常不包括与生产率、避免浪费或资源利用相关的信息。然而，改进的质量保证带来了许多长期的成本效益。有效实施协调的 CCS 可以降低制造成本，减少因重复起草和维护单个 CCS 文件而产生的浪费，并支持全组织范围的持续改进和资本支出规划。
The CCS may be referenced when making strategic investment decisions by providing a clear explanation of facilities and equipment, process controls, contamination risk mitigation and monitoring approaches. These impact operational expenditure, cost of goods and productivity. CCS content may put future investment decisions into context by illustrating the cost or complexity of current controls vs the business, quality, supply, and compliance benefits that may be achieved through investment in facility, equipment, and technology. Alternatively, when investment is prioritized towards other areas of the business, the CCS can be an effective tool to outline any additional risk mitigation measures required to maintain regulatory compliance and product quality. In essence, a forward looking CCS provides context of the business risks that can be avoided by implementing more reliable facilities, processes and systems.
在做出战略投资决策时，可以参考 CCS，它提供了对设施和设备、工艺控制、污染风险缓解和监测方法的清晰解释。这些因素影响运营支出、制造成本和生产率。CCS 内容可以通过说明当前控制的成本或复杂性，与通过投资设施、设备和技术可能获得的业务、质量、供应和合规效益进行对比，从而为未来的投资决策提供背景。或者，当投资优先用于业务的其他领域时，CCS 可以作为一种有效工具，概述维持监管合规性和产品质量所需的任何额外风险缓解措施。本质上，前瞻性的 CCS 提供了通过实施更可靠的设施、工艺和系统可以避免的业务风险背景。
Using the CCS summary of contamination risks and mitigations, an organization can quantify resources attributed to a particular process design strategy, and potential savings following investment (e.g. replacing a legacy ‘open’ aseptic process by investing in isolator technology/closed system may provide opportunity to reduce clean area classification, personnel gowning and qualification, environmental monitoring, process and environmental monitoring, allow for greater utilization of manufacturing areas, and other risk mitigation measures). OPEX savings from this process improvement may be an important aspect of the business case, and aid in the organization’s financial planning.
利用 CCS 对污染风险和缓解措施的总结，组织可以量化归因于特定工艺设计策略的资源，以及投资后的潜在节约（例如，通过投资隔离器技术 / 封闭系统取代传统的 “开放式” 无菌工艺，可能提供减少洁净区分类、人员更衣和确认、环境监测、工艺和环境监测的机会，允许更大程度地利用制造区域，并采取其他风险缓解措施）。这种工艺改进带来的运营支出（OPEX）节省可能是商业案例的重要方面，并有助于组织的财务规划。
Group 2: Equipment and Facilities 第二组：设备与设施
Introduction 简介：
This section of the white paper discusses the challenges involved regarding compliance within sterile medicinal product facilities and ensuring that Industry, suppliers and the regulators have a common understanding of the requirements that underpin compliant facilities and equipment. The white paper discusses a number of key areas including: Restricted Access Barrier Systems (RABS) versus Isolators, Indirect contact part sterilization (RABS and Isolators), PUPSIT and closed systems.
白皮书的这一部分讨论了无菌药品设施合规性所涉及的挑战，并确保行业、供应商和监管机构对支撑合规设施和设备的要求有共同的理解。白皮书讨论了若干关键领域，包括：限制进入屏障系统（RABS）与隔离器、间接接触部件的灭菌（RABS 和隔离器）、PUPSIT（使用前灭菌后完整性测试）和封闭系统。
Although not directly covered by this paper, the team also encourages the adoption of suitable innovative technologies. These technologies include well designed robotics systems for aseptic filling (to further remove human interventions) and also the use of rapid and alternative monitoring systems to ensure that companies have rapid feedback on how their aseptic systems and controls are functioning, potentially enabling nearer to real time reactive measures to be taken.
虽然本文未直接涵盖，但团队也鼓励采用合适的创新技术。这些技术包括设计良好的无菌灌装机器人系统（以进一步减少人为干预），以及使用快速和替代监测系统，以确保公司能够快速反馈其无菌系统和控制的运行情况，从而有可能采取接近实时的应对措施。
RABS versus Isolators RABS 与隔离器：
It is widely accepted that aseptic filling facilities should include a separate barrier between personnel and the critical zones. Barrier technologies provide protection of pen exposed sterilized packaging components (e.g., syringes, vials, IV bags, stoppers) and the filling process from the operators (which are considered one of the highest risks of microbial, and particulate contamination to aseptically prepared medicinal products). Currently, the main options for achieving this goal are either Isolators or RABS. Facilities of older design where there is no or little separation are no longer considered appropriate.
人们普遍认为，无菌灌装设施应在人员和关键区域之间设置单独的屏障。屏障技术可保护暴露的无菌包装组件（例如注射器、西林瓶、静脉输液袋、胶塞）和灌装过程免受操作人员的污染（操作人员被认为是无菌制备药品微生物和微粒污染的最高风险之一）。目前，实现这一目标的主要选择是隔离器或 RABS。设计较旧、几乎没有或完全没有分离的设施不再被认为是合适的。
The recently updated EU and PIC/S Annex 1 for sterile medicinal products directs the manufacturer to use either RABS or Isolators. The USA FDA Guidance for Sterile Drug Products Produced by Aseptic Processing (September 2004) only refers to Isolators and discusses the need for barriers to achieve segregation of the aseptic processing line. FDA inspections of sterile medicinal filling facilities demonstrate that there is an acceptance of well designed and controlled RABS and isolator technology. At recent conferences a number of regulators have expressed a preference for Isolators over RABS, although currently open and Closed RABS are accepted as well as Isolators.
最近更新的欧盟和 PIC/S 无菌药品附录 1 指示制造商使用 RABS 或隔离器。美国 FDA《无菌工艺生产的无菌药品指南》（2004 年 9 月）仅提及隔离器，并讨论了实现无菌生产线隔离的屏障需求。FDA 对无菌药品灌装设施的检查表明，设计良好且受控的 RABS 和隔离器技术是被接受的。在最近的会议上，许多监管机构表示更倾向于隔离器而非 RABS，尽管目前开放式和封闭式 RABS 以及隔离器均被接受。
Although the majority of new facilities and filling lines appear to be designed as Isolators, there is still a number of RABS lines that form a large part of the manufacturing capacity across the world and therefore a restriction on the use of RABS could limit new product applications.
尽管大多数新设施和灌装线似乎设计为隔离器，但全球仍有许多 RABS 线构成了生产能力的很大一部分，因此限制 RABS 的使用可能会限制新产品的应用。
Although Isolators may appear to be the better options, in actuality, they may not be suitable for all processes and themselves may provide a challenge for some products and processes.
尽管隔离器似乎是更好的选择，但实际上，它们可能并不适用于所有工艺，并且本身可能对某些产品和工艺构成挑战。
Some of the concerns over the use of RABS is based on the fact that there does not appear to be a harmonized approach to the design of RABS with some not being optimized to protect the patient. Generally, there are open and closed RABS which appears to be only two designs, however when looking at the operations of these systems, there is a wide variety of interpretations, especially regarding open RABS. These variations include (but are not limited to):
对使用 RABS 的一些担忧基于这样一个事实，即 RABS 的设计似乎没有统一的方法，有些设计并未经过优化以保护患者。通常，RABS 分为开放式和封闭式两种设计，但观察这些系统的操作时，存在各种各样的解释，特别是关于开放式 RABS。这些变化包括（但不限于）：
Open door set up, but the setup is not optimized to minimize the durations of the door opening. 开门设置，但设置未经过优化以最大限度地缩短开门时间。 Aseptic assembly of the filling system are not optimized e.g. the product pumps, filling needles and product manifold are sterilized separately and then assembled aseptically, sometimes through glove ports, sometimes with the RABS doors open. Rather than pre assembly prior to. 灌装系统的无菌组装未经过优化，例如产品泵、灌装针和产品歧管分别灭菌，然后无菌组装，有时通过手套口，有时在 RABS 门打开的情况下进行，而不是预先组装。 Once set up of the filling system is complete then some companies do not allow any further open door interventions, whilst others will allow a wide range of open door interventions (potentially negating the benefit of the RABS). 一旦灌装系统设置完成，一些公司不允许任何进一步的开门干预，而另一些公司则允许广泛的开门干预（这可能会抵消 RABS 的好处）。
It is therefore proposed that rather than pushing the industry into isolators due to the concerns relating to the inconsistencies in operation of RABS, the paper provides guidance as to what Industry considers the suitable operation of a RABS to be. There should also be guidance on the operations of RABS and definitions, and these can be found in the PDA Points To Consider (PTC) published June 2025.
因此，本文建议，不应因对 RABS 操作不一致的担忧而将行业推向隔离器，而是提供行业认为 RABS 应具备的合适操作指南。还应有关于 RABS 操作和定义的指南，这些内容可以在 2025 年 6 月发布的 PDA《考虑要点》（PTC）中找到。
It should be noted that the control measures for RABS or isolators should be clearly defined in the Contamination Control Strategy (CCS). The CCS is discussed in detail other sections of the white paper and will not be discussed further in this section.
应当指出，RABS 或隔离器的控制措施应在污染控制策略（CCS）中明确定义。CCS 在白皮书的其他部分有详细讨论，本节不再进一步讨论。
Key requirements for existing RABS facilities 现有 RABS 设施的关键要求：
Equipment, including indirect contact parts, should be frequently sterilized (typically this is per batch or occasionally per campaign (if short) using validated methods such as moist heat sterilization. 设备（包括间接接触部件）应经常灭菌（通常每批一次，或偶尔每个生产周期一次（如果周期较短）），使用经过验证的方法，如湿热灭菌。 The sterilized equipment should be wrapped in such a way that it can be transported from the sterilizer to the filling line whilst minimizing risk of reintamination e.g. by a minimum of double wrapping. 灭菌后的设备应以能够从灭菌器运输到灌装线同时最大限度减少再污染风险的方式进行包装，例如至少进行双层包装。 Open door interventions during set up should be minimized by optimizing the set up process to ensure that, as much as possible, can be performed through gloveports. 应通过优化设置过程，确保尽可能多的操作通过手套口进行，从而最大限度地减少设置期间的开门干预。 Aseptic set up of the equipment should be optimized to remove the need for unprotected aseptic connections by either by pre assembly prior to sterilization or using intrinsic aseptic connections. 应优化设备的无菌设置，通过在灭菌前预先组装或使用内置无菌连接，消除对无保护无菌连接的需求。 Open door interventions on completion of the set up process should be prohibited. 设置过程完成后，应禁止开门干预。
For new installations of RABS, all of the above should be included in the consideration but in addition wider consideration should be given to the meaning of the S (System) in RABS. This should include items such as:
对于新安装的 RABS，上述所有内容都应纳入考虑，但此外还应更广泛地考虑 RABS 中 “S”（系统）的含义。这应包括以下项目：
CIP and SIP of reusable contact parts such as the filling system 可重复使用接触部件（如灌装系统）的在线清洗（CIP）和在线灭菌（SIP） Automated sanitization of the RABS using systems such as VHP 使用 VHP 等系统对 RABS 进行自动化消毒
Indirect contact part sterilization 间接接触部件的灭菌：
Regulators have had a concern regarding the set up and sterilization of indirect contact part in isolators for a number of years. Indirect contact parts are defined in clause 5.5 of Annex 1 for the manufacture of sterile medicinal products as:
多年来，监管机构一直关注隔离器中间接接触部件的设置和灭菌。无菌药品生产附录 1 第 5.5 条将间接接触部件定义为：
“Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components).”
“间接产品接触部件是指不与产品接触，但可能与其他无菌表面接触的设备部件，这些表面的无菌性对整体产品无菌性至关重要（例如胶塞碗和导向器等无菌物品，以及无菌组件）。”
Regulators are concerned because these parts come into contact with primary container-closure system components and directly contact the sterile product (e.g. stoppers), and therefore they should themselves be sterile. However, the challenge has been what constitutes a true sterilizing agent. A number of companies have interpreted this as meaning that Vapour Hydrogen Peroxide (VHP) can be used as a sterilizing agent as it is capable of producing a six log reduction of highly resistant Geobacillus stearothermophilus spores. However, this view of VHP is not universally held due to issues seen in the application of this technology where it has failed to achieve sterilization due to unforeseen challenges. These challenges have included unidentified hotspots, changes in temperature/humidity and difficult to penetrate areas. This concern was first expressed in the MHRA Blog “VHP Fragility” April 2018 and has continued to be an area of debate to the current day. It is still argued that the conditions and differences in an isolator, such as different materials of construction, mean that the VHP process cannot be consistently controlled to ensure that there is no risk to the patient. Given these concerns this paper does not propose using VHP as a sterilization process, only as a robust decontamination.
监管机构之所以关注，是因为这些部件与初级容器密封系统组件接触，并直接接触无菌产品（例如胶塞），因此它们本身应该是无菌的。然而，挑战在于什么构成真正的灭菌剂。许多公司将其解释为可以使用汽化过氧化氢（VHP）作为灭菌剂，因为它能够对高抗性的嗜热脂肪地芽孢杆菌孢子产生 6 个对数的减少。然而，由于在该技术的应用中出现了因不可预见的挑战而未能实现灭菌的问题，对 VHP 的这种看法并未得到普遍认同。这些挑战包括未识别的热点、温度 / 湿度的变化以及难以穿透的区域。这一担忧最初在 2018 年 4 月的 MHRA 博客 “VHP 的脆弱性” 中表达，并一直持续到今天。人们仍然认为，隔离器内的条件和差异（如不同的构造材料）意味着 VHP 工艺无法得到持续控制，以确保对患者没有风险。鉴于这些担忧，本文不建议将 VHP 用作灭菌工艺，仅作为一种稳健的去污手段。隔离器内的条件和差异（如不同的构造材料）意味着 VHP 工艺无法得到持续控制，以确保对患者没有风险。鉴于这些担忧，本文不建议将 VHP 用作灭菌工艺，仅作为一种稳健的去污手段。
The purpose of this section of the white paper is to propose the approach that should be taken to the sterilisation of indirect contact parts for isolators.
白皮书本节的目的是提出隔离器间接接触部件应采取的灭菌方法。
Key considerations for indirect contact part sterilization and assembly intended to be used in isolators:
拟用于隔离器的间接接触部件灭菌和组装的关键考虑因素：
Equipment design 设备设计：
As far as possible the equipment should be designed to allow ease of removal from the isolator (thus preventing damage) and transfer to and from the sterilisation equipment (typically an autoclave). 设备设计应尽可能便于从隔离器中取出（从而防止损坏）并往返于灭菌设备（通常是高压灭菌器）。 It should allow loading into the sterilization equipment. Older designs of filling lines have had equipment, such as stopper descrambler bowls that have been too large and too heavy to move into the equipment. 它应允许装载到灭菌设备中。旧设计的灌装线设备（如胶塞理瓶碗）体积过大、重量过重，无法移入设备。 Allow a logical flow of equipment assembly and set up e.g. top down and inside of the isolator to the outside. 允许设备组装和设置的逻辑流程，例如从上到下，从隔离器内部到外部。 Allows for the setup of the equipment using sterile tools. 允许使用无菌工具进行设备设置。 Allows for appropriate wrapping that supports the logical sequence of set up. 允许进行支持设置逻辑顺序的适当包装。 Allows for the cleaning of the equipment and removal residues such as silicon from stoppers as well residual cleaning agent (e.g., including water). 允许清洁设备并去除残留物，如胶塞上的硅以及残留清洁剂（例如水）。 Allows for ergonomic handling of the parts both for health and safety reasons but also to aid in handling so as not to re-contaminate or compromise sterile surfaces. 允许符合人体工程学的部件处理，这既是出于健康和安全原因，也是为了帮助处理，以免重新污染或损害无菌表面。
Sterilisation 灭菌：
The equipment will be wrapped in such a way that it protects the equipment from recontamination during transport through the Isolator surrounding area (typically grade C). 设备包装方式应能保护设备在通过隔离器周围区域（通常为 C 级）运输期间免受再污染。 Wrapping of the equipment in such a way that different layers can be removed at the interface of the grade C surrounding the isolator but then allows the equipment to remain covered whilst the isolator doors remain open so that transfer of sterilized wrapped parts does not represent risk of introducing contamination into the isolator (sterilized parts as contamination vector). Furthermore, not only multilayer wrapping but also properly designed transfer and set up procedures play a role here. 设备包装方式应允许在隔离器周围 C 级界面处去除不同层，但在隔离器门保持打开时允许设备保持覆盖状态，以便无菌包装部件的转移不会对隔离器造成污染风险（无菌部件作为污染载体）。此外，不仅多层包装，而且设计合理的转移和设置程序在这里也发挥着作用。 Loading into the sterilizer in a methodical manner that allows the set up in a logical manner. 有条理地装载到灭菌器中，以便以逻辑方式进行设置。 Wrapping that allows ease of removal, so as not to breach first air principles. 包装应便于移除，以免违反 “第一空气” 原则。
Primary packaging components addition 初级包装组件的添加：
This area of activity should include a number of considerations:
该活动领域应包括若干考虑因素：
If not pre-loaded in isolator prior to decontamination, (e.g., for very small batches), then introduction to the isolator of components such as stoppers should be either through transfer isolators or the use of Rapid Transfer Ports (RTP). 如果在去污前未预先装载到隔离器中（例如对于非常小的批次），则胶塞等组件应通过转移隔离器或使用快速转移端口（RTP）引入隔离器。 Where RTP ports are used the method of opening the beta ports need to be designed so as not to breach first air that travels over the stoppers or indirect contact part systems (controlled beta port open should be considered). 如果使用 RTP 端口，β 端口的打开方法需要设计为不破坏流经胶塞或间接接触部件系统的第一空气（应考虑受控的 β 端口打开）。 Vials should be transferred directly into the isolator using a dry heat sterilization/depyrogenation tunnel or use similar systems and considerations to those listed above for RTP systems. 西林瓶应通过干热灭菌 / 除热原隧道直接转移到隔离器中，或使用与上述 RTP 系统类似的系统和考虑因素。 If using nested components, then these may be transferred into the isolator using 2 main methodologies, either using sound material contamination methods (i.e., VHP, electron beam), sanitization of in the tube or transfer chamber(s) and a No Touch Transfer (NTP) approach. 如果使用嵌套组件，则可以通过两种主要方法将其转移到隔离器中：使用可靠的材料污染方法（即 VHP、电子束）、管内或转移室的消毒，以及无接触转移（NTP）方法。 NTP relies on the removal of multiple layers of sterilized wraps that are removed at the interface to each grade, and helps to avoid direct manual contact with sterilized supplies. NTP 依赖于在每个等级的界面处去除多层无菌包装，有助于避免与无菌用品的直接手动接触。 The removal of each layer of Wrap either for E beam or NTP should be at a minimum be performed through glove ports but if possible using well designed robotic systems. 无论是电子束还是 NTP，每一层包装的去除至少应通过手套口进行，但如果可能，应使用设计良好的机器人系统。
Set up process 设置过程：
The setup process will be performed with personnel enhanced gowning (e.g. sterile clothing, whilst the isolator doors remain open). Although this should be considered a contamination reduction step and a key part of the Contamination Control Strategy, it should not be considered an aseptic process with the surrounding background room remaining classified as grade C. 设置过程将由加强更衣的人员进行（例如无菌服，同时隔离器门保持打开）。虽然这应被视为污染减少步骤和污染控制策略的关键部分，但不应将其视为无菌工艺，周围背景房间仍为 C 级。 The process could be performed using at least two operators designated as “primary/receiving” and “transferring/support” operator. This involves the second “non clean” operator removing the first outer sterilized wrap at the interface of the isolator and handing the equipment to the first (clean) operators without touching the next sterile layer. The “tube of tooth paste” method would be commonly used. The clean operators would then transfer the equipment into the isolator. Also, it should be noted that the operators will also use good aseptic behavior during the set up even though the process is not an aseptic process. 该过程可由至少两名指定为 “主要 / 接收” 和 “转移 / 支持” 操作员的人员执行。这涉及第二名 “非洁净” 操作员在隔离器界面处去除第一层外部无菌包装，并在不接触下一层无菌层的情况下将设备交给第一名（洁净）操作员。通常使用 “牙膏管” 法。然后，洁净操作员将设备转移到隔离器中。此外，应注意，尽管该过程不是无菌工艺，但操作员在设置过程中也将使用良好的无菌行为。 The isolator must maintain a positive airflow during the door open process to ensure airflows from the isolator into the surrounding grade C area minimize the risk of biological burden into the isolator that would create a greater challenge to the VHP decontamination process. 在开门过程中，隔离器必须保持正向气流，以确保空气从隔离器流入周围的 C 级区域，最大限度地减少生物负荷进入隔离器的风险，否则会给 VHP 去污过程带来更大挑战。 The company must have air visualization e.g. smoke studies of the setup process demonstrating appropriate airflows are maintained to minimize the risk of contamination during this process. 公司必须进行空气可视化研究，例如设置过程的烟雾研究，以证明维持了适当的气流，从而最大限度地减少此过程中的污染风险。 The final wrapping will be removed with the Isolator doors closed and immediately prior to running the qualified decontamination cycle. 最终包装将在隔离器门关闭且即将运行合格的去污周期之前移除。
Note 1: The above proposals are intended to minimize risk of microbial contamination during the set-up process but should not be considered a truly aseptic process.
注 1： 上述建议旨在最大限度地减少设置过程中的微生物污染风险，但不应被视为真正的无菌工艺。
Note 2: It is generally agreed that isolators provide an increased level of protection from the operator once the process is running, but that there is a significant cost associated with implementation of Isolators rather than RABS. Caution should be taken not to apply requirements that are fully reflective of an aseptic process that would potentially inhibit industry from investing in Isolator technology.
注 2： 人们普遍认为，一旦工艺运行，隔离器提供了更高水平的操作员防护，但实施隔离器而非 RABS 会带来显著的成本。应注意不要应用完全反映无菌工艺的要求，这可能会抑制行业对隔离器技术的投资。
Pre Use Post Sterilisation Integrity testing (PUPSIT):
使用前灭菌后完整性测试 (PUPSIT)：
Although not a new requirement, the updated Annex 1 published 2022 is far clearer that the previously published version from 2009 in the requirement to perform PUPSIT on the primary sterilizing filter during aseptic filling. (This clear expression of the expectation had led to divergent approaches amongst Industry and regulators). The industry is discussing how best to implement PUPSIT (where not already in place) and this section will detail expectations and options that will help harmonize the design, and therefore the inspection process. The Annex 1 does allow some area for risk assessment for a company to define when it does not feel that the use of PUPSIT is in the best interest of the patient (rather than just operational challenges, this risk assessment will include elements such as the filtration system design (e.g. pre filters etc.) and the likelihood of the product masking a damaged filter, but this risk assessment will be very specific to each product and will not be further discussed in this paper.
The implementation of PUPSIT should be taken as a minimum requirement. However, on the assumption that the company has performed the assessment and will perform PUPSIT the following are considerations for successful implementation:
PUPSIT 的实施应被视为最低要求。然而，假设公司已进行评估并将执行 PUPSIT，以下是成功实施的考虑因素：
Filtration design: 过滤设计：
The manufacture of the medicinal product will use either a single sterilizing filter or a dual sterilizing filter system; this will be based on product and process design and filter validation. In general, dual filters are recommended. 药品生产将使用单除菌过滤器或双除菌过滤器系统；这将基于产品和工艺设计以及过滤器验证。一般建议使用双过滤器。 Where a dual filter system is used then the manufacturer will define what and how the filters are designated, examples include: 当采用双重过滤系统时，制造商将定义滤芯的类型及标识方式，例如： Filter one (upstream) sterilizing filter, filter two (downstream) redundant 过滤器一（上游）灭菌过滤器，过滤器二（下游）冗余 Filter one, redundant, filter two, final sterilizing filter 第一级过滤器，冗余过滤器，第二级过滤器，最终灭菌过滤器
Filter one and two sterilizing filters 第一级和第二级灭菌过滤器
Based on the definitions chosen, this will define the strategy used for PUPSIT and what action will be taken in the event of an integrity test failure. 根据选择的定义，这将定义用于 PUPSIT 的策略以及在完整性测试失败时将采取的行动。 If both filters are designated as sterilizing filters the implication is that they are both integral to the final sterilization of the product. In this case both filters must have PUPSIT performed, and any failure implicates the batch. 如果两个过滤器都被指定为除菌过滤器，这意味着它们都是产品最终灭菌不可或缺的一部分。在这种情况下，两个过滤器都必须进行 PUPSIT，任何失败都意味着批次受影响。 One filter sterilizing, one redundant then it is only required to perform PUPSIT on the filter designated as the sterilizing filter. In the event that this filter fails, then post integrity (pre use) integrity data is required for both filers) can be performed on the filter designated as redundant. If this filter fails, the product would then be in question. 一个过滤器为除菌，一个为冗余，则只需要对指定为除菌过滤器的过滤器进行 PUPSIT。如果该过滤器失败，则需要对指定为冗余的过滤器进行完整性后（使用前）完整性数据测试。如果该过滤器也失败，则产品将受到质疑。
Filter location: 过滤器位置：
The are arguments for the location of the filters e.g., inside or outside the filling cabinet or isolators. The following considerations should be clearly considered during the design and subsequent description of the filtration process in the Contamination Control strategy.
关于过滤器的位置存在争议，例如在灌装柜或隔离器的内部还是外部。在污染控制策略中过滤过程的设计和后续描述中，应明确考虑以下因素。
Inside the filling cabinet or isolator: 在灌装柜或隔离器内部：
The filtration equipment has to be transferred into the critical zone and therefore adds potential risk to the critical zone. 过滤设备必须转移到关键区域，因此增加了关键区域的潜在风险。 PUPSIT has the potential risk of contributing microbial contamination due to activities such as venting of the non-sterile liquid during the wetting process. PUPSIT 存在导致微生物污染的潜在风险，例如在润湿过程中排放非无菌液体。 The design of the system should include appropriate vent filters (which themselves generally require integrity testing) and closed systems that allow the collection of unfiltered waste without compromising the critical zone. 系统设计应包括适当的排气过滤器（其本身通常需要完整性测试）和封闭系统，允许在不损害关键区域的情况下收集未过滤的废物。 Filtration systems are often complex systems that can cause issues by breaching first air in the isolator and impacting airflows. 过滤系统通常是复杂的系统，可能会因破坏隔离器中的第一空气并影响气流而导致问题。
Outside of the cabinet: 在柜外：
This removes the risk to the critical zone but does introduce the risk that if non integral then air that is not of a grade A quality could be introduced into the system after the final filtration of the product. However, this is mitigated by placement of this part of the equipment train in a specified area that is protected by extensive HEPA-filtration. 这消除了对关键区域的风险，但确实引入了风险，即如果是非整体式的，则在产品最终过滤后，非 A 级质量的空气可能被引入系统。然而，通过将设备链的这一部分放置在由广泛 HEPA 过滤保护的指定区域，可以减轻这种风险。
Annex 1 clause 8.80 states that: 附录 1 第 8.80 条规定：
“Suitable bioburden reduction prefilters and/or sterilising grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the final sterilising filter. Due to the potential additional risks of a sterile filtration process, as compared with other sterilisation processes, an additional filtration through a sterile sterilising grade filter, as close to the point of fill as possible, should be considered as part of an overall CCS.”
“在制造过程中的多个点可以使用合适的生物负荷减少预过滤器和 / 或除菌级过滤器，以确保最终除菌过滤器之前液体的低且受控的生物负荷。由于与其他灭菌工艺相比，无菌过滤工艺存在潜在的额外风险，应考虑通过无菌除菌级过滤器进行额外过滤，尽可能靠近灌装点，作为整体 CCS 的一部分。”
It is not defined what “as close to the point of fill as possible” means and consideration should be given to ensure that the number of aseptic connections after the sterilizing filter should be avoided (via SIP) or minimized, and only performed in Grade A and also using intrinsic sterile connectors where possible.
“尽可能靠近灌装点” 的含义未作定义，应考虑确保避免（通过 SIP）或尽量减少除菌过滤器后的无菌连接数量，并且仅在 A 级区域进行，并尽可能使用内置无菌连接器。
The preference would be to locate the filtration system outside the filling cabinet or in a separate section but as close to the point of fill as possible to minimize the potential impacts discussed previously.
优先选择将过滤系统放置在灌装柜外或单独的区域，但尽可能靠近灌装点，以最大限度地减少前面讨论的潜在影响。
Closed Systems: 封闭系统：
The updated Annex 1 has a new section relating to closed systems discussing both re-usable and disposable systems. The addition is indicative of a general industry move towards closed systems. The use of closed systems has a number of benefits including creating a secure barrier preventing contamination from external contamination. Closed systems take the form of fixed systems such as those used in API manufacture and older biological drug substance manufacture and single use systems such as commonly seen in vaccine manufacture. The annex gives a lot of guidance regarding the use of closed systems but is silent on key items such as the background to be used when using these systems. This section gives guidance on key considerations for the selection of backgrounds. Much of the decision on the background environment will be based on the ability to detect a breach in the integrity of a systems, assuming that a robust system is used e.g. pressure decay or helium leakage rather than solely relying on manual visual inspection.
更新后的附录 1 新增了一个关于密闭系统的章节，讨论了可重复使用系统和一次性使用系统。这一新增内容表明，行业正普遍向密闭系统转型。密闭系统的使用具有诸多益处，包括建立一道安全屏障，防止来自外部的污染。密闭系统既可以是固定系统（如原料药生产和早期生物药原液生产中使用的系统），也可以是一次性使用系统（如疫苗生产中常见的系统）。该附录提供了大量关于密闭系统使用的指导，但对于一些关键项目（例如使用这些系统时应采用的背景环境）并未提及。本节针对背景环境选择的关键考量因素提供了指导。关于背景环境的大部分决策，将取决于检测系统完整性破坏的能力，前提是采用了稳健的检测系统（例如压力衰减法或氦气泄漏检测），而非仅仅依赖人工目视检查。
Key Considerations: 关键考虑因素：
Where it is not possible to detect a leak by post use integrity testing:
The background should be a higher grade e.g. Grade A, as the system itself could not be guaranteed as closed and therefore must be considered at risk of contamination from the environment.
背景应为更高等级（例如A级），因为系统本身无法保证处于封闭状态，因此必须考虑其存在环境污染风险。
Where it is possible to assure integrity by the use of a validated integrity test and no manipulations are performed in the area, then the system could potentially can be used in a lower grade area below Grade A classification, e.g. grade D (see Annex 1 Table 4 which gives examples from Grade A through D bearing in mind the appropriate risk). But any failure in integrity would potentially lead to rejection of the product. 若能通过验证的完整性测试确保完整性，且该区域未进行任何操作，则该系统可考虑用于低于A级的区域（例如D级区域，详见附件1表4中从A级到D级的示例，需结合相应风险考量）。但任何完整性失效都可能导致产品被拒收。
Mitigation Strategies: 缓解策略：
There is a concern that despite the annex having been effective for equipment and facilities since August 2023, some companies are not yet able to fully meet the expectations If this is the case it is necessary for each company to assess the specific risk(s) and Gap(s) identified and then assess the patient need versus the GAP and potential patient risk. This assessment will be company, facility, equipment and product specific so will not be addressed in this paper but general key considerations should include:
尽管该附件自2023年8月起对设备和设施生效，但令人担忧的是部分企业仍未能完全满足预期要求。若存在此类情况，各企业有必要评估已识别的具体风险与差距，并权衡患者需求与差距及潜在患者风险。该评估需针对企业、设施、设备及产品特性开展，故本文不予赘述，但普遍关键考量应包括：
Risk to patient 患者风险
Existing mitigation 现有缓解措施
Identification and implementation of new control measures to reduce the risk
识别并实施新的控制措施以降低风险
Limitations of detection systems
检测系统的局限性 Record of the decision of risk acceptance (or otherwise)
风险接受（或不接受）决定记录 Longer term commitments to address the Gaps:
为弥合差距而作出的长期承诺：
To include the longer term CAPA(s) to be formalized in the Quality system.
将长期纠正措施纳入质量体系进行正式化。
Senior management acceptance of the current state and commitment to the CAPA (especially where the CAPA may require large Capital Expenditure).
高层管理层对现状的认可及对纠正措施（CAPA）的承诺（尤其当纠正措施可能需要大量资本支出时）。
A periodic review of the current process to ensure that there are no changes in the level of risk identified and therefore the decision regarding risk acceptance.
对当前流程进行定期审查，以确保已识别的风险水平未发生变化，从而维持风险接受决策的有效性。
Note 1: It should be noted that, due to the fact that the Annex was published in 2022 with an already extended implementation date of August 2023, the regulatory tolerance for acceptance of gaps will be reducing with passing time. However, it is also noted that the regulator is also adverse to the causation of product shortages. For this reason, it would be advisable for each company to have their regulatory outreach strategy defined, this may include a proactive approach to the regulator to ensure that they are aware of the gaps and accepting of the company’s proposed strategy. Such strategies would need to be supported by qualification/validation and subsequently proven as durable and reproducible over time once implemented commercially.
注1：需注意的是，由于该附件于2022年发布时已将实施日期延至2023年8月，监管机构对接受差距的容忍度将随时间推移而降低。但同时需知，监管机构同样反对因监管要求导致产品短缺的情况。因此，建议各企业制定监管沟通策略，包括主动向监管机构通报差距情况，确保其知晓并接受企业提出的解决方案。此类策略需以确认/验证为支撑，并在商业化实施后持续证明其持久性和可重复性。
Note 2: It should be noted that mitigation of risk should not be based solely on the output of monitoring systems such as Aseptic Process Simulations, Environmental monitoring and sterility testing. Mitigation is likely to be formed of a mix of operational measures (e.g. enhanced procedures and training) and Technical measures (e.g. design such as additional use of barrier technology and automation).
注2：需注意的是，风险缓解措施不应仅基于无菌工艺模拟、环境监测及无菌检测等监控系统的输出结果。缓解措施通常由操作性措施（如强化操作规程和培训）与技术性措施（如采用额外屏障技术和自动化等设计方案）共同构成。
