这份文件是一份面向无菌及低生物负荷药品制造商的综合性白皮书，核心目的是帮助企业在2022版欧盟/PIC/S GMP Annex 1框架下建立、实施并持续优化“污染控制策略”（CCS），以兼顾合规、产品质量与患者安全。全文可概括为四大主题：
CCS的战略价值
新修订的Annex 1首次强制要求建立CCS，用于系统识别、评估和控制污染风险。
CCS不仅是质量体系的“总蓝图”，也是跨部门、跨厂区沟通工具，可支撑资本支出决策、审计答辩和持续改进。
设施与设备层面的落地要点
隔离器 vs RABS：两者均被接受，但需在设计、传输、灭菌和干预方式上给出基于风险的控制细节；推荐使用“封闭+自动化”降低人为干扰。
间接接触部件必须真正灭菌（不推荐仅用VHP），并采用多层包装、逻辑流布局和首风保护。
PUPSIT（使用前灭菌后完整性测试）现成明确要求：双滤器设计、滤器位置、排气管理及完整性失效处理需在CCS中写明。
人员与程序管理
将“无菌行为”纳入岗位资质：培训覆盖基础微生物、着装、干预模拟、烟雾研究，并定期再确认。
通过可视化辅助、VR/AI工具、现场教练和Gemba Walk强化“为什么”文化；领导层需在场示范、及时纠偏。
将人为失误纳入QRM：SOP细化、工位防错、CAPA闭环、现场质量伙伴式辅导，共同降低污染概率。
低生物负荷生产的特别考量
Annex 1原则可“选择性借用”：按QRM决定环境级别（如发酵D级、纯化C/B级），封闭系统可在更低背景运行。
设定数据化的生物负荷限值（如≤10 CFU/100 mL），结合预/后完整性测试、快速微生物方法(RMM)和趋势分析，实现近实时监测。
CCS应覆盖厂房设计、物料流转、供应商管理、维护与清洁、偏差/CAPA、持续改进等全生命周期，并定期回顾更新。
结论：没有单一措施可保证无菌或低生物负荷质量；企业必须以CCS为核心，分层叠加设计、程序、监测与文化控制，通过数据、技术与培训持续验证体系有效性，才能在监管趋严的背景下稳健供应、保护患者。
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.本白皮书旨在连接近期运营现实与对稳健无菌及污染控制操作的长期投资。白皮书概述了制造商如何在对关键活动进行控制和监测的同时，采用符合当前期望的设施和设备策略。白皮书还强调了有资质的人员（文章较多讨论了人员培训和资质控制，故此翻译上应该不是QP质量受权人）、正确着装及规范行为在维持受控环境和防止污染中的关键作用。
ScopeThis 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 multicompany 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. 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.范围本白皮书提供了附录1范围内生产操作的原则和实际期望，聚焦于四个领域：环境监测与控制；无菌工艺验证；设备与设施设计；人员实践。每个主题由多家公司、多学科团队作为独立章节起草，并由GPMLF委员会监督以确保信息一致性。还与监管机构进行了非正式反馈，确保所阐述原则符合监管期望且无重大缺口或矛盾，但这不代表监管批准或背书。认识到需与当前监管解释保持一致，可促进缓解风险的方法，在设备和设施升级的设计、执行及确认过程中保障供应连续性和创新疗法的批准。本白皮书不替代现行法律法规，而是在变革时期提供面向行业的指导，以支持合规和无菌保证。值得注意的是，本文基于现有技术状况撰写，并不阻止采用创新实践。公司应考虑无手套隔离器、快速微生物方法、自动清洁消毒系统以及人工智能等新兴技术，作为行业进一步发展和强化当前污染控制策略的下一步举措。
Group 1: Strategic Approach for Maximizing Use of CCS in GMP FacilitiesAim: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. 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. 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.第一组：在GMP设施中最大化使用CCS的战略方法目的：2022年修订的欧盟/PIC/S GMP附录1引入了“污染控制策略”（CCS）的概念，用于界定关键控制点，并评估用于管理污染风险的控制和监测措施的有效性。本文件提供战略指导，使CCS在符合GMP的质量治理中得以有效运用，总体目标是确保产品质量并保护患者。所述策略亦适用于促进组织在污染预防方面的整体方法在内部沟通及监管检查中的一致且有效沟通，并展示与资本支出及其他与设施污染控制相关的战略业务决策有关的质量、合规及运营效益。本文件范围包括无菌、低生物负荷及其他需要污染控制的GMP活动领域（如无菌检查）。在为非无菌产品开发CCS时，制造场地应理解适用于其产品与工艺的附录1及CCS部分，CCS负责人必须能够阐明基于风险的理由，以排除不适用的附录1内容。
Background:Several publications are available that provide guidance on the technical content and structure of a contamination control strategy. Examples include:·Parenteral Drug Association (PDA)³·BioPhorum (CCS guidance for low bioburden drug substance)*·European Compliance Academy ECA⁵However, 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. 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.背景：已有多份出版物就污染控制策略的技术内容与结构提供指导，例如：·注射用药物协会（PDA）³·BioPhorum（低生物负荷药物物质的CCS指导）*·欧洲合规学院ECA⁵。然而，仅具备技术全面的CCS若未有效实施并整合入药品生产质量体系（PQS），仍无法达到监管期望。本指导旨在展示CCS如何（i）嵌入日常运营，以及（ii）通过促进整个组织识别、缓解和回顾污染危害的清晰沟通，为质量和战略决策提供信息。本指导将概述CCS如何整合以在制造运营、质量体系监督及战略决策中发挥最大影响，并通过实例说明如何在实践中实现。
Implementing a CCS in multi-site organizations: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. 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). 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.跨多基地/工厂组织实施CCS：
通过在遵循全球/集团规程与标准的同时兼顾本地特色，可在整个组织内提升效率并确保一致性。建议制定全球/集团CCS SOP及模板，用以阐述对污染控制和/或监测有贡献的全球/集团体系的设计、原理与实施。这为整个组织网络提供教育工具，帮助理解设施设计、设备选型、工艺设计、维护、环境监测、培训、确认及物料采购等如何单独及共同作用于污染控制，并作为合规验证（如自检或审计）的基准。全球/集团方法可使60–70 %的CCS内容无需在各基地/工厂/子公司重复编写，同时允许根据产品、制造工艺、设备及设施布局进行本地微调。最终文件由通用摘要加上现场描述/解读构成，整合进入现场药品质量体系。切勿将全球/集团污染控制措施描述生搬硬套进现场CCS文件而无法解释本地变更，否则全球/集团描述与现场实践不一致时会导致合规失败。
Integrating the CCS into the Pharmaceutical Quality System (PQS):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. 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. 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.将CCS整合入药品质量体系（PQS）：
通过调查、偏差、变更以及对数据（环境、人员、公用系统监测）的定期回顾等常规QMS活动，将CCS整合入PQS可确保对污染风险及缓解措施进行持续审查。这使得风险变化、工艺知识提升以及对控制措施或监测策略的修订能够持续被考虑。CCS作为战略工具被日常运用，以确保受控状态。CCS可在调查过程中为质量影响决策提供信息（如评估减少设施内污染引入或增殖的机会、围堵及检测机会），或PQS调查可能导致对CCS本身的改进。相关情况下，CCS变更可纳入GMP更新培训。除事件驱动审查外，还应作为常规质量风险管理审查周期或现场主计划审查/年度产品质量回顾的一部分，对CCS中描述的风险、缓解及监测活动进行定期回顾，可纳入管理评审或其他质量体系监督，并应让高级管理层可见。
Use of the CCS as a training tool: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. For example: Enabling personnel responsible for aseptic processing to understand the importance of procedural compliance in protecting the patient from product contamination due to: oThe limited capability to remove viable contamination introduced during processing, particularly at final steps of finished product manufacturing (e.g. fill-finish). The statistical weakness of end-stage sterility testing, where a contaminated batch may pass a sterility test.将CCS用作培训工具：
CCS可作为整个组织的培训与教育工具。CCS中描述的污染控制与监测活动的相互作用，包括对有效性及剩余风险的评估，使人员能够理解其工作对制造或控制其他阶段关键质量属性的影响。这种理解彰显了他们各自对保护患者的贡献，并对质量文化产生积极影响。例如：使负责无菌工艺的人员理解程序合规对保护患者免受产品污染的重要性，原因在于：
o在生产过程中去除活性污染的能力有限，尤其在成品制造最后步骤（如灌装-封装）。
o最终阶段无菌测试的统计薄弱性，受污染批次可能通过无菌测试。
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 supplier quality management, which can affect product or process contamination control and monitoring.使支持职能（如采购团队）理解供应商选择决策对物料输入或过程控制的影响，包括在确保稳健供应商质量管理的同时合理平衡成本，这会影响产品或过程的污染控制与监测。
Use of CCS in Inspection and Audit: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 bring 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. 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.CCS在检查与审计中的运用：
CCS可作为对内对外利益相关者沟通风险与缓解措施的单一、全面风险及控制措施综述。CCS流程负责人应能解释总体CCS方法，并在需要时引入其他主题专家。适宜的总结材料（图示或其他展示控制措施关系的工具）可用于此目的。建议在任何外部评估审计或检查中尽早审查CCS，使组织能清晰解释风险识别以及良好设施与工艺设计中控制策略的累积影响，最小化物料、环境及人员引入污染危害的潜在风险，并监测环境与过程的失效。在PQMS内展示CCS作为日常使用的战略工具，可向监管机构彰显主动文化。
Using the CCS as a tool in strategic business decision making: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. 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. 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.将CCS用作战略业务决策工具：
CCS通常不包括与生产力、避免浪费或资源利用相关的信息，然而改进的质量保证可带来诸多长期成本效益。有效实施统一的CCS可降低商品成本，减少重复起草与维护各CCS文件的浪费，并使组织能够全范围规划持续改进与资本支出。在进行战略投资决策时可参考CCS，通过清晰阐述设施与设备、过程控制、污染风险缓解及监测方法，为决策提供依据，这些会影响运营支出、商品成本及生产力。CCS内容可通过展示当前控制的成本/复杂度与在设施、设备、技术方面投资可获得的业务、质量、供应与合规收益，为未来投资决策提供背景。抑或，当投资优先于业务其他领域时，CCS可有效概述需采取的额外风险缓解措施以维持合规与产品质量。本质上，前瞻性的CCS提供了可避免的业务风险背景，通过实施更可靠的设施、工艺与系统来实现。利用CCS对污染风险与缓解措施的总结，组织可量化归因于特定工艺设计策略的资源及投资后的潜在节约（例如，通过投资隔离器技术/封闭系统替代传统“开放”无菌工艺，可降低洁净区级别、减少人员着装及确认、环境监测、工艺与环境监测，提高制造区域利用率及其他风险缓解措施）。此类工艺改进带来的运营支出节约可作为商业案例的重要方面，并辅助组织财务规划。
Group 2: Equipment and FacilitiesIntroduction: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. 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.第二组：设备与设施引言：本白皮书本节讨论无菌药品设施合规所面临的挑战，并确保行业、供应商与监管机构对合规设施与设备的要求有共同理解。本节重点讨论：限制进入屏障系统（RABS）与隔离器、间接接触部件灭菌（RABS与隔离器）、使用前灭菌后完整性测试（PUPSIT）及封闭系统等关键领域。尽管本文未直接涵盖，团队亦鼓励采用合适的创新技术，包括设计良好的无菌灌装机器人系统（进一步减少人工干预）以及快速/替代监测系统，使企业能快速获得其无菌系统与控制运行状态的反馈， 实现更接近实时的应对措施。
RABS versus Isolators:It is widely accepted that aseptic filling facilities should include a separative barrier between personnel and the critical zones. Barrier technologies provide protection of 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. 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. 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. 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. 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): Open door set up, but the setup is not optimized to minimize the durations of the door opening. 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 sterilization. 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).RABS与隔离器：
业界普遍认为无菌灌装设施应在人员与关键区域之间设置隔离屏障。屏障技术用于保护已暴露的已灭菌包装组件（如注射器、西林瓶、输液袋、胶塞）及灌装过程免受操作人员影响（操作人员被视为对无菌药品微生物及粒子污染的最高风险之一）。目前实现该目标的主要选择为隔离器或RABS。老旧设计、几乎无分隔的设施已不再被视为适宜。近期更新的欧盟及PIC/S无菌药品附录1指示制造商使用RABS或隔离器。美国FDA《无菌药品无菌工艺生产指南》（2004年9月）仅提及隔离器，并讨论需通过屏障实现无菌工艺线的隔离，FDA对无菌药品灌装设施的检查表明其对设计良好且受控的RABS与隔离器技术均予接受。在近期会议上，一些监管者表示更倾向隔离器而非RABS，尽管目前开放及封闭RABS与隔离器均被接受。尽管大多数新设施及灌装线似乎设计为隔离器，全球仍有大量RABS线构成产能的重要部分，因此对RABS使用的限制可能限制新产品申报。虽然隔离器看似更优，实际上并非对所有工艺均适宜，且其本身对某些产品及工艺可能构成挑战。对RABS使用的部分担忧源于其设计缺乏一致性，有些设计并未优化以保护患者。通常认为RABS分开放与封闭两种设计，然而观察其运行，存在多种解读，尤其在开放RABS方面。这些差异包括但不限于：开放门设置但未优化以缩短开门时长；灌装系统无菌组装未优化，例如产品泵、灌装针及产品管排分别灭菌后再无菌组装，有时通过手套口，有时RABS门敞开，而非在灭菌前预组装；灌装系统设置完成后，有些公司不再允许任何开门干预，而有些则允许多种开门干预（可能使RABS优势丧失）。
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. 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.因此，本文建议，与其因担忧RABS运行不一致而推动行业转向隔离器，不如提供行业认为适宜RABS运行的指导。还应有RABS运行及定义的指引，可参见PDA于2025年6月发布的《考虑要点》（PTC）。应注意，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在本白皮书其他部分详述，本节不再讨论。
Key requirements for existing RABS facilities: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. 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 recontamination e.g. by a minimum of double wrapping. 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. 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. Open door interventions on completion of the set up process should be prohibited. 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: CIP and SIP of reusable contact parts such as the filling system, Automated sanitization of the RABS using systems such as VHP.现有RABS设施的关键要求：
设备（包括间接接触部件）应频繁灭菌（通常每批或短周期活动）采用经验证的方法如湿热灭菌。已灭菌设备应包装妥当，使其从灭菌器转移至灌装线时最小化再污染风险，例如至少双层包装。流程设计中应通过优化设置流程尽量减少开门干预，尽可能通过手套口完成。设备无菌设置应优化，以消除无保护无菌连接的需要，可通过灭菌前预组装或使用内在无菌连接。设置完成后应禁止开门干预。对于新建RABS，除上述要求外，还应更广考虑RABS中“S（系统）”的含义，包括：灌装系统等可重复使用接触部件的CIP及SIP、采用VHP等系统对RABS进行自动消毒。
Indirect contact part sterilization:Regulators have had a concern regarding the set up and sterilization of indirect contact parts 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: "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)." 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. 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.间接接触部件灭菌：
多年来，监管机构一直对隔离器中间接接触部件的设置与灭菌表示担忧。附录1第5.5条将“间接产品接触部件”定义为：不接触产品但可能接触其他已灭菌表面的设备部件，这些表面的无菌性对产品整体无菌至关重要（如已灭菌的胶塞斗、导轨及组件）。监管机构担忧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（如胶塞），因此其本身必须无菌。然而，挑战在于何为真正的灭菌剂。一些公司认为汽化过氧化氢（VHP）可作为灭菌剂，因其可对高抗性的嗜热脂肪芽孢杆菌达到六对数降。然而，由于VHP在应用中因不可预见的挑战（如未识别热点、温湿度变化、难渗透区域）未能实现灭菌，该观点并非普遍接受。此担忧首次见于MHRA博客《VHP脆弱性》（2018年4月），至今仍是争议领域。有人认为隔离器内不同构造材料等条件差异使VHP工艺无法一贯受控，从而无法确保对患者无风险。鉴于这些担忧，本文不建议将VHP用作灭菌工艺，仅作为强力去污手段。本节旨在提出隔离器间接接触部件灭菌应采取的方法。
Key considerations for indirect contact part sterilization and assembly intended to be used in isolators.Equipment design: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). 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. Allow a logical flow of equipment assembly and set up e.g. top down and inside of the isolator to the outside. Allows for the setup of the equipment using sterile tools. Allows for appropriate wrapping that supports the logical sequence of set up. Allows for the cleaning of the equipment and removal residues such as silicon from stoppers as well residual cleaning agent (e.g., including water). 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.Sterilisation: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). 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. Loading into the sterilizer in a methodical manner that allows the set up in a logical manner. Wrapping that allows ease of removal, so as not to breach first air principles.用于隔离器的间接接触部件灭菌与组装的关键考虑：设备设计：应尽可能设计设备以便从隔离器中易于移除（防止损坏）并往返于灭菌设备（通常为高压灭菌器）。应允许顺利装入灭菌设备。老旧灌装线曾有胶塞解 scramble 斗等设备过大过重无法装入。应允许设备组装与设置的逻辑流程，例如自上而下、从隔离器内到外。应允许使用无菌工具进行设备设置。应允许适当包装以支持设置的逻辑顺序。应允许清洁设备并去除胶塞硅油等残留物及清洁剂残留（包括水）。应允许部件的人体工学搬运，既为健康与安全，也为避免再污染或破坏无菌表面。灭菌：设备应包装妥当，使其在穿越隔离器周围区域（通常为C级）时免受再污染。包装方式应能在隔离器周围C级界面去除不同层，但在隔离器门开启时设备仍被覆盖，从而使已灭菌包装部件的转移不会将污染引入隔离器（已灭菌部件作为污染载体）。此外，多层包装及合理设计的转移与设置程序均起作用。应以允许逻辑设置的有序方式装入灭菌器。包装应易于去除，以不破坏首过气流原则。
Primary packaging components addition:This area of activity should include a number of considerations: 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). 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). 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. 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. 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. 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.初级包装组件加入：
此活动区域应考虑多项内容：若未在隔离器去污前预装（如极小批次），则胶塞等组件应通过转移隔离器或快速转移端口（RTP）引入隔离器。使用RTP时，打开beta端口的方法需设计为不破坏流经胶塞或间接接触部件系统的首风（应考虑受控beta端口开启）。西林瓶应通过干热灭菌/去热原隧道直接转入隔离器，或采用与上述RTP系统类似的系统及考虑。若使用巢式组件，可通过两种主要方法转入隔离器：采用可靠的物料污染方法（如VHP、电子束）对管道或转移舱进行消毒，以及无接触转移（NTP）方式。NTP依赖在各级别界面去除多层已灭菌包装，避免与已灭菌供应品直接手动接触。对于电子束或NTP，每一层包装的去除至少应通过手套口完成，如可能则采用设计良好的机器人系统。
Set up process: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. 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 toothpaste" 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. 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. 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. The final wrapping will be removed with the Isolator doors closed and immediately prior to running the qualified decontamination cycle.设置过程：流程设计将在人员加强着装（如无菌衣，隔离器门保持开启）下进行。尽管此步骤应被视为减少污染的关键环节及污染控制策略的重要组成部分，但不应被视为无菌工艺，周围背景房间仍维持C级。该过程可由至少两名操作员执行，分别指定为主/接收操作员及“转移/支持”操作员。第二名“非洁净”操作员在隔离器界面去除第一件外层已灭菌包装，并在不接触下一无菌层的情况下将设备交给第一名（洁净）操作员，通常采用“牙膏管”方式。洁净操作员随后将设备转入隔离器。应注意，即使该过程非无菌工艺，操作员在设置过程中仍应遵循良好无菌行为。隔离器在开门过程中必须保持正压气流，确保气流由隔离器流向周围C级区，最小化生物负荷进入隔离器而给VHP去污工艺带来更大挑战。公司必须进行空气可视化，例如设置过程的烟雾研究，证明维持适当气流以最小化此过程中的污染风险。最后一层包装将在隔离器门关闭后、运行经验证的去污循环前立即去除。
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.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1：上述建议旨在最小化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。注2：普遍认为，隔离器在工艺运行后可提供较高级别的操作员防护，但实施隔离器相较于RABS成本显著。应注意不要施加完全体现无菌工艺的要求，以免阻碍行业投资隔离器技术。
Pre Use Post Sterilisation Integrity testing (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:使用前灭菌后完整性测试（PUPSIT）：尽管并非新要求，2022年发布的更新版附录1相较于2009版更明确要求在无菌灌装过程中对主要除菌过滤器进行PUPSIT。（此明确表述导致行业与监管者做法分歧）。行业正讨论如何最佳实施PUPSIT（尚未实施者），本节将详述有助于统一设计及检查流程的期望与可选方案。附录1确实允许企业通过风险评估界定何时认为使用PUPSIT不符合患者最佳利益（而非仅运营挑战），该风险评估将包括过滤系统设计（如预过滤等）及产品掩盖破损过滤器的可能性等因素，但此类风险评估将非常具体且本文不再进一步讨论。PUPSIT的实施应被视为最低要求。然而，假设企业已完成评估并将实施PUPSIT，以下为成功实施的考虑要点：
Filtration design: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. Where a dual filter system is used then the manufacturer will define what and how the filters are designated, examples include: oFilter one (upstream) sterilizing filter, filter two (downstream) redundant oFilter one, redundant, filter two, final sterilizing filter oFilter one and two sterilizing filters 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. 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. 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 filters) can be performed on the filter designated as redundant. If this filter fails, the product would then be in question.过滤设计：药品生产将采用单支除菌过滤器或双支除菌过滤系统，依据产品与工艺设计及过滤器验证确定。通常推荐双过滤器。使用双过滤系统时，制造商将定义过滤器及其命名，例如：
o过滤器一（上游）除菌过滤器，过滤器二（下游）冗余
o过滤器一冗余，过滤器二最终除菌过滤器
o过滤器一与二均为除菌过滤器。
基于所选定义，将确定PUPSIT策略及完整性测试失败时的措施。若两支过滤器均定义为除菌过滤器，则意味着二者均为产品最终灭菌的关键，此时必须对两支过滤器进行PUPSIT，任何失败均牵连批次。若一支为除菌，一支为冗余，则仅需对除菌过滤器进行PUPSIT。若该过滤器失败，则可对冗余过滤器进行使用后完整性测试（需两支过滤器均有使用前完整性数据）。若冗余过滤器亦失败，则产品将受质疑。
Filter location:There 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.Inside the filling cabinet or isolator:o The filtration equipment has to be transferred into the critical zone and therefore adds potential risk to the critical zone.PUPSIT has the potential risk of contributing microbial contamination due to activities such as venting of the non-sterile liquid during the wetting process.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.Filtration systems are often complex systems that can cause issues by breaching first air in the isolator and impacting airflows.Outside of the cabinet: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.oAnnex 1 clause 8.80 states that:'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.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.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.过滤器位置：过滤器位置（如灌装柜或隔离器内外）存在争议，以下考虑应在污染控制策略的过滤工艺设计及后续描述中明确：灌装柜或隔离器内：
o过滤设备需转移至关键区，因此增加关键区潜在风险。
oPUPSIT可能因润湿过程中排放非无菌液体等活动带来微生物污染风险。
o系统设计应包括适当排气过滤器（其本身通常需完整性测试）及封闭系统，可在不破坏关键区的前提下收集未过滤废液。
o过滤系统往往复杂，可能因破坏隔离器首风或影响气流而引发问题。柜外：这可消除对关键区的风险，但引入若过滤器不完整则非A级空气可能在产品最终过滤后进入系统的风险；然而，通过将该部分设备布置在具备高效HEPA过滤的指定区域可缓解此风险。
o附录1第8.80条指出：“在制造过程多个点可使用适宜的生物负荷降低预过滤器和/或除菌级过滤器，以确保液体在最终除菌过滤器前具有低且受控的生物负荷。由于无菌过滤工艺相较于其他灭菌工艺存在潜在额外风险，应尽可能靠近灌装点通过一支无菌除菌级过滤器进行额外过滤，作为整体CCS的一部分。”未定义“尽可能靠近灌装点”的含义，应考虑确保除菌过滤器后的无菌连接应避免（通过SIP）或最小化，且仅在A级进行，并尽可能使用内在无菌连接器。首选将过滤系统置于灌装柜外或独立区域，但尽可能靠近灌装点，以最小化前述潜在影响。
Closed Systems: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.封闭系统：更新版附录1新增一节讨论封闭系统，涵盖可重复使用及一次性系统，显示行业总体向封闭系统迈进。封闭系统的益处包括建立安全屏障，防止外部污染。封闭系统包括API生产及早期生物药物质生产中的固定系统，以及疫苗生产中常见的单次使用系统。附录1就封闭系统使用提供大量指导，但对使用这些系统时的背景环境等关键事项未予说明。本节就背景选择的关键考虑提供指导。背景环境的决策大多基于对系统完整性破坏的检测能力，假设采用稳健系统如压力衰减或氦泄漏检测，而非仅依赖人工目视检查。
Key Considerations:.Where it is not possible to detect a leak by post-use integrity testing:oThe 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.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 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.关键考虑：若无法通过使用后完整性测试检测泄漏：
o背景应为更高级别如A级，因系统无法保证封闭，必须视为存在环境污染风险。若可通过经验证的完整性测试确保完整性且该区域无操作，则系统可在低于A级的低级别环境使用，如D级（参见附录1表4，其给出A至D级示例，需考虑相应风险）。但任何完整性失败均可能导致产品报废。
Mitigation Strategies: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:.Risk to patient.Existing mitigation.Identification and implementation of new control measures to reduce the risk.Limitations of detection systems.Record of the decision of risk acceptance (or otherwise).Longer term commitments to address the Gaps:o To include the longer term CAPA(s) to be formalized in the Quality systemo Senior management acceptance of the current state and commitment to the CAPA (especially where the CAPA may require large Capital Expenditure).oA 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.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.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).缓解策略：令人担忧的是，尽管附录1自2023年8月起已对设备与设施生效，一些公司仍无法完全满足期望。若如此，每家公司需评估所识别的具体风险与缺口，然后评估患者需求与缺口及潜在患者风险。该评估将因公司、设施、设备及产品而异，本文不再展开，但一般关键考虑应包括：.患者风险.现有缓解.识别并实施新控制措施以降低风险.检测系统的局限性.风险接受决定（或其他）的记录.
弥补缺口的长期承诺：
o将长期CAPA正式纳入质量体系
o高级管理层对现状的认可及对CAPA的承诺（尤其CAPA需大量资本支出时）
o对当前工艺定期审查，确保风险水平无变化，从而风险接受决定依然有效。
注1：应注意的是，由于附录1于2022年发布且实施日期已延至2023年8月，监管对缺口接受的容忍度将随时间推移而降低；但也应注意到监管者亦不愿导致产品短缺。因此，建议每家公司制定监管沟通策略，可包括主动向监管者报告缺口并使其认可公司提出的策略。此类策略需经确认/验证支持，并在商业化实施后证明其持久与可重现。注2：应注意的是，风险缓解不应仅依赖于监测系统输出如无菌工艺模拟、环境监测及无菌测试。缓解可能由运营措施（如强化程序与培训）与技术措施（如设计，如增加屏障技术与自动化）共同构成。
Group 3: Personnel Training and ProceduresIt is a well-established truth that aseptic operators must be qualified to a level that allows a facility to perform its operations in a way that minimizes contamination risk to products and meets regulatory requirements for producing sterile products. To this end, companies operating in this space invest heavily in the recruitment and training of skilled and talented personnel to carry out aseptic operation functions. The rationale for such recruitment and training is clear: aseptic behavior is crucial in clean rooms to maintain product sterility and prevent product contamination. A key contamination risk in such an environment is human error and therefore the combination of experience, training and task execution as the criteria for operator qualification is vital to ensure product sterility and the assurance of product quality. The criteria to ensure appropriate levels of qualification are well defined, highlighting the importance of ensuring robust training programs are in place with ongoing effectiveness monitoring and periodic requalification strategies. They include:Designing Equipment and Processes to Minimize Contamination Risk: Personnel errors are a significant source of contamination in aseptic processing. Good design sets operators up for success. In addition, proper training and qualification ensure that operators understand and implement behaviors and techniques to prevent microbial contamination and to ensure product sterility and that these techniques and behaviors are systematically implemented.Regulatory Requirements: Regulatory bodies acknowledge the importance of personnel training and qualification in aseptic processing. For example, the FDA's Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing outlines the need for knowledge and skill-based training on aseptic technique, cleanroom behavior, microbiology, gowning, personal hygiene, and job-specific training.Aseptic Process Simulation & Smoke Studies: A key aspect of qualification is ensuring operators can properly simulate manufacturing operations and that this can be confirmed prior to manufacturing via APS and Smoke Studies activities.Gowning Qualification: A key aspect of qualification is ensuring operators can properly don and wear appropriate gowning and other protective equipment to provide a barrier between themselves and sterile materials.Continuous Training: Initial qualification is followed by ongoing training programs to maintain and enhance operator skills and knowledge, covering theoretical and practical aspects of GMP, microbiology, and hygiene.Monitoring: Personnel monitoring, including routine checks of gloves and gowns, is crucial for detecting contamination and identifying adverse trends.That said, operator effectiveness is not solely determined by training; it also depends on softer criteria such as mindset and behaviors. This includes the ability to make sound decisions, assess risks accurately, and exercise good judgment during production activities. Operators must actively recognize potential contamination risks and take appropriate actions to minimize them. To do so requires that they understand the "why."Despite these intensive levels of training, qualification, and monitoring, personnel issues continue to be prevalent regulatory observations. Key observational themes include:Inadequate Training: Observations highlight the lack of proper training and qualifications for personnel, leading to non-compliance with procedures.Improper Gowning and Gowning Technique: Many instances of personnel wearing inappropriate gowning for aseptic processing, compromising sterile conditions.Inadequate Supervision: Vigilant supervision of daily operations is critical to provide feedback to operators and prevent contamination hazards.Poor Monitoring Practices: Inadequate environmental and personnel monitoring techniques, impacting the reliability of microbial data collection.Failure to Follow Procedures: Observations of personnel not adhering to established procedures, resulting in contamination risks and other issues.As properly qualified operators are essential for various aseptic processing tasks, including Setting up and Operating Equipment, completing Documentation, Cleanroom Maintenance and Media Fill Procedures, non-compliance with established qualification criteria can have a significant impact. For example, contaminated product lot rejections, recalls, and the legal repercussions of non-compliance may all be outcomes of a non-robust training and qualification program.第三组：人员培训与程序众所周知，无菌操作员必须达到相应资质，使设施能够以最小化产品污染风险的方式进行操作，并满足生产无菌产品的监管要求。为此，在该领域运营的公司大力投资于招聘与培训熟练且有才华的人员以执行无菌操作职能。此类招聘与培训的理由明确：无菌行为在洁净室中至关重要，以维持产品无菌并防止污染。此类环境中的关键污染风险是人为错误，因此将经验、培训与任务执行结合作为操作员资质标准，对确保产品无菌与质量保障至关重要。确保适当资质水平的标准已明确界定，强调必须实施稳健培训计划，并持续监测有效性及定期再确认策略，包括：设备与工艺设计以最小化污染风险：人员错误是无菌工艺中重要污染源，良好设计为操作员成功奠定基础；此外，适当培训与确认确保操作员理解并实施防止微生物污染的行为与技术，确保产品无菌，并系统性地落实这些技术与行为。监管要求：监管机构认可人员培训与资质的重要性，例如FDA《无菌药品无菌工艺生产指南》指出需进行基于知识与技能的培训，涵盖无菌技术、洁净室行为、微生物学、着装、个人卫生及岗位专门培训。无菌工艺模拟与烟雾研究：确认的关键是确保操作员能正确模拟生产操作，并可通过APS与烟雾研究在活动前得到确认。更衣确认：确认的关键是确保操作员正确穿戴适当着装及其他防护设备，在自身与无菌材料间形成屏障。持续培训：初始确认后需持续开展培训项目，维持并提升操作员技能与知识，涵盖GMP、微生物学及卫生的理论与实践。监测：人员监测包括手套与更衣的常规检查，对检测污染及识别不良趋势至关重要。然而，操作员有效性不仅由培训决定，还取决于软性标准如心态与行为，包括做出正确决策、准确评估风险、在生产活动中行使良好判断的能力。操作员必须主动识别潜在污染风险并采取适当措施最小化风险，这要求他们理解“为什么”。尽管培训、确认与监测强度很高，人员问题仍是监管观察的常见问题，主要观察主题包括：培训不足：观察显示缺乏适当培训与资质导致程序不合规；着装与着装技术不当：多发现人员着装不当破坏无菌条件；监督不足：日常操作的严密监督对提供反馈及预防污染危害至关重要；监测实践差：环境与人员监测技术不足，影响微生物数据可靠性；不遵守程序：人员不遵守既定程序，导致污染风险及其他问题。由于有资质的操作员对各项无菌工艺任务（设备安装与操作、文件填写、洁净室维护及培养基灌装程序）至关重要，未遵守既定资质标准可能产生重大影响，例如产品批次污染拒收、召回及不合规的法律后果，均可能源于不完善的培训与确认计划。
So, what are some key strategies that can be employed by companies to ensure proper task execution?Quality Management System (QMS): Robust QMS Implementation that aligns with both operational needs and compliance requirements, including frequent internal audits by qualified quality assurance staff to proactively identify and address deviations before FDA inspections. In addition, the implementation and management of a robust document control system (ideally automated) to ensure proper version control, revision history, and approval processes for procedures and other relevant documents. Finally, a robust Corrective and Preventive Action (CAPA) program to investigate the root causes of deviations and implement effective measures to prevent recurrence.Reduce Human Error: Ensure SOPs are clear, detailed, and regularly updated to reflect current practices and regulations. Where possible, introduce simple, task-focused job aids and work instructions and visual aids to support SOPs. In addition to improving conformance to current standards, human error is also improved by identifying areas for continual improvement of facilities, equipment, and processes.Quality Culture: Ensure that the behaviors of everyone in the organization prioritizes the provision of safe, effective, and high quality pharmaceutical products to patients.Senior Management Presence: A strong and visible presence of senior leadership on the production floor is essential to sustaining a culture of operational excellence and quality. Leaders should regularly conduct Gemba walks to observe adherence to standards, engage directly with operators, and build trust-based relationships that encourage open dialogue about challenges and risks. This proactive engagement fosters a psychologically safe environment where operators feel empowered to speak up, enabling timely interventions and continuous improvement. Leadership's role extends beyond observation—it includes setting clear expectations, reinforcing accountability, and guiding teams back to standard when drift occurs. It's not just about operators; supervisors and managers play a critical role in shaping behaviors and ensuring consistency. Similarly, quality professionals must be embedded in the Gemba, not as auditors but as partners ready to support, coach, and resolve issues in real time. "Quality on the floor" means being physically present to understand the reality of operations, simplify processes, and co-create effective control strategies. Even the best training and technology can erode over time if not reinforced by leadership and quality engagement preventing the "slippery slope" where standards quietly shift and risks escalate.Aseptic Coaches: Designating qualified experts as aseptic coaches can provide another resource to operators to provide support on the shop floor, where these coaches can augment existing training programs and provide real-time feedback on aseptic behaviors and practices.Leverage Technology: Utilization of novel methodologies such as Virtual Reality, AI tools can play a critical role in the training and qualification of personnel. Even then, the most robust operator training programs can lose their effectiveness over time if not actively sustained. Initial qualification may ensure technical competence, but without periodic reinforcement, the deeper understanding of why certain behaviors and standards matter, especially in contamination control, can erode. The best programs ensure operators undergo intensive aseptic training that includes both classroom instruction and hands-on practice, covering topics like microbiology, cleanroom behaviors, and environmental monitoring. However, sustaining this level of awareness requires more than a one-time effort; programs must include recurring training and requalification that revisit not just the how, but the why—why glove integrity matters, why first air must be protected, and why vigilance is essential in every movement. This emphasizes the need for periodic requalification and a culture that challenges the notion of "we've always done it this way." Without this mindset shift, even well-trained operators may default to habits that compromise product quality and patient safety.Examples of training methods to support understanding of the linkage between equipment and facilities with personnel could include a combination of:oHands-On SimulationoVideo-Based InstructionoVirtual Reality (VR) ModulesoClassroom InstructionoMentorship ProgramsEquipment Design: The complexity of drug product filling equipment such as isolators, Restricted Access Barrier Systems (RABS), and closed systems demands that operators understand not only how to use the equipment but also how their actions impact product sterility and regulatory compliance. Operators and supervision should be trained in the setup, operation, and maintenance of equipment including filling lines, glove ports, and transfer systems. Understanding sterilization cycles (e.g. SIP, VHP), aseptic assembly, and intervention protocols is essential. Operators and supervisors should understand cleanroom classifications (Grade A-D) and how environmental controls support sterility assurance; therefore training must include procedures for working in classified areas without compromising airflow or surface integrity. Human factors consideration during equipment design should be executed to ensure feasibility of operators to utilize equipment as designed. Given Annex 1 emerging guidance, training should embed certain specific concepts such as isolator glove utilization given they are sanitized and not sterilized, as well as techniques for operators to avoid impacting first air at all times. To achieve this training, equipment training programs should consider.Risk-Based Scenarios: Training should include simulations of contamination events, equipment failures, emergency interventions to build decision-making skills such as mock interventions (e.g. smoke studies) to demonstrate impact on first air.Cross-Functional Collaboration: Design training that includes input from Quality Assurance, engineering, maintenance to ensure holistic understanding such as joint workshops where operators practice equipment set up with QA oversight and engineering support.Finally, operations management (executives as well as shopfloor supervisors) should visibly champion and reward all of the above, in tandem with quality assurance managers.那么，公司可采用哪些关键策略确保任务正确执行？质量管理体系（QMS）：实施与运营需求及合规要求一致的稳健QMS，包括由有资质的QA人员频繁进行内部审计，在FDA检查前主动识别并处理偏差；实施并管理稳健的文件控制系统（最好自动化），确保程序及其他相关文件的版本控制、修订历史及批准流程；建立稳健的纠正与预防措施（CAPA）计划，调查偏差根本原因并实施有效措施防止再发。减少人为错误：确保SOP清晰、详细并定期更新以反映现行实践与法规；可能情况下，引入简单、任务导向的工作辅助、作业指导书及视觉辅助以支持SOP；除提高对现行标准的符合性外，通过识别设施、设备及工艺持续改进领域亦可减少人为错误。质量文化：确保组织内每个人员的行为均以向患者提供安全、有效、高质量药品为优先。高级管理层在场：高级领导在生产现场的强有力且可见的存在对维持卓越运营与质量文化至关重要。领导应定期进行现场巡视（Gemba walk），观察标准遵守情况，直接与操作员互动，建立基于信任的关系，鼓励就挑战与风险进行开放对话。这种主动参与营造心理安全环境，使操作员敢于发声，实现及时干预与持续改进。领导作用超越观察——包括设定清晰期望、强化问责、在偏差发生时引导团队回归标准。这不仅关乎操作员；主管与经理在塑造行为与确保一致性方面亦起关键作用。同样，质量专业人员必须深入现场，不是作为审计员而是作为随时支持、指导并实时解决问题的伙伴。“现场质量”意味着亲临现场理解运营实际，简化流程，共同制定有效控制策略。即使最佳培训与技术，若无领导与质量参与的强化，也会随时间推移而削弱，防止标准悄然滑移、风险升级的“滑坡”。无菌教练：指定合格专家担任无菌教练，可为操作员提供现场支持，这些教练可强化现有培训项目并对无菌行为与实践提供实时反馈。利用技术：利用虚拟现实、AI工具等新颖方法在人员培训与资质认定中发挥关键作用。即使如此，最稳健的操作员培训项目若未持续强化，其效果也会随时间减弱。初始确认可确保技术能力，但若缺乏定期强化，对特定行为与标准为何重要（尤其在污染控制中）的深层理解会削弱。最佳项目确保操作员接受强化无菌培训，包括课堂讲授与实操练习，涵盖微生物学、洁净室行为及环境监测。然而，维持该意识水平需超越一次性努力；项目必须包括反复培训与再确认，不仅重温“如何做”，更要重温“为什么”——为什么手套完整性重要、为什么首风必须保护、为什么每一次操作都需警惕。这强调定期再确认及挑战“我们一直这样做”的文化必要性。若无此思维转变，即使训练有素的操作员也可能陷入损害产品质量与患者安全的习惯。支持理解设备设施与人员关联的培训方法示例可包括：o实操模拟o视频教学o虚拟现实（VR）模块o课堂讲授o师徒计划设备设计：灌装设备（隔离器、RABS、封闭系统）的复杂性要求操作员不仅理解如何使用设备，更要理解其行为如何影响产品无菌与合规。操作员与监督人员应接受设备（灌装线、手套口、转移系统）设置、操作与维护培训；理解灭菌循环（如SIP、VHP）、无菌组装及干预协议至关重要；应理解洁净室分级（A-D级）及环境控制如何支持无菌保证，因此培训必须包括在分级区域工作而不破坏气流或表面完整性的程序。设备设计时应考虑人因工程，确保操作员可按设计使用设备。鉴于附录1新兴指导，培训应嵌入特定概念如隔离器手套使用（已消毒非灭菌），及操作员避免始终影响首风的技术。为实现此培训，设备培训项目应考虑：基于风险的场景：培训应包括污染事件、设备故障、紧急干预的模拟，以建立决策技能，如模拟干预（烟雾研究）展示对首风的影响。跨职能协作：设计培训时应纳入QA、工程、维修的输入以确保整体理解，如联合工作坊中操作员在QA监督与工程支持下练习设备设置。最后，运营管理（高管及现场主管）应与QA经理一同倡导并奖励上述所有内容。
In conclusion, there is no one thing which can be done to address the ongoing concerns highlighted by regulators with regard to the behaviors and expertise of the human in the aseptic environment. As manufacturing technology develops, so must the tools and techniques implemented to ensure that operators are appropriately trained and qualified, contamination controls are maximized, and patient-related risks, due to product quality and/or supply interruption, are minimized.总之，针对监管者就无菌环境中人员行为与专业知识的持续担忧，没有单一措施可解决。随着制造技术发展，所实施的工具与技术也必须发展，以确保操作员获得适当培训与资质、污染控制最大化，并最小化因产品质量和/或供应中断带来的患者相关风险。
Group 4: Applicability of EU Annex 1 to Low Bioburden Biologic Drug Substance ManufacturingMaintaining adequate contamination control in pharmaceutical manufacturing is critical for product quality and patient safety. This document explains how EudraLex, Volume 4, Annex 1 and Annex 2 guidelines intersect and complement each other in managing contamination control for low bioburden processes, emphasizing a risk-based approach tailored to specific manufacturing steps.EudraLex, Volume 4, 'Annex 2, Manufacture of Biological active substances and Medicinal products for Human Use" provides general guidance and considerations for low bioburden manufacturing related to Personnel, Premises and Equipment, Animal derived materials, Documentation, Production, Starting and Raw Materials, Seed lot and Cell bank system, Operating principles and Quality control. Maintaining overall low bioburden levels is a cornerstone of product quality and patient safety. "Manufacturing and storage facilities, processes and environmental classifications should be designed to prevent the extraneous contamination of products. Prevention of contamination is more appropriate than detection and removal, although contamination is likely to become evident during processes such as fermentation and cell culture. Where processes are not closed and there is therefore exposure of the product to the immediate room environment (e.g. during additions of supplements, media, buffers, gases), control measures should be put in place, including engineering and environmental controls on the basis of QRM principles. These QRM principles should take into account the principles and guidance from the appropriate sections of Annex 1 to EudraLex, Volume 4, when selecting environmental classification cascades and associated controls".While EudraLex, Volume 4, Annex 1, "Manufacture of Sterile Medicinal Products" is associated with sterile manufacturing of medicinal products, the updated guidance (August 22, 2022) offers valuable considerations for non-sterile, low bioburden processes. The scope of the guidance indicates that the principles may be applied to other non-sterile processes where microbial controls are considered important. "The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, 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 biological intermediates, but where the control and reduction of microbial, particulate and endotoxin/pyrogen contamination is considered 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."Annex 2 refers to Annex 1 specifically when choosing environmental classification cascades and associated controls, emphasizing that Annex 1 is cited because it remains the only current EU GMP source of guidance available on this subject. The use of Quality Risk Management (QRM) principles is also encouraged, to consider not to mandate full compliance with Annex 1 for low bioburden manufacturing, but to use its guidance as a valuable reference for informed decision-making. "Although the title of Annex 1 refers to the manufacture of sterile medicinal products it is not the intention to force the manufacture of sterile product at a stage when a low bioburden is appropriate and authorized. Its use is because it is the only EU GMP source of guidance on all of the classified manufacturing areas including the lower grades D and C."The importance of strategies related to contamination control is evident across both Annexes where the level of control can often increase in detail from early to later steps in the manufacture of biological active substances to drug products. A risk-based Contamination Control Strategy (CCS) or program is recommended to be in place for each manufacturing facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks to product quality and safety.第四组：欧盟附录1在低生物负荷生物药物质生产中的适用性在药品生产中保持充分的污染控制对产品质量与患者安全至关重要。本文阐述EudraLex第四卷附录1与附录2指南如何在低生物负荷工艺的污染控制管理中交叉互补，强调针对特定制造步骤的基于风险的方法。EudraLex第四卷“附录2：生物活性物质及人用药品的生产”就人员、厂房与设备、动物源材料、文件、生产、起始与原材料、种子批与细胞库系统、操作原则及质量控制等方面为低生物负荷生产提供通用指导与考虑。保持整体低生物负荷水平是产品质量与患者安全的基石。“制造与储存设施、工艺及环境分级应设计为防止产品受到外来污染。预防污染优于检测与去除，尽管污染在发酵与细胞培养等过程中可能显现。若工艺非封闭且产品因此暴露于直接房间环境（如添加补充剂、培养基、缓冲液、气体时），应基于QRM原则采取控制措施，包括工程与环境控制。在选择环境分级阶梯及相关控制时，这些QRM原则应考虑EudraLex第四卷附录1相应章节的原则与指导。”尽管EudraLex第四卷附录1《无菌药品生产》与无菌药品生产相关，2022年8月22日的更新版为非无菌、低生物负荷工艺提供了宝贵考虑。指南范围指出，其原则可应用于其他非无菌工艺，只要微生物控制被认为重要。“附录旨在为无菌产品生产提供指导；然而，一些原则与指导，如污染控制策略、厂房设计、洁净室分级、确认、验证、监测及人员着装，可用于支持其他非无菌产品的生产，如某些液体、乳膏、软膏及低生物负荷生物中间体，只要微生物、粒子及内毒素/热原污染的控制与减少被认为重要。若制造商选择将本指南应用于非无菌产品，应清楚记录所采用的原则，并承认应证明对这些原则的符合性。”附录2在选择环境分级阶梯及相关控制时明确提及附录1，强调引用附录1是因为其是当前欧盟GMP在此方面唯一的指导来源。亦鼓励使用质量风险管理（QRM）原则，并非强制低生物负荷制造完全符合附录1，而是将其指导作为明智决策的宝贵参考。“尽管附录1标题为无菌药品生产，但并无意在适宜且获授权的低生物负荷阶段强制实施无菌生产；其被使用是因为它是欧盟GMP对包括较低级别D级与C级在内所有分级生产区域的唯一指导来源。”两份附录均强调污染控制策略的重要性，控制水平通常随生物活性物质生产步骤由早期到后期逐步细化。建议每个生产设施建立基于风险的污染控制策略（CCS）或计划，以界定所有关键控制点并评估所采用的所有控制（设计、程序、技术及组织）及监测措施在管理产品质量与安全风险方面的有效性。
The development of the CCS requires assessment by those with detailed technical and process knowledge. Properly executed contamination control strategy assessment of low bioburden manufacturing facility considering applicable Annex 1 and QRM principles should help to deliver and justify proper level of controls required for given manufacturing steps. A governance structure to provide oversight of the CCS, the effectiveness of the contamination controls, the lifecycle management, and to escalate and remediate control issues is necessary to ensure the required outcomes are achieved and maintained.Elements to be considered within a CCS for application to low bioburden manufacturing should include (but are not limited to):.Design of both the facility and processes including the associated documentationPremises and equipmentPersonnel and trainingUtilitiesRaw material controls including in-process controlsProduct containers and closuresVendor approval - such as key component suppliers, sterilization of components and single use systems (SUS), and critical service suppliersManagement of outsourced activities and availability/transfer of critical information between parties (e.g. contract sterilization services)Process risk managementProcess validationValidation of sterilization processes, as well as processes intended to reduce or minimize bioburdenPreventative maintenance - maintaining equipment, utilities, and premises, (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contaminationCleaning and disinfectionMonitoring systems - including an assessment of feasibility of the introduction of scientifically sound, alternative methods that optimize the detection of environmental contamination (e.g. Rapid Microbial Methods (RMMs).Prevention mechanisms - trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools.Continuous improvement based on information derived from the above.The CCS should also be periodically reviewed and updated to ensure that the contamination controls consistently deliver acceptable results. CCS should drive continual improvement of the manufacturing and control methods.Note: Certain sections of Annex 1 are tailored exclusively for sterile manufacturing, for example, Section 8 (including Blow Fill Seal technology), Aseptic Process Simulation, PUPSIT of the final sterilizing filter and Sterility Testing. These requirements do not need to be applied or evaluated in processes focused on low bioburden manufacturing.CCS的制定需要具备详细技术与工艺知识的人员进行评估。对低生物负荷制造设施执行充分的污染控制策略评估，并考虑适用附录1及QRM原则，应有助于提供并证明特定制造步骤所需控制水平的合理性。必须建立治理结构，以监督CCS、污染控制的有效性、生命周期管理，并升级及补救控制问题，确保所需结果得以实现与维持。适用于低生物负荷制造的CCS应考虑要素包括（但不限于）：.设施与工艺设计及相关文件.厂房与设备.人员与培训.公用系统.原材料控制包括过程控制.产品容器与密封件.供应商批准——如关键组件供应商、组件及一次性系统（SUS）的灭菌、关键服务供应商.外包活动管理及关键信息在各方间的可用性/传递（如合同灭菌服务）.工艺风险管理.工艺验证.灭菌工艺及旨在减少或最小化生物负荷的工艺验证.预防性维护——按计划与计划外维护设备、公用系统及厂房，确保不增加污染风险.清洁与消毒.监测系统——包括评估引入科学合理的替代方法以优化环境污染检测（如快速微生物方法RMM）的可行性.预防机制——趋势分析、详细调查、根本原因确定、纠正与预防措施（CAPA）及综合调查工具的需求.基于上述信息的持续改进。CCS还应定期审查与更新，以确保污染控制持续产生可接受结果，并推动制造与控制方法的持续改进。注：附录1某些章节专为无菌制造制定，例如第8节（包括吹灌封技术）、无菌工艺模拟、最终除菌过滤器的PUPSIT及无菌测试，这些要求无需在低生物负荷制造过程中应用或评估。
Regulatory landscape - Inspectors from some health agencies have been using aspects of Annex 1 as best practices for the manufacturing of low bioburden or non-sterile drug substances. The 2022 update to Annex 1 places a strong focus on contamination control and continuous improvement. Even when products are not manufactured under sterile conditions, manufacturers are still expected to proactively identify and manage microbial or contamination risks. Annex 1 serves as a practical resource for developing robust contamination control strategies; it can essentially act as a blueprint for designing cleaner, safer processes.Real-world example: A company producing monoclonal antibodies will use microbial controls to maintain the integrity of their cell culture process but may not need to maintain strict aseptic conditions during the various stages of their process, where microbial levels are typically low, to avoid downstream contamination. The company in this case chooses to use closed bioreactors and automated sampling to minimize human contact and reduce risk. In low bioburden manufacturing, one of the key concerns is the ability of microorganisms to grow in the cell culture process.Risk-based facility planning, one size doesn't fit all - Instead of strictly applying Grade A/B cleanrooms everywhere, EU Annex 1 and EU Annex 2 encourages a risk-based approach. That means designing environments to appropriately minimize likelihood of contamination and identifying effective applicable controls at each step.Real-world example: A fermentation suite might operate in a Grade D environment because the process is essentially closed, and microbial risks are low. But downstream purification, where the product is more vulnerable, might require Grade C or even Grade B conditions. In other cases where the process may not be fully closed, the control of higher grade conditions may be more applicable.Build controls into the process - Closed systems reduce exposure and can allow for lower-grade environments in manufacturing and allow filling in a lower-grade environment, without the closed system in place, further consideration of the filling environment is required to control the environment.Real-world example: A drug substance filling operation for a low bioburden product uses a sterile closed filling operation to ensure a sterile boundary and may be moved into an (ISO 8) Grade C environment. This setup not only meets Annex 1's recommendation but also improves operational efficiency, reduced risk and environmental monitoring activities. Furthermore, this improves conforming product and reduces the risk of reject batches and potential market shortages.Framing the CCS - The CCS is the playbook for minimizing the risk of contamination. It should cover everything from facility design to cleaning procedures, environmental and gowning monitoring, and how people, material and waste move through the facility into the production spaces. The playbook can help identify higher risks requiring greater controls, and lower risks with appropriate controls. This approach can help in maximizing quality, reducing risks, and controlling costs.Real-world example: A biologics manufacturer documents their CCS with detailed risk assessments, cleaning protocols, and microbial monitoring plans. They also track personnel movement and use color-coded zones to reinforce hygiene practices. Materials are transferred over lines of demarcation and go through contact times - all to reinforce contamination controls. Reducing unnecessary gowning and maintenance requirements in non-critical areas helped to reduce waste and meet sustainability goals at the facility without adding unnecessary risks.Setting bioburden limits - the EMA's Guideline on the sterilization of the medicinal product active substance, excipient and primary container, developed in parallel to Annex 1 suggests a bioburden limit of 10 CFU/100 mL prior to final filtration can be a practical target. When appropriate, higher limits can be justified if the process includes effective microbial reduction steps with process specification requirements supported by data. Equally important is the characterization of your bioburden that is present in the product.What is normal, what is an outlier, excessive, and everything in between, knowing establishing what is 'typical' (through sound quality risk management and data analysis) helps identify any shifts and are typically associated with potential root causes. This can help in the rapid identification of sources and remediation, including organisms of concern (e.g. molds, gram negative and spore forming organisms). It is important to also establish microbial control strategies associated with upstream manufacturing processes. Upstream microbial control through risk assessment and process detection methods alone are not acceptable to rely on during upstream manufacturing.Real-world example: A company running downstream purification occasionally sees bioburden levels above 10 CFU/100 mL. The company has strong procedures in place for monitoring and identification of microorganisms above the bioburden limit. A further example, considering bioreactor set up, results in bioburden contamination during bioreactor assembly which can lead to batch contamination. With strong risk management, deviation, and trending program, the company implements corrective actions to control the bioburden limit, especially organisms that could impact the quality of the product and process.Filtration - Filtration is key to controlling bioburden, but it is not just about the correct use of a 0.2 μm filter to remove microbial contamination (Ref Annex 1 clause 8.81). Demonstration, through validation, that the filter is effective under real process conditions is required. Pre-filters and bioburden filters also play an important role.Real-world example: The manufacturer validates filters using high-viscosity protein solutions. A QRM review confirmed that pre- and post-use integrity testing is required and already implemented. Proper product characterization supports filter validation and identifies potential masking effects.Embracing technology - Modern tools can make microbial monitoring faster and more reliable. Traditional methods rely on incubation and manual inspection and only provide data after many days. More companies are leveraging technology not only to reduce risk but also to come close to 'real-time' results.Real-world example: A company uses a validated ATP bioluminescence to check surface cleanliness in minutes instead of days. Another company integrates automated air samplers with their building management system for real-time alerts, while minimizing unnecessary testing costs of traditional microbiological methods.Culture, training and accountability - Contamination control is not limited to equipment and process controls, people are critical and building a culture of hygiene and accountability is essential.Real-world example: Operators at a biologics plant undergo quarterly training that includes gowning simulations and contamination case studies. Environmental monitoring results are shared openly to reinforce good habits. Ideas to reduce risks are openly discussed and integrated into facility procedures when beneficial.Final Thoughts:Low bioburden manufacturing is a balancing act between science, regulation, and practicality. By applying Annex 1 and QRM principles thoughtfully and learning from real-world examples, manufacturers can build robust, compliant processes that protect both product and patient. There is no singular control measure that gives microbial quality assurance and ensuring adequate contamination controls; the manufacturing process relies on building layers, forming a robust and integrated process with patient safety being at the focal point.Key Takeaways:Design smart, not sterile: Design and qualification of the facility and equipment should come first, including automation, integration, and isolator/closed systems where possible. Then leverage other QRM principles to manage residual risk through procedures and finally leverage detection mechanisms as confirmation that design controls are functioning correctly.Build a strong CCS: Document integrated risk and control strategies and revisit it regularly.Validate your filters and justify your limits: Data is your best defense.Invest in technology and training: They can pay off in reliability and speed.Foster a contamination prevention culture: It starts with multi-functional leadership and grows with accountability.Consider sharing best practices and solutions by publication or at conferences.监管环境——一些卫生机构的检查员已将附录1部分内容用作低生物负荷或非无菌药物物质制造的最佳实践。2022年附录1更新版强烈聚焦污染控制与持续改进。即使产品非无菌条件下生产，制造商仍被期望主动识别并管理微生物或污染风险。附录1可作为制定稳健污染控制策略的实用资源，本质上可作为设计更清洁、更安全工艺的蓝图。真实案例：一家生产单抗的公司在细胞培养过程中使用微生物控制以维持工艺完整性，但在微生物水平通常较低的各阶段可能无需维持严格无菌条件以避免下游污染。该公司选择使用封闭生物反应器与自动采样以最小化人员接触并降低风险。在低生物负荷制造中，关键担忧之一是微生物在细胞培养工艺中生长的能力。基于风险的设施规划——并非一刀切：欧盟附录1与附录2鼓励基于风险的方法，而非处处严格应用A/B级洁净室。这意味着设计环境以合理降低污染可能性，并在每一步确定有效适用控制。真实案例：某发酵车间可在D级环境运行，因工艺基本封闭且微生物风险低；但下游纯化因产品更易受污染，可能需C级甚至B级。在其他工艺非完全封闭情况下，更高级别控制可能更适用。将控制构建入工艺——封闭系统减少暴露，可允许在较低级别环境制造及灌装，在无封闭系统情况下需进一步考虑灌装环境以控制环境。真实案例：某低生物负荷药物物质的灌装操作采用无菌封闭灌装以确保无菌边界，可移至（ISO 8）C级环境。该设置不仅满足附录1建议，还提高运营效率、降低风险及环境监测活动，此外提高符合性产品并降低批次拒收及潜在市场短缺风险。构建CCS框架——CCS是最大限度降低污染风险的剧本，应涵盖从设施设计到清洁程序、环境与着装监测，及人员、物料、废物在设施内如何进入生产区域。剧本可帮助识别需更高级别控制的较高风险及可适用适当控制的较低风险，此方法有助于最大化质量、降低风险并控制成本。真实案例：某生物药制造商以详细风险评估、清洁协议及微生物监测计划记录其CCS，还追踪人员流动并使用颜色编码区域强化卫生实践。物料穿越分界线并经历接触时间——所有均为强化污染控制。减少非关键区域不必要的着装与维护要求帮助减少浪费并实现设施可持续性目标，而未增加不必要风险。设定生物负荷限值——EMA同步于附录1制定的《药品活性物质、辅料及初级包装灭菌指南》建议最终过滤前生物负荷限值为10 CFU/100 mL可作为实用目标。若工艺包含有效微生物减少步骤且有数据支持的工艺规范要求，可适当放宽限值。同样重要的是对产品内生物负荷的特性分析。明确何为正常、异常、超标及介于两者之间，通过可靠质量风险管理与数据分析建立“典型”水平，有助于识别任何偏移及其潜在根本原因，可快速识别来源与补救，包括关注微生物（如霉菌、革兰阴性菌及芽孢形成菌）。还应建立与上游制造工艺相关的微生物控制策略，仅依赖风险评估与过程检测方法对上游制造是不够的。真实案例：某公司进行下游纯化时偶尔出现生物负荷水平高于10 CFU/100 mL，公司已制定强有力程序监测并识别超出生物负荷限值的微生物。另一示例，生物反应器组装过程中的生物负荷污染可导致批次污染，公司通过强有力的风险管理、偏差及趋势程序实施纠正措施以控制生物负荷限值，尤其是可能影响产品与工艺质量的微生物。过滤——过滤是控制生物负荷的关键，但不仅是正确使用0.2 μm过滤器去除微生物污染（参见附录1第8.81条），还需通过验证证明过滤器在实际工艺条件下的有效性，预过滤器及生物负荷过滤器亦起重要作用。真实案例：制造商使用高黏度蛋白溶液验证过滤器，QRM审查确认需进行使用前后完整性测试并已实施，恰当的产品表征支持过滤器验证并识别潜在掩盖效应。拥抱技术——现代工具可使微生物监测更快更可靠，传统方法依赖培养与人工检查，数日后才提供数据。越来越多公司利用技术不仅降低风险，还实现接近“实时”的结果。真实案例：某公司使用验证的ATP生物发光法在数分钟内检测表面清洁度，而非数日；另一公司将自动空气采样器与楼宇管理系统集成实现实时警报，同时降低传统微生物方法的不必要检测成本。文化、培训与问责——污染控制不限于设备与工艺控制，人员至关重要，建立卫生与问责文化不可或缺。真实案例：某生物药厂操作员每季度接受培训，包括着装模拟与污染案例研究；环境监测结果公开分享以强化良好习惯；降低风险的想法公开讨论并有益时纳入设施程序。最终思考：低生物负荷制造是科学、监管与实用性之间的平衡。通过 thoughtful 地应用附录1与QRM原则并借鉴真实案例，制造商可建立稳健、合规的工艺，保护产品与患者。微生物质量保证没有单一控制措施，确保充分污染控制需构建多层次，形成稳健、集成并以患者安全为核心的工艺。关键要点：智能设计，而非强制无菌：设施与设备的设计与确认应优先，包括尽可能采用自动化、集成及隔离器/封闭系统，然后利用其他QRM原则通过程序管理剩余风险，最后利用检测机制确认设计控制运行正确。构建强有力CCS：记录集成风险与控制策略并定期回顾。验证过滤器并证明限值合理性：数据是你最好的防御。投资技术与培训：它们在可靠性与速度上可带来回报。培育污染预防文化：始于多功能领导层，并在问责中成长。考虑通过发表或会议分享最佳实践与解决方案。
