Optimizing Sampling of Airborne Particle CountsWhy do we care about Particle Counts?我们为什么关注尘埃粒子计数？•Particles as “contamination” negatively affect a process or product颗粒作为”污染物”,对工艺流程或产品会起负作用•Change chemical composition 改变化学成分•Affect stability 影响稳定性•Affect purity 影响纯度•Affect safety 影响安全•Affect reliability 影响可靠性•Contamination affects the “yield” of a process污染将影响整个工艺流程的“投资收益”•Increases cost to produce 增加生产成本•Increases cost to maintain or service增加维护或维修成本•Increases “cost of ownership” [COO] 增加投资成本•Decreases ROI of capital equipment purchase降低了重要设备的投资回报率Why do we care about Particle Counts?我们为什么关注尘埃粒子计数？制药、、生物工程Pharmaceutical, Biotechnology 制药–Particles in injection could cause occlusion of bloodvessels 注射液中的颗粒会导致血管堵塞•Red Blood cells are about 5 µm 红细胞约5 µm•Capillary (5 to 10 µm) 毛细血管(5 to 10 µm)•Large veins (10 to 50 µm) 静脉(10 to 50 µm)–Viables in injection can trigger infection活性颗粒能导致传染病–Possibility of reaction to foreign substances(RES/allergic reaction)对外来物质产生反应（过敏反应）•Medical Devices 医疗设备–Poor adhesion of medicated coating in stentcreates embolisms会影响药物的疗效•Medical and photographic films 医学影像–Contamination prevents complete imagerecovery污染会影像医学影像What price patient safety?什么价值的药品对病人才安全？Injections and infusions for people with suppressed immunological systems免疫系统不正常病人的注射剂和输液Bypassing all ‘barriers’ to infection with injection straight into bloodstream.注射液直接输入病人血液Why monitor for particles?为什么要监测颗粒？•Greatest concern is for viable microorganisms主要是为了关注微生物的繁殖–Technology is not available today to measure viable counts in real time 当前的科技决定了我们不能对微生物进行实时计数–Total particle counts used as a surrogate (non-viable)不可繁殖的空气尘埃粒子可作为参考100,000 billion bacteria on andin the human body一个人身体上有100万亿个细菌General Air Monitoring 空气监测•Viable counts 活性计数–Can be cultured 能被繁殖–Will grow into “colonies”将成长为“群体”•requires optimum growthmedium需要最适宜的生长介质•requires sufficient incubation需要充分的培养–Enumerated as 计算单位：•CFU = Colony-Forming Units•VU = Viable UnitsGeneral Air Monitoring 空气监测•Non-viable counts 无活性计数–Sometimes referred to as “total count”往往被归纳为总的颗粒数–Includes all types of airborne material包含各种类型空气中的物质，如：•Solid particles 固体颗粒•Fibers 纤维•Microorganisms 微生物•Skin flakes 皮肤屑•Droplets 水滴How an airborne particle counter works …一台空气粒子计数仪是如何工作的？Detector 光感应器Particle 颗粒Laser Diode 激光二极管Mirror 光学反射镜Light Trap 光阻器Principle: Light Scattering 原理：光散射Relative sizes of particulate matterBacteria 细菌Table salt 食盐Pencil cells 铅笔芯Relative Sizes of Particulate MatterSkin Flake 皮肤屑Fiber纤维Alumino-silicate withTalc 滑石粉K and Ti 含钾和钛的铝硅酸盐Particle Counting Applications 颗粒计数应用Two types of activities performed with anairborne particle counter: 颗粒计数器的两种应用颗粒计数器的两种应用：：Classification focuses primarily on the environment环境洁净度等级分级；Monitoring Environmentfocuses on process, people and the environment 生产过程、人员活动及环境监控；PeopleProcessPeople as a Contamination Source人被视为污染源Shed 5 to 10 million skin cells each day每天释放出500万-1000万个细胞2000 to 5000 microorganisms/cm 2 on skin2000-5000个微生物/cmFilter efficiency of clothing or garment varies greatly衣服的过滤性能变化Particle Counting Applications 颗粒计数应用WhatProcess Monitoring 过程监控•Minimum number of sample points defined by QA •Determine readiness of room to carry out designated task 选定房间履行指定任务•Performed whenever relevant activity occurs –daily work 任何情况下都要履行-日常工作QA 决定最少取样点–Area of cleanroom or clean zone 洁净区面积–Activity 动态–Risk to product 产品风险•Frequency and volume of sample points defined by QA QA 决定采样频率及采样量–Frequent enough to show control 频次足够保证控制所需–Frequent enough to manage financial risk of product contamination 频次足够控制产品污染带来的风险Not controlled by regulation…but by risk!取决于风险，而不是规则Three Common Methods of Sampling三种常见的的取样方法•Manually with a handheld or portable particle counter用手持式或便携式颗粒计数仪人工巡检•Sequentially with a manifold/scanner and particle counter 用多路切换装置和颗粒计数仪顺序监测•Continuously with portable or remote particle counters •用便携式或远程传感器进行连续监测MET ONE 6000 & 7000 Seriesfor production monitoring Grade A & B areasMET ONE 3400 Series Cleanroom classification Environmental monitoring Short-term online samplingMET ONE HHPCHandheld particle counter Used for troubleshootingManual Monitoring 人工巡检Manual Monitoring 人工巡检DisadvantageAdvantage 优点缺点Simple 简单 Varying intervals 时间间隔不同Flexible 灵活 Inconsistent in probe position采样点位置不固定Low initial investment 初期投资少 Intrusive to work process 干扰生产过程Traditional method of sampling 传统取样方法 Production worker often notinformed of high counts操作人员常常不报告风险High labor cost 工作量大Usually not continuous 不是连续监测Sequential Monitoring 顺序监测Consistently samples fixed positionsSamples every position one or more times per hourCan operate 24 hours per daySequential Monitoring 顺序监测Advantage 优点Disadvantage 缺点Frequent sampling 取样频繁 Samples at fixed locations 固定位置取样 Consistent sampling position 稳定的取样位置 Can miss events 可能错失风险Statistical data for historical purposes有历史数据可统计Particle loss in tubing 管道颗粒损失Consistency of data allows SPC analysis 稳定的数据支持SPC分析 Requires auxiliary pump(s) to maintain constant flow through all tubes 需要备用泵保证动力Can be part of FMS 可以作为连续监测的一部分 Single counter to calibrate 校验方便Tubing Transport Loss 管道传输损失Continuous Monitoring 连续监测Able to detect fast, intermittent eventsUses dedicated counter at each sample pointAvoids effects of long tubing runsContinuous Monitoring 连续监测Advantage 优点Disadvantage 缺点Consistent sample points 固定取样点 Requires lots of initial planning需要大量的的初期计划All points are monitored simultaneously 所有取样点同时监测 Larger initial investment 初期投资多Build statistical database 可建立数据库 Calibration for each counter需要为每个传感器校验Relate particle events to process activity 发现异常可立即处理 Generates large amounts of data to process and analyze会产生大量的数据需要处理及分析Quick operator feedback 及时的操作反馈Comparison: Frequency of SamplingGuidances for Monitoring 监测指南•FDA:•Guidance for Industry•Sterile Drug Products Produced by Aseptic Processing•EU Guide to Good Manufacturing Practice: •Annex 1•Manufacture of Sterile Medicinal ProductsContains Nonbinding RecommendationsAir in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of appropriate particle quality when it has a per-cubic-meter particle count of no more than 3520 in a size range of 0.5 µm and larger when counted at representative locations normally not more than 1 foot away from the FDA’s Guidance for Industry:Sterile Drug Products Produced by Aseptic Processing“Nonviable particle monitoring with a remote countingsystem is generally less invasive than the use of portable counting units and provides the most comprehensive data.”使用颗粒监控系统监测颗粒比使用便携式颗粒计数器少干扰流work site, within the airflow, and during filling/closing operations. This level of air cleanliness is also known as Class 100 (ISO 5).We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product, containers, and closures. The particle counting probe should be placed in anorientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters.From Section IV. Buildings and Facilities, Sub-part A, Critical Area –Class 100 (ISO 5)程,且提供最全面的数据EU Annex I: “continuous measurement”EU附录I：连续监测2003: “A continuous measurementsystem should be used for monitoringthe concentration of particles in thegrade A zone, and is recommended forthe surrounding grade B areas.”在A区监测颗粒浓度应当使用一个连续测量的系统,而且建议B区也是这样做.2009: “The Grade A zone should be monitored atsuch a frequency and with suitable sample size thatall interventions, transient events and any systemdeterioration would be captured and alarms triggeredif alert limits are exceeded.”2009：“A 级区域的监测频率和采样量应能检出对环境的所有干扰所有干扰、、瞬时的事件和任何系统的损坏瞬时的事件和任何系统的损坏，，并在超过警戒EU Annex I: “continuous measurement”限度时启动报警限度时启动报警。