Harnessing HACCP for Aseptic Filling

使用HACCP进行无菌分装

 

Strengthening Contamination Control Strategy under EU GMP Annex 1

EU GMP 附录 1 下的污染控制策略

 

HACCP has proven especially valuable during drug product development for determining critical process parameters (CPPs) that influence critical quality attributes (CQAs). In this article, however, the focus will be on the usability of HACCP in managing microbial and particulate contamination risks specific to aseptic filling, and how it complements a facility-wide CCS.

在药品开发过程中，HACCP 在确定影响关键质量属性（CQAs）的关键工艺参数（CPPs）方面已被证明具有特别重要的价值。然而，本文的重点将放在 HACCP 在管理无菌分装特有的微生物和微粒污染风险方面的实用性，以及它如何补充整个设施的污染控制策略（CCS）。

 

HACCP Principles in Aseptic Filling Context

无菌分装环境中的 HACCP 原则

 

When we apply the HACCP principles to the aseptic filling process, we can systematically identify contamination risks and establish robust controls. Table 1 shows a contextual breakdown of each HACCP principle as it applies to aseptic operations:

将 HACCP 原则应用于无菌分装过程时，我们能够系统性地识别污染风险并建立完善的控制措施。

 

Table 1 Application of HACCP Principles to Aseptic Filling Operations

表 1 按场景详细列出了每项 HACCP 原则在无菌操作中的具体应用：

 

Sl.No. 序号	HACCP Principle 危害分析与关键控制点（HACCP）原则	Application to    Aseptic Filling 在无菌罐装的应用
1	Hazard Analysis 危害分析	Identifying microbial and   particulate contamination risks across man and material movement, equipment   setup, operator interventions and process execution 识别人流物流、设备设置、操作人员干预和工艺执行过程中的微生物和颗粒污染风险
2	Identify CCPs 确定关键控制点	Pinpointing stages like   filtration, sterile assembly, Grade A airflow maintenance, and media fills 确定过滤、无菌组装、A 级气流维持和培养基分装等阶段
3	Critical Limits 关键限值	Defining acceptable thresholds   (e.g., Air flow/change rates, no microbial growth in Grade A, other viable   and NVPC limits, PUPSIT integrity pass, air pressure limits etc.) 定义可接受的阈值（例如，气流 / 换气率、A 级区域无微生物生长、其他存活和非存活粒子计数限值、人员与产品表面接触完整性通过、气压限值等）
4	Monitoring Procedures 监测程序	Real-time particle counts, EM,   aseptic behavioral audits, APS outcomes 实时颗粒计数、环境监测、无菌操作行为审核、空气粒子监测结果
5	Corrective Actions 纠正措施	Predefined actions for deviations   (e.g., line stop, root cause analysis, impact assessment) 针对偏差的预定义措施（例如，生产线停止、根本原因分析、影响评估）
6	Verification Activities 验证活动	Trending of EM, integrity test   logs, media fill success rates, intervention logs and trending etc. 环境监测趋势、完整性测试日志、培养基分装成功率、干预日志及趋势等
7	Documentation 文件记录	Batch records, deviation logs, and   CCS dashboards 批记录、偏差日志和洁净室CCS仪表板

 

Hazard Analysis for Aseptic Filling

无菌分装的危害分析

 

Table 2 summarizes key microbial, endotoxin and particulate risks identified via HACCP analysis in aseptic filling, aligned with CCS for proactive control.

表 2 总结了通过 HACCP 分析在无菌分装中识别出的关键微生物、内毒素和微粒风险，这些风险与污染控制策略（CCS）相契合，旨在实现前瞻性控制。

 

Table 2 HACCP-Based Hazard Analysis of Aseptic Filling Process Steps

表 2 ：基于危害分析关键控制点（HACCP）的无菌分装工艺步骤危害分析

 

Process Step 流程步骤	Potential    Contamination Risk 潜在污染风险	Risk Type 风险类型	Hazard Source 危害来源
Personnel Gowning 人员着装	Shedding of skin flora, incorrect   gowning technique 皮肤菌群脱落、着装技术不正确	Microbial 微生物	Operators and samplers 操作人员和采样人员
Entry to Filling Room 进入分装间	Transfer of non-sterile components 转移非无菌组件	Microbial/Particulate 微生物 / 颗粒	Materials, equipment 物料、设备
Equipment Setup 设备设置	Use of unclean or misassembled tools,   connectors 使用不干净或组装错误的工具	Microbial 微生物	Cleaning/disinfection gaps 清洁 / 消毒环节缺陷
Glove Port (RABS/Isolator) 手套口（限制进入屏障系统 / 隔离器）	Undetected glove pinholes or tears   before or after use 使用前后手套针孔或撕裂未被检测到	Microbial 微生物	Glove degradation, testing omission 手套老化、检测遗漏
Aseptic Interventions 无菌操作	Glove integrity breach, poor   aseptic technique 无菌完整性破坏、无菌技术差	Microbial 微生物	Operator/samplers 操作人员 / 采样人员
Grade A Airflow A 级气流	Air turbulence, loss of   unidirectional flow, HEPA leak 气流紊乱、高效空气过滤器功能丧失、泄漏	Microbial/Particulate 微生物 / 颗粒	HEPA system failure 高效空气过滤系统故障
Sterile Filtration 无菌过滤	Filter integrity failure 过滤器完整性失效	Microbial 微生物	Damaged or unverified filters 损坏或未经验证的过滤器
Filling Needle 分装针头	Improper assembly or contact contamination 组装不当或接触污染	Microbial 微生物	Human error, vibration 人为失误、振动
Stoppering 压塞	Particle generation from component   movement 组件移动产生颗粒污染	Particulate 颗粒	Rubber particles, static   electricity 橡胶颗粒、静电
Vial Closures 西林瓶封口	Particulate contamination during   feeding 封口过程中的颗粒污染	Particulate 颗粒	Component transport 组件运输
Primary Packaging Material Feeding 内包材进料	Introduction of contaminated or   non-sterile packaging materials 引入受污染或未灭菌的包装材料	Microbial/Particulate 微生物 / 颗粒	Improper sterilization, handling,   or transfer 灭菌、处理或转移不当
Container/Vial Washing &   Depyrogen Ation 容器 / 西林瓶清洗与去热原	Introduction of particulates or   endotoxins pre-filling 分装前存在颗粒、微生物或内毒素	Particulate/Microbial/Endotoxin 颗粒 / 微生物 / 内毒素	Faulty washer/depyro tunnel,   improper loading 清洗机 / 去热原隧道故障、装载不当
Hold Time 保持时间	Product degradation or microbial   ingress due to extended hold 因温度 / 时间偏差导致产品降解或微生物滋生	Microbial 微生物	Temperature/time deviation 温度 / 时间偏差
Environmental Conditions 环境条件	Excursions in viable or non-viable   particle levels 活菌或非活菌颗粒水平波动	Microbial/Particulate 微生物 / 颗粒	Poor cleaning/disinfection, HVAC   lapse 清洁 / 消毒不足、暖通空调系统故障
Utilities (WFI, Steam, Compressed   Air) 公用设施（注射用水、压缩空气、蒸汽）	Introduction of biofilm,   particulates or endotoxins through critical utilities 通过关键公用设施边界的生物膜、颗粒或内毒素	Microbial/Endotoxin/Particulate 微生物 / 内毒素 / 颗粒	Inadequate system maintenance and   monitoring 基础设施系统维护和监测不当
Waste Removal 废弃物处理	Breach of sterile boundaries or   backflow of contaminated air 无菌边界破坏或气流回流	Microbial/Particulate 微生物 / 颗粒	Improper waste handling procedures 废弃物处理程序不当

 

The list of critical contamination risks and control points may vary depending on the type of filling machine (e.g., RABS vs. isolator) and the specific operation design. A tailored HACCP analysis should always be conducted based on process-specific configurations and risk profiles.

关键污染风险和控制点的清单可能会因分装机类型（例如，限制进入屏障系统与隔离器）以及具体操作设计的不同而有所差异。应始终根据特定工艺的配置和风险概况，开展量身定制的HACCP分析。

 

Critical Control Points Supporting CCS in Aseptic Filling

无菌分装中支持污染控制策略（CCS）的关键控制点

 

A well-structured HACCP analysis identifies critical control points (CCPs) aligned with key contamination vectors in the CCS—such as personnel, air, materials, equipment, utilities and surfaces. Table 3 below maps CCPs to these vectors, associated barriers and control measures, supporting effective CCS implementation and lifecycle management.

结构完善的HACCP分析所识别出的关键控制点（CCPs），与污染控制策略中人员、空气、物料、设备、公用设施和表面等关键污染传播途径相契合。下表3将关键控制点与这些传播途径、相关屏障及控制措施相对应，为污染控制策略的有效实施和生命周期管理提供支持。

 

Table 3 Key CCPs and their role in preventing contamination during aseptic filling

表3：关键洁净控制程序及其在无菌分装过程中防止污染的作用

 

CCP 关键洁净工艺参数	Contamination Vector 污染途径	CCS Barrier 洁净室控制措施（CCS）屏障	Example Controls 示例控制措施
CCP1: Personnel Entry   & Gowning CCP1：人员进入与更衣	Human shedding (skin flora) 人体皮屑（皮肤菌群）	Procedural 程序控制	Gowning qualification, aseptic behavior training,   behavior audits, glove testing 更衣资质认证、无菌操作行为培训、行为审核、手套测试
CCP2: Entry of   Materials & Equipment CCP2：物料与设备进入	Non-sterile items 非无菌物品	Technical/Procedural 技术 / 程序控制	Transfer disinfection SOPs, material airlocks,   validated sanitization methods 转移消毒标准操作程序（SOP）、物料气锁、经验证的消毒方法
CCP3: Equipment Setup   & Assembly CCP3：设备设置与组装	Dirty/misaligned tools 脏污 / 未灭菌工具	Procedural 程序控制	Validated cleaning/disinfection, aseptic assembly   protocols, equipment logs 经验证的组装消毒程序、无菌组装规程、设备清洁
CCP4: RABS/Isolator   Glove Integrity CCP4：隔离器 / 限制进入屏障系统（RABS）手套完整性	Glove breaches 手套破损	Technical 技术控制	Glove leak tests (pre/post-use), routine integrity checks,   glove change procedures 手套泄漏测试（前后、常规）、手套完整性检查、手套更换程序
CCP5: Aseptic   Interventions CCP5:无菌干预	Direct contamination 直接污染	Procedural 程序控制	Aseptic Process Simulation (APS), intervention   training, video review of behavior 无菌工艺模拟（APS）干预培训、视频回顾行为
CCP6: Grade A Airflow   Integrity CCP6:A 级气流完整性	Airborne particulates/microbes 空气中的颗粒 / 微生物	Technical 技术控制	Smoke studies, pressure differentials, unidirectional   airflow verification, alarms 烟雾测试、压差、气流方向验证、气流异常警报
CCP7: Sterile Filtration   & PUPSIT CCP7:无菌过滤与除菌	Filter failure 过滤器故障	Technical 技术控制	Pre-/post-use integrity testing, validated   sterilizing-grade filters 过滤器前后完整性测试、使用经灭菌的过滤器
CCP8: Filling Needle   Handling CCP8:分装针头处理	Touch contamination 接触污染	Procedural 程序控制	Assembly SOPs, visual checks, pre-use cleaning,   vibration isolation 组装标准操作程序、目视检查、预使用清洁、振动验证
CCP9: Component   Transfer & Feeding CCP9:组件转移与送料	Contaminated closures/stoppers 受污染的瓶盖 / 塞子	Technical 技术控制	Sterilization validation, sterile packaging, environmental monitoring during transfer 灭菌隔离、无菌包装、转移过程中的环境监测
CCP10: Environmental   Monitoring (EM) CCP10：环境监测（EM）	Air/surface contamination 空气 / 表面污染	Monitoring 监测控制	Real-time viable and non-viable particle monitoring,   swab/contact plates 实时监测活性和非活性颗粒、擦拭接触平板
CCP11: Primary   Packaging Material Feeding CCP11：内包装材料送料	Contaminated vials, syringes 受污染的小瓶、注射器	Technical 技术控制	Sterile transfer systems, supplier qualification,   material traceability 无菌转移系统、供应商资质认证、物料追溯
CCP12: Vial Washing   & Depyrogenation CCP12：洗瓶与去热原	Endotoxin or particulate risk 内毒素或颗粒风险	Technical 技术控制	Tunnel performance verification, endotoxin challenge   studies, temp/time monitoring 隧道性能验证、内毒素挑战测试、温度时间监测
CCP13: Hold Time Control CCP13：保持时间控制	Microbial ingress 微生物侵入	Procedural 程序控制	Time/temp limits, hold time justification, deviation   tracking 时间 / 温度限制、保持时间验证、偏差跟踪
CCP14: Utility Supply   (WFI, steam, gases) CCP14：公用设施供应（注射用水、蒸汽、气体）	Biofilm/particulate contamination 生物膜 / 颗粒污染	Technical 技术控制	Sterile filters, utility monitoring, sanitization and   maintenance procedures 无菌过滤器、设施监测程序和维护
CCP15: Cleaning &   Disinfection of Surfaces CCP15：表面清洁与消毒	Surface microbial risk 表面微生物风险	Procedural 程序控制	Disinfection rotation plans, residue checks, visual   inspections 消毒轮换计划、残留检查、目视检查
CCP16: Waste Removal   & Segregation CCP16：废弃物移除	Backflow, exposure 回流、暴露	Procedural/Technical 程序控制/技术控制	Closed waste systems, one-way transfer protocols,   pressure zoning 封闭废弃物系统、预真空转移规程、废弃物分区

 

HACCP-Driven Monitoring and Verification Plan

由 HACCP 驱动的监控与验证计划

 

Each CCP identified in the aseptic filling process must be actively monitored using defined CCS-aligned performance indicators. These metrics are linked to the pharmaceutical quality system (PQS) and form the basis for ongoing process verification, deviation response and lifecycle contamination control.

在无菌分装过程中识别出的每个关键控制点（CCP）都必须采用与污染控制策略（CCS）相符的既定性能指标进行主动监控。这些指标与药品质量体系（PQS）相关联，构成了持续过程验证、偏差响应和全生命周期污染控制的基础。

 

Below is an outline of monitoring and verification activities per contamination vector and CCP group:

以下是按污染传播途径和关键控制点组划分的监控与验证活动概述：

 

Personnel Controls: Gowning qualification records, glove integrity test logs, aseptic behavior observation reports and video monitoring of interventions.

人员控制：更衣资质记录、手套完整性测试日志、无菌操作行为观察报告以及干预措施的视频监控。

 

Air & Environmental Controls: Continuous viable and non-viable particle monitoring in Grade A/B areas, HVAC pressure differential alarms, airflow velocity checks and smoke visualization studies.

空气与环境控制：对A级/B级区域进行持续的活微生物和非活微粒监测、HVAC 压差警报、气流速度检查以及烟雾可视化研究。

 

Filtration Systems: Documentation of pre- and post-use filter integrity testing (PUPSIT), pressure drop trend analysis and validated sterilizing-grade filter certification.

过滤系统：使用前灭菌后过滤器完整性测试（PUPSIT）文档、压降趋势分析以及已验证的除菌级过滤器认证。

 

Aseptic Interventions & Isolator/RABS Use: Aseptic Process Simulation (APS) data, intervention frequency and type logs, and glove port integrity testing before/after operations.

灭菌干预及隔离器/限制进入屏障系统（RABS）的使用：无菌工艺模拟（APS）数据、干预频率和类型日志，以及操作前后的手套端口完整性测试。

 

Equipment and Surface Sanitation: Swab/contact plate environmental monitoring (EM), visual inspection checklists, ATP-based rapid cleanliness assays and residue tests following disinfection.

设备与表面卫生：擦拭/接触碟环境监测（EM）、目视检查清单、基于ATP的快速洁净度检测以及消毒后的残留物测试。

 

Material Transfer and Packaging Control: Component traceability logs, validated decontamination procedures, packaging sterilization certificates and post-transfer EM verification.

物料转移与包装控制：组件可追溯性日志、经过验证的去污程序、包装灭菌证书以及转移后的环境监测验证。

 

Utility Systems (WFI, Steam, Gases): Utility microbiological monitoring, Total Organic Carbon (TOC) and conductivity testing, endotoxin levels (LAL tests) and maintenance/sanitization logs.

公用设施系统（注射用水、蒸汽、气体）：公用设施微生物监测、总有机碳（TOC）和电导率测试、内毒素水平（LAL测试）以及维护/消毒日志。

 

Waste Management Controls: Closed waste container validation, pressure cascade mapping for waste zones and waste flow process audits.

废弃物管理控制：封闭式废弃物容器验证、废弃物区域的压力梯度测绘以及废弃物流程审计。

 

Corrective and Preventive Actions

纠正与预防措施

 

An effective HACCP-based contamination control system requires a strong CAPA program. In aseptic filling, corrective and preventive actions (CAPA) should be triggered by deviations at identified CCPs—such as microbial recovery in Grade A, filtration failure or glove breach—to ensure timely corrective actions.

一个有效的基于HACCP的污染控制系统需要强有力的纠正与预防措施（CAPA）计划。在无菌分装中，当已识别的关键控制点出现偏差（如A级区域检出微生物、过滤失败或手套破损）时，应启动纠正与预防措施，以确保及时采取纠正行动。

 

Corrective actions address the immediate issue and typically include:

纠正措施用于解决即时问题，通常包括：

 

Placing impacted batches on hold to prevent release.

对受影响的批次实施暂存，防止其放行。

 

Stopping the aseptic line to prevent further risk.

停止无菌生产线，以避免进一步的风险。

 

Conducting root cause investigations using structured tools such as fishbone analysis, 5 Whys, or fault tree analysis.

使用鱼骨图分析、5Why 分析或故障树分析等结构化工具进行根本原因调查。

 

Performing impact assessment to evaluate potential effects on product quality and patient safety.

开展影响评估，以评估对产品质量和患者安全的潜在影响。

 

Retesting, requalification, or reprocessing (as applicable) of the affected material, equipment, or environment.

对受影响的物料、设备或环境进行重新测试、再确认或再加工（如适用）。

 

Preventive actions focus on addressing systemic vulnerabilities to avoid recurrence and may involve:

预防措施侧重于解决系统性漏洞以避免问题再次发生，可能包括：

 

Updating standard operations and procedures (SOPs) and aseptic techniques based on lessons learned.

根据经验教训更新标准操作程序（SOPs）和无菌技术。

 

Re-training personnel involved in the deviation or across the relevant functional teams.

对涉及偏差的人员或相关职能团队进行再培训。

 

Enhancing cleaning and disinfection procedures, environmental monitoring frequency or intervention limits.

加强清洁和消毒程序、提高环境监测频率或调整干预限制。

 

Modifying equipment or facility design (e.g., improved airflow verification, HEPA filter upgrades).

修改设备或设施设计（如改进气流流形验证、升级 HEPA过滤器）。

 

Revising risk assessments (e.g., HACCP and/or others risk assessment tools) and updating the CCS documentation accordingly.

修订风险评估（如HACCP和/或其他风险评估工具）并相应更新污染控制策略（CCS）文件。

 

To ensure CAPA effectiveness, follow-up verification must be performed. This includes:

为确保纠正与预防措施的有效性，必须进行后续验证。这包括：

 

Tracking implementation timelines and responsibilities.

跟踪实施时间表和责任分工。

 

Monitoring trends in deviations, interventions or contamination rates to assess sustained improvement.

监控偏差、干预或污染率的趋势，以评估持续改进情况。

 

Conducting CAPA effectiveness checks to verify the long-term success of the corrective and preventive actions.

进行纠正与预防措施有效性检查，以验证纠正和预防行动的长期成效。

 

Linking CAPA outcomes to HACCP and CCS indicators drives continuous improvement, ensures compliance with EU GMP Annex 1 and ICH Q10, and strengthens sterility assurance in aseptic filling.

将纠正与预防措施的结果与HACCP和污染控制策略（CCS）指标相结合，可推动持续改进，确保符合GMP要求，并加强无菌分装中的无菌保证。

 

Contribution to Contamination Control Strategy

对污染控制策略（CCS）的贡献

 

The implementation of HACCP within the aseptic filling process could serve as a cornerstone of a well-structured CCS, offering a consistent and proactive methodology for risk identification, control, and verification. Key contributions include:

在无菌分装过程中实施HACCP可作为结构完善的污染控制策略（CCS）的基石，为风险识别、控制和验证提供一致且前瞻性的方法。其主要贡献包括：

 

Comprehensive Risk Mapping: Clearly defines contamination vectors (e.g., human, air, surface, material, utilities) and links them to specific operational hazards and controls.

全面的风险图谱：清晰界定污染传播途径（如人员、空气、表面、物料、公用设施），并将其与特定的操作危害和控制措施相关联。

 

Systematic CCP Identification: Enables the designation of measurable and auditable control points aligned with CCS lifecycle expectations, per Public Health Services & Solutions and Annex 1 guidance.

系统性的关键控制点（CCP）识别：根据公共卫生服务与解决方案以及GMP的指导，确定与污染控制策略（CCS）生命周期预期相符的可测量且可审计的控制点。

 

Support for Zoning and EM Strategy: Justifies environmental monitoring frequencies, locations and alert/action limits based on identified contamination risks and their criticality.

支持分区和环境监测（EM）策略：根据已识别的污染风险及其重要性，确定环境监测的频率、位置以及警戒 / 行动限度。

 

Integration with Quality Risk Management and Pharmacy Quality Solutions: Facilitates structured deviation handling, root cause investigation and trending, allowing data-driven decision-making and continual improvement.

与质量风险管理和药品质量解决方案相整合：促进结构化的偏差处理、根本原因调查和趋势分析，支持基于数据的决策制定和持续改进。

 

Cross-Functional Engagement: Promotes shared ownership of contamination control between quality assurance, operations, engineering, microbiology and validation teams using a common risk language.

跨职能参与：通过通用的风险语言，促进质量保证、运营、工程、微生物学和验证团队对污染控制的共同责任。

 

By aligning HACCP outputs with CCS design and performance verification, the facility ensures a holistic contamination control lifecycle from design qualification through routine operation and periodic review.

通过使 HACCP 的输出与污染控制策略（CCS）的设计和性能验证保持一致，设施能够确保从设计确认到日常运营和定期审查的全面污染控制生命周期。

 

Conclusion

小结

 

HACCP serves as a powerful, structured risk management tool for mitigating microbial and particulate contamination in aseptic filling operations. It provides a framework that not only meets regulatory expectations under Annex 1 but also strengthens alignment with a facility’s CCS.

HACCP 是一个强大的、结构化的风险管理工具，可用于降低无菌分装操作中的微生物和微粒污染风险。它提供的框架不仅满足GMP的监管要求，还加强了与设施污染控制策略（CCS）的一致性。

 

That said, HACCP is not a simple or quick fix. It is a time-consuming, detail-intensive, and often tedious process that requires deep process knowledge, cross-functional collaboration, and structured brainstorming. From hazard identification to CCP verification, the effectiveness of HACCP depends entirely on how thoughtfully it is designed and implemented. A rushed or superficial exercise may yield little value, whereas a well-executed HACCP plan can profoundly enhance contamination control.

话虽如此，HACCP 并非一个简单或快速的解决方案。它是一个耗时、注重细节且往往繁琐的过程，需要深厚的工艺知识、跨职能协作和结构化的头脑风暴。从危害识别到关键控制点（CCP）验证，HACCP 的有效性完全取决于其设计和实施的周密程度。仓促或表面化的实施可能收效甚微，而一个执行良好的 HACCP 计划则能显著加强污染控制。

 

When applied diligently and integrated with the PQS, HACCP enables facilities to:

当认真实施并与药品质量体系（PQS）整合时，HACCP 使设施能够：

 

Deliver consistent product quality

提供一致的产品质量

 

Ensure patient safety

确保患者安全

 

Maintain regulatory compliance

维持合规性

 

Moreover, by reducing batch failures, contamination-related recalls and regulatory risks, HACCP contributes to business resilience and long-term cost savings. In essence, a better HACCP process results in better outcomes—for the patient and the organization alike.

此外，通过减少批次失败、与污染相关的召回和监管风险，HACCP 有助于提高业务韧性并实现长期成本节约。本质上，更完善的 HACCP 过程会带来更好的结果 —— 无论是对患者还是对公司而言。

 

来源：GMP办公室

关键词： 无菌生产 风险评估