Group 3: Personnel Training and Procedures 第三组：人员培训与程序
It 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.
无菌操作人员必须具备足够的资质，使设施能够以最大限度降低产品污染风险并满足无菌产品生产法规要求的方式进行操作，这是公认的事实。
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.
为此，该领域的公司在招聘和培训具备技能和才干的人员以执行无菌操作职能方面投入巨资。
The rationale for such recruitment and training is clear: aseptic behavior is crucial in clean rooms to maintain product sterility and prevent product contamination.
此类招聘和培训的理由很明确：在洁净室中，无菌行为对于维持产品无菌状态和防止产品污染至关重要。
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.
在这种环境中，一个关键的污染风险是人为错误，因此将经验、培训和任务执行情况结合作为操作人员资质认定的标准，对于确保产品无菌性和产品质量保证至关重要。
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:
确保适当资质水平的标准已明确界定，强调必须制定强有力的培训计划，并实施持续的有效性监测和定期再资质认定策略。这些标准包括：
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.
设计设备和工艺以最大限度降低污染风险：人员错误是无菌工艺中一个重要的污染源。良好的设计有助于操作人员成功完成任务。此外，适当的培训和资质认定确保操作人员理解并实施防止微生物污染和确保产品无菌性的行为和技术，并确保这些技术和行为得到系统执行。
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.
法规要求：监管机构认可人员培训和资质认定在无菌工艺中的重要性。例如，FDA 的《无菌工艺生产的无菌药品行业指南》明确要求提供基于知识和技能的培训，包括无菌技术、洁净室行为、微生物学、更衣、个人卫生以及岗位专项培训。
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.
无菌工艺模拟与烟雾研究：资质认定的一个关键方面是确保操作人员能够正确模拟生产操作，并在生产前通过 APS 和烟雾研究活动予以确认。
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.
更衣资质认定：资质认定的一个关键方面是确保操作人员能够正确穿戴适当的更衣和其他防护装备，以在自身与无菌物料之间形成屏障。
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.
持续培训：在初始资质认定之后，需要实施持续培训计划，以维持和提升操作人员的技能和知识，包括 GMP、微生物学和卫生的理论与实践方面。
Monitoring: Personnel monitoring, including routine checks of gloves and gowns, is crucial for detecting contamination and identifying adverse trends.
监测：人员监测（包括手套和更衣的常规检查）对于发现污染和识别不良趋势至关重要。
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”.
尽管如此，操作人员的有效性不仅取决于培训，还取决于心态和行为等较 “软性” 的标准。这包括在生产活动中做出合理决策、准确评估风险和运用良好判断力的能力。操作人员必须主动识别潜在污染风险并采取适当行动将其降至最低。这需要他们理解 “为什么” 要这样做。
Despite these intensive levels of training, qualification, and monitoring, personnel issues continue to be prevalent regulatory observations. Key observational themes include:
尽管培训、资质认定和监测的力度很大，但人员问题仍然是监管机构常见的检查发现项。主要发现主题包括：
Inadequate Training: Observations highlight the lack of proper training and qualifications for personnel, leading to non-compliance with procedures.
培训不足：检查发现强调人员缺乏适当的培训和资质，导致不遵守程序。
Improper Gowning and Gowning Technique: Many instances of personnel wearing inappropriate gowning for aseptic processing, compromising sterile conditions.
不正确的更衣和更衣技术：许多案例中，人员在无菌工艺中穿戴不适当的更衣，从而损害无菌条件。
Inadequate Supervision: Vigilant supervision of daily operations is critical to provide feedback to operators and prevent contamination hazards.
监督不足：对日常操作进行严格监督对于向操作人员提供反馈并防止污染危害至关重要。
Poor Monitoring Practices: Inadequate environmental and personnel monitoring techniques, impacting the reliability of microbial data collection.
监测做法不佳：环境和人员监测技术不足，影响微生物数据收集的可靠性。
Failure to Follow Procedures: Observations of personnel not adhering to established procedures, resulting in contamination risks and other issues.
未遵守程序：检查发现人员未遵守既定程序，导致污染风险和其他问题。
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.
由于具备适当资质的操作人员对于各种无菌工艺任务（包括设备安装和操作、文件记录、洁净室维护和培养基模拟灌装程序）至关重要，因此不遵守既定资质标准可能会产生重大影响。例如，受污染产品批次被拒收、召回以及不合规带来的法律后果，都可能是培训和资质认定计划不健全的结果。
So, what are some key strategies that can be employed by companies to ensure proper task execution?
那么，公司可以采用哪些关键策略来确保任务的正确执行？
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.
质量管理体系（QMS）：实施强有力的质量管理体系，使其既符合运营需求又满足合规要求，包括由合格的质量保证人员进行频繁的内部审计，以便在 FDA 检查前主动识别并解决偏差。此外，实施和管理强有力的文件控制系统（最好是自动化的），以确保程序和其他相关文件的版本控制、修订历史和批准流程的正确性。最后，建立强有力的纠正和预防措施（CAPA）程序，以调查偏差的根本原因并实施有效措施防止再次发生。
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.
减少人为错误：确保 SOP 清晰、详细，并定期更新以反映当前做法和法规。在可能的情况下，引入简单、以任务为中心的工作辅助工具、作业指导书和视觉辅助工具来支持 SOP。除了提高对当前标准的符合性外，通过识别设施、设备和工艺的持续改进领域，也可以减少人为错误。
Quality Culture: Ensure that the behaviors of everyone in the organization prioritizes the provision of safe, effective, and high quality pharmaceutical products to patients.
质量文化：确保组织中每个人的行为都优先考虑为患者提供安全、有效和高质量的药品。
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.
高级管理层参与：高级领导层在生产现场的强大且可见的参与对于维持卓越运营和质量文化至关重要。领导者应定期进行现场走动管理，观察标准的遵守情况，直接与操作人员互动，并建立基于信任的关系，鼓励就挑战和风险进行公开对话。这种积极参与营造了心理安全的环境，使操作人员敢于发声，从而能够及时采取干预措施并持续改进。领导层的作用不仅限于观察，还包括设定明确的期望、强化问责制，并在出现偏差时指导团队回到标准。这不仅关乎操作人员；主管和经理在塑造行为和确保一致性方面也发挥着关键作用。同样，质量专业人员必须深入现场，不是作为审计员，而是作为合作伙伴 —— 随时准备提供支持、指导并实时解决问题。“现场质量” 意味着亲自到场了解运营的实际情况，简化流程，并共同制定有效的控制策略。如果没有领导层和质量部门的持续强化，即使是最好的培训和技术也会随着时间的推移而失效 —— 从而防止标准悄然变化、风险不断升级的 “滑坡效应”。
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.
无菌教练：指定合格的专家作为无菌教练，可以为操作人员提供另一种现场支持资源，他们可以补充现有的培训计划，并就无菌行为和做法提供实时反馈。
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.
利用技术：利用虚拟现实、人工智能工具等新方法可以在人员培训和资质认定中发挥关键作用。即便如此，如果不积极维持，最强大的操作人员培训计划也会随着时间的推移而失去效力。初始资质认定可以确保技术能力，但如果没有定期强化，对某些行为和标准（尤其是在污染控制方面）重要性的深入理解可能会减弱。
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.
最佳计划确保操作人员接受强化的无菌培训，包括课堂教学和实践操作，涵盖微生物学、洁净室行为和环境监测等主题。
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:
然而，维持这种意识水平不仅仅是一次性的努力。计划必须包括反复培训和再资质认定，不仅回顾 “怎么做”，还要回顾 “为什么”—— 为什么手套完整性很重要，为什么必须保护第一股气流，以及为什么每一个动作都必须保持警惕。这强调了定期再资质认定的必要性，并需要一种敢于挑战 “我们一直都是这样做的” 这种观念的文化。如果没有这种心态转变，即使是受过良好培训的操作人员也可能会默认采取损害产品质量和患者安全的习惯做法。支持理解设备、设施与人员之间联系的培训方法示例可能包括：
Hands-On Simulation 动手模拟
Video-Based Instruction 视频教学
Virtual Reality (VR) Modules 虚拟现实（VR）模块
Classroom Instruction 课堂教学
Mentorship Programs 导师计划
Equipment 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.
设备设计：隔离器、限制进入屏障系统（RABS）和密闭系统等药品灌装设备的复杂性要求操作人员不仅要了解如何使用设备，还要了解他们的行为如何影响产品无菌性和法规合规性。操作人员和管理人员应接受设备安装、操作和维护方面的培训，包括灌装线、手套口和转移系统。理解灭菌周期（如 SIP、VHP）、无菌组装和干预方案至关重要。操作人员和主管应理解洁净室分类（A-D 级）以及环境控制如何支持无菌保证，因此培训必须包括在不损害气流或表面完整性的情况下在分类区域工作的程序。在设备设计过程中应考虑人为因素，以确保操作人员能够按设计使用设备。根据 Annex 1 的新指南，培训应融入某些特定概念，例如隔离器手套的使用（因为它们是消毒而非灭菌的），以及操作人员在任何时候避免影响第一股气流的技术。
To achieve this training, equipment training programs should consider:
为实现此类培训，设备培训计划应考虑：
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.
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，以培养决策技能，例如通过模拟干预（如烟雾研究）展示对第一股气流的影响。
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.
跨职能协作：设计包含质量保证、工程和维护部门意见的培训，以确保全面理解，例如联合研讨会，让操作人员在 QA 监督和工程支持下练习设备安装。
Finally, operations management (executives as well as shopfloor supervisors) should visibly champion and reward all of the above, in tandem with quality assurance managers.
最后，运营管理层（高管以及车间主管）应与质量保证经理一起，明显地支持并奖励上述所有措施。
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.
总之，对于监管机构强调的关于无菌环境中人员行为和专业知识的持续关注，没有任何单一措施可以完全解决。
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.
随着制造技术的发展，也必须实施相应的工具和技术，以确保操作人员得到适当的培训和资质认定，最大限度地加强污染控制，并将因产品质量和 / 或供应中断而导致的患者相关风险降至最低。
Group 4: Applicability of EU Annex 1 to Low Bioburden Biologic Drug Substance Manufacturing 第四组：欧盟附录 1 对低生物负荷生物药原液生产的适用性
Maintaining 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.
在制药生产中保持充分的污染控制对于产品质量和患者安全至关重要。本文档解释了《欧盟药品管理规范》（EudraLex）第 4 卷附录 1 和附录 2 指南在低生物负荷工艺的污染控制管理中如何相互交叉和补充，强调针对特定生产步骤采取基于风险的方法。
EudraLex, Volume 4, “Annex 2, Manufacture of Biological active substances and Medicinal product 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.
《欧盟药品管理规范》第 4 卷 “附录 2 人用生物活性物质和药品的生产” 提供了低生物负荷生产的一般指导和考虑因素，涉及人员、厂房和设备、动物源性材料、文件记录、生产、起始和原材料、种子批和细胞库系统、操作原则和质量控制。保持整体低生物负荷水平是产品质量和患者安全的基石。“生产和储存设施、工艺和环境分类的设计应能防止产品受到外来污染。防止污染比检测和去除污染更合适，尽管在发酵和细胞培养等过程中污染可能会显现出来。
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”.
如果工艺不是密闭的，产品因此暴露于室内直接环境中（例如在添加补料、培养基、缓冲液、气体期间），则应实施控制措施，包括基于质量风险管理（QRM）原则的工程和环境控制。在选择环境分类等级和相关控制措施时，这些 QRM 原则应考虑《欧盟药品管理规范》第 4 卷附录 1 相关章节的原则和指导。”
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.
虽然《欧盟药品管理规范》第 4 卷附录 1 “无菌药品的生产” 与药品的无菌生产相关，但更新后的指南（2022 年 8 月 22 日）为非无菌、低生物负荷工艺提供了有价值的考虑因素。
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.“
该指南的范围表明，这些原则可应用于其他微生物控制被认为重要的非无菌工艺。本附录的目的是为无菌产品的生产提供指导。
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.
然而，某些原则和指导，例如污染控制策略、厂房设计、洁净室分类、资质认定、验证、监测和人员更衣，可用于支持其他非无菌产品的生产，例如某些液体、乳膏、软膏和低生物负荷生物中间体，但这些产品对微生物、微粒和内毒素 / 热原污染的控制和降低被认为是重要的。
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.
”如果制造商选择将本指南应用于非无菌产品，则应明确记录已应用哪些原则，并确认应证明对这些原则的符合性。”
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.
附录 2 在选择环境分类等级和相关控制措施时特别引用了附录 1，强调引用附录 1 是因为它是目前欧盟 GMP 中唯一可获得的相关指导文件。同时也鼓励使用质量风险管理（QRM）原则，不是强制要求低生物负荷生产完全遵守附录 1，而是将其指导作为知情决策的宝贵参考。
“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.”
尽管附录 1 的标题涉及无菌药品的生产，但并不意味着在低生物负荷是适当且经授权的阶段强制要求无菌生产。使用它是因为它是欧盟 GMP 中唯一涵盖所有分类生产区域（包括较低等级 D 和 C）的指导文件。”
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.
污染控制相关策略的重要性在两个附录中都很明显，在从生物活性物质到药品的生产过程中，控制水平通常会从早期步骤到后期步骤变得更加详细。建议每个生产设施都制定基于风险的污染控制策略（CCS）或计划，以确定所有关键控制点，并评估用于管理产品质量和安全风险的所有控制措施（设计、程序、技术和组织）以及监测措施的有效性。
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.
CCS 的制定需要由具备详细技术和工艺知识的人员进行评估。结合适用的附录 1 和 QRM 原则，对低生物负荷生产设施进行适当的污染控制策略评估，有助于确定并论证特定生产步骤所需的适当控制水平。需要建立治理结构，对 CCS、污染控制的有效性、生命周期管理进行监督，并对控制问题进行升级和补救，以确保实现并维持所需的结果。
Elements to be considered within a CCS for application to low bioburden manufacturing should include (but are not limited to):
适用于低生物负荷生产的 CCS 应考虑的要素包括（但不限于）：
Design of both the facility and processes including the associated documentation
厂房和工艺的设计，包括相关文件
Premises and equipment 厂房和设备
Personnel and training 人员和培训
Utilities 公用工程
Raw material controls - including in-process controls 原材料控制 —包括过程控制
Product containers and closures 产品容器和密封件
Vendor approval - such as key component suppliers, sterilization of components and single use systems (SUS), and critical service suppliers
供应商批准 —— 例如关键组件供应商、组件和一次性系统（SUS）的灭菌，以及关键服务供应商
Management of outsourced activities and availability/transfer of critical information between parties (e.g., contract sterilization services)
外包活动的管理以及各方之间关键信息的可用性 / 转移（例如合同灭菌服务）
Process risk management 工艺风险管理
Process validation 工艺验证
Validation of sterilization processes, as well as processes intended to reduce or minimize bioburden
灭菌工艺的验证，以及旨在降低或最小化生物负荷的工艺验证
Preventative maintenance - maintaining equipment, utilities, and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination
预防性维护 —— 将设备、公用工程和厂房维持在确保不会增加污染风险的标准（包括计划内和计划外维护）
Cleaning and disinfection 清洁和消毒
Monitoring 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)).
监测系统 —— 包括评估引入科学合理的替代方法的可行性，以优化环境污染的检测（例如快速微生物方法 RMM）。
Prevention mechanisms - trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools.
预防机制 —— 趋势分析、详细调查、根本原因确定、纠正和预防措施（CAPA）以及对综合调查工具的需求。
Continuous improvement based on information derived from the above.
基于上述信息的持续改进
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.
CCS 还应定期审查和更新，以确保污染控制持续产生可接受的结果。CCS 应推动生产和控制方法的持续改进。
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.
注：附录 1 的某些章节专门针对无菌生产，例如第 8 节（包括吹灌封技术）、无菌工艺模拟、最终灭菌过滤器的 PUPSIT 以及无菌测试。这些要求不需要在专注于低生物负荷生产的工艺中应用或评估。
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.
监管环境 —— 一些卫生机构的检查员一直将附录 1 的某些方面作为低生物负荷或非无菌原料药生产的最佳实践。2022 年附录 1 的更新高度关注污染控制和持续改进。即使产品不是在无菌条件下生产，制造商仍需主动识别和管理微生物或污染风险。附录 1 是制定强有力污染控制策略的实用资源；它实质上可以作为设计更清洁、更安全工艺的蓝图。
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.
现实案例：一家生产单克隆抗体的公司将使用微生物控制来维持其细胞培养工艺的完整性，但在其工艺的各个阶段（微生物水平通常较低）可能不需要维持严格的无菌条件，以避免下游污染。在这种情况下，该公司选择使用密闭生物反应器和自动取样，以最大限度减少人员接触并降低风险。在低生物负荷生产中，关键问题之一是微生物在细胞培养过程中生长的能力。
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.
基于风险的设施规划，并非 “一刀切”—— 欧盟附录 1 和附录 2 鼓励基于风险的方法，而不是在所有地方严格应用 A/B 级洁净室。这意味着设计环境以适当降低污染可能性，并在每个步骤确定有效的适用控制措施。
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.
现实案例：发酵车间可能在 D 级环境中运行，因为该工艺本质上是密闭的，微生物风险较低。但下游纯化过程中产品更脆弱，可能需要 C 级甚至 B 级条件。在工艺可能未完全密闭的其他情况下，控制更高等级的条件可能更适用。
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 in required to control the environment.
将控制措施融入工艺 —— 密闭系统减少暴露，可允许在较低等级环境中进行生产和灌装；如果没有密闭系统，则需要进一步考虑灌装环境以控制环境。
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.
现实案例：低生物负荷产品的原液灌装操作使用无菌密闭灌装操作以确保无菌边界，并可在（ISO 8）C 级环境中进行。这种设置不仅符合附录 1 的建议，还提高了运营效率，降低了风险和环境监测活动。此外，这提高了合格品率，降低了批次拒收和潜在市场短缺的风险。
Framing the CCS - The CCS is the playbook for minimizing the risk of contamination.
制定 CCS——CCS 是最大限度降低污染风险的行动指南。
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.
它应涵盖从厂房设计到清洁程序、环境和更衣监测，以及人员、物料和废物如何通过设施进入生产区域的所有内容。该指南有助于识别需要更强控制的高风险，以及具有适当控制的低风险。这种方法有助于最大限度提高质量、降低风险并控制成本。
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.
现实案例：一家生物制品制造商通过详细的风险评估、清洁方案和微生物监测计划记录其 CCS。他们还跟踪人员流动，并使用颜色编码区域来强化卫生做法。物料通过分界线转移并经过接触时间 —— 所有这些都是为了强化污染控制。减少非关键区域不必要的更衣和维护要求有助于减少浪费并实现设施的可持续性目标，同时不会增加不必要的风险。
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.
设定生物负荷限度 ——EMA 与附录 1 并行制定的《药品活性物质、辅料和初级容器灭菌指南》建议，最终过滤前的生物负荷限度为 10 CFU/100 mL 是一个实用目标。在适当情况下，如果工艺包括有效的微生物降低步骤，并具有数据支持的工艺规范要求，则可以论证更高的限度。同样重要的是对产品中存在的生物负荷进行表征。什么是正常的，什么是异常值、过高值，以及介于两者之间的情况，了解并确定 “典型” 情况（通过合理的质量风险管理和数据分析）有助于识别任何变化，而这些变化通常与潜在根本原因相关。
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.
这有助于快速识别来源并进行补救，包括关注的微生物（例如霉菌、革兰氏阴性菌和产芽孢菌）。建立与上游制造工艺相关的微生物控制策略也很重要。仅通过风险评估和工艺检测方法进行上游微生物控制在下游生产中是不可接受的。
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.
现实案例：一家进行下游纯化的公司偶尔会看到生物负荷水平超过 10 CFU/100 mL。该公司制定了强有力的程序来监测和识别超过生物负荷限度的微生物。另一个例子是，在生物反应器设置过程中，生物反应器组装期间发生生物负荷污染，可能导致批次污染。通过强大的风险管理、偏差和趋势分析程序，该公司实施纠正措施以控制生物负荷限度，特别是可能影响产品和工艺质量的微生物。
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.
过滤 —过滤是控制生物负荷的关键，但不仅仅是正确使用 0.2 μm 过滤器去除微生物污染（参考附录 1 第 8.81 条）。需要通过验证证明过滤器在实际工艺条件下有效。预过滤器和生物负荷过滤器也发挥重要作用。
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.
现实案例：制造商使用高粘度蛋白质溶液验证过滤器。QRM 审查确认需要并已实施使用前和使用后的完整性测试。适当的产品表征支持过滤器验证，并识别潜在的掩蔽效应。
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 later.More companies are leveraging technology not only to reduce risk but also to come close to “real-time” results.
拥抱技术 —— 现代工具可以使微生物监测更快、更可靠。传统方法依赖培养和人工检查，并且只能在许多天后提供数据。越来越多的公司正在利用技术，不仅为了降低风险，还为了获得接近 “实时” 的结果。
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.
现实案例：一家公司使用经过验证的 ATP 生物发光技术在几分钟内检查表面清洁度，而不是几天。另一家公司将自动空气采样器与其楼宇管理系统集成，以实现实时警报，同时最大限度减少传统微生物方法的不必要测试成本。
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.
文化、培训和问责制 —— 污染控制不仅限于设备和工艺控制，人员至关重要，建立卫生和问责文化必不可少。
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.
现实案例：一家生物制品工厂的操作人员每季度接受培训，包括更衣模拟和污染案例研究。环境监测结果被公开分享，以强化良好习惯。降低风险的想法被公开讨论，并在有益时纳入设施程序。
Final Thoughts: 最终思考：
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.
低生物负荷生产是科学、法规和实用性之间的平衡行为。通过深思熟虑地应用附录 1 和 QRM 原则，并从现实案例中学习，制造商可以建立强大、合规的工艺，保护产品和患者。没有任何单一的控制措施可以提供微生物质量保证并确保充分的污染控制；生产过程依赖于建立多层防护，形成以患者安全为中心的强大且集成的工艺。
