1、Without air we cannot breathe,so as long as we require personnel to operate our processes we need an air supply.没有空气我们无法呼吸，所以只要我们需要人员操作我们的工艺，我们就需要空气供应。Even in clean rural areas air is contaminated with about 108 particles of 0.5m and greater per m3,many of these will be microorganisms depending on t
2、he nature of the area and the season of the year so air is a contamination problem即使在干净的农村地区，空气也被大约即使在干净的农村地区，空气也被大约108颗每平方米颗每平方米0.5微微米甚至更大的颗粒污染，其中许多是微生物，这取决于该地米甚至更大的颗粒污染，其中许多是微生物，这取决于该地区的性质和一年中的季节区的性质和一年中的季节-因此空气是一个污染问题因此空气是一个污染问题However in the pharmaceutical industry air flow is the answer to many
3、 contamination problems然而，在制药工业中，空气然而，在制药工业中，空气流动是许多污染问题的答案流动是许多污染问题的答案So we are going to discuss this dual relationship of the pharmaceutical industry with air因此，我们将讨论制药业与空气的这种双重关系Microorganisms do not grow and increase in numbers in air微生物不会在空气中生长和增加Most microorganisms find it hard to survive in a
4、ir because the environment is so desiccating and because of the exposure to UV radiation.大多数微生物发现它难以在空气中存活，因为环境是如此干燥并且因为暴露于紫外线辐射Survival often depends on being carried on“rafts”of physical matter,such as skin flakes.生存通常取决于携带物理物质的“筏”，例如皮屑。Typical airborne microorganisms are spores of the genus Bacil
5、lus and related genera,and Micrococcus or Staphylococcus.典型的空气传播微生物是芽孢杆菌属和相关属的孢子，以及微球菌或葡萄球菌。There are four principle applying to control of air-borne microorganisms in clean rooms.控制洁净室中的空气传播微生物有四个原则。Filtration过滤过滤Dilution稀释稀释Directional Air Flow定向气流定向气流Air Movement空气运动I will address each one separa
6、telyFiltration removes microorganisms:过滤去除微生物：过滤去除微生物：HEPA(high efficiency particulate air)filters remove up to about 99.997%of particles from airHEPA（高效微粒空气）过滤器可（高效微粒空气）过滤器可从空气中去除高达约从空气中去除高达约99.997的的颗粒颗粒HEPA Filters are protected from blockage by pre-filters which remove up to about 90%of particles
7、 from airHEPA过滤器通过预过滤器防止堵过滤器通过预过滤器防止堵塞，预过滤器可从空气中去除多塞，预过滤器可从空气中去除多达约达约90的颗粒的颗粒Therefore if air contains about 3 x 108 particles per m3,and you have one pre-filter and one HEPA Filter:因此，如果空气中每立方米包含因此，如果空气中每立方米包含约约3 x 108个颗粒，并且您有一个个颗粒，并且您有一个预过滤器和一个预过滤器和一个HEPA过滤器：过滤器：Pre-filter leaves about 3 x 107 per
8、 m3 as a challenge to the HEPA filter预过滤器每立方米约预过滤器每立方米约3 x 107，作，作为对为对HEPA过滤器的挑战过滤器的挑战The terminal HEPA Filter leaves about 103 per m3.终端终端HEPA过滤器每立方米留下约过滤器每立方米留下约103个。个。In EU GMP this is within the limits for Grade A and B“at rest”(Annex 1.4)在欧盟GMP中，这是A级和B级“静态”的限制（附件1.4）In fact most pharmaceutical
9、air handling system recirculate up to 80%of the air supplied to clean rooms.实际上，大多数制药空气处理系统再循环高达80的空气供应给洁净室。Therefore the initial challenge to the HEPA Filters is probably only about 106 particles per m3.因此，对HEPA过滤器的最初挑战可能是每立方米仅约106个颗粒。So we probably get no more than 3 x 102 particles per m3 supplie
10、d to pharmaceutical clean rooms因此，我们可能每立方米提供不超过3 x 102颗粒供应给制药洁净室This is even further within the limits of Grade A and Grade B“at rest”in EU GMP(Annex 1.4)这进一步在欧盟GMP中的A级和B级“静态”范围内（附件1.4）Air must be passed through HEPA filters空气必须通过HEPA过滤器These will have a certified“efficiency rating”which applies to
11、the medium这些将具有适用于介质的经认证的“效率等级”BPL uses H14 filtersBPL使用H14过滤器On installation and at interval it is necessary to test the integrity of the whole assembly of filter and ductwork在安装和间隔时，有必要测试整个过滤器和管道系统组件的完整性Structural Slab结构板（建筑）HEPA Filter高效过滤器Inlet duct入口管道False ceiling天花板Integrity test probe完整性测试探针
12、Gaskets垫圈Seals密封件Typical HEPA filter installation典型的HEPA过滤器安装Because potential leakage is not confined to the filter media there is a requirement to perform an In Situ Filter INTEGRITY Test由于潜在泄漏不仅限于过滤介质，因此需要执行原位过滤器完整性测试This is commonly called the DOP test after Di-octyl phthallate one of the first
13、substances used as an aerosol challenge for this test这通常被称为DOP测试之后的二辛基邻苯二甲酸酯作为该测试的气溶胶挑战的第一种物质之一The standard is that the tolerable leakage of an aerosol challenge shall be not more than 0.01%-this is NOT the reciprocal of the efficiency标准是气溶胶挑战的可容忍泄漏不应超过0.01-这不是效率的倒数Particles build up in enclosed spa
14、ces where there is no ventilation that is why in the past there was so much tuberculosis in winter in the slums of northern Europe颗粒在没有通风的封闭空间中积聚颗粒在没有通风的封闭空间中积聚-这就是为什么过去在欧这就是为什么过去在欧洲北部贫民窟冬季有如此多的结核病洲北部贫民窟冬季有如此多的结核病Ventilation is the process by which any particles generated in clean rooms(in addition
15、to those which pass the filters)are carried away for any remaining in the room to be diluted with new“clean”air通风是将洁净室中产生的任何颗粒（除了通过过滤器的颗通风是将洁净室中产生的任何颗粒（除了通过过滤器的颗粒）带走的过程，以便用新的粒）带走的过程，以便用新的“清洁清洁”空气稀释房间内剩空气稀释房间内剩余的任何颗粒。余的任何颗粒。The minimum ventilation rate expected in pharmaceutical clean rooms is 20 air
16、 changes per hour(the modern requirement up to twice as many as this,and up to 75 for a changing room)the air in a clean room is replaced at least every 3 minutes.An office might have 2-3 air-changes per hour.制药洁净室预计的最低通风率为每小时20次换气（现代要求高达此数量的两倍，更换房间高达75次）-洁净室内的空气至少每隔3分钟更换一次。办公室每小时可能有2-3次换气。Ventilati
17、on is measured as air changes per hour通气量以每小时换气量来衡量This is not a“real”measure,it is a calculated measure based on air velocity measurement这不是“真实”测量，它是基于空气速度测量的计算测量The air velocity is measured close to its point of entry into the clean-room using an anemometer or a balometer使用风速计或压力计测量空气速度接近其进入洁净室的点T
18、he velocity is measured as units of length divided by units of time(ft per minute,metres per hour etc)速度以长度单位除以时间单位（英尺/分钟，米/小时等）来衡量The velocity is multiplied by the area of the entry ducts measured in units of area(square feet or m2 etc)giving a figure which now in units of volume divided by units o
19、f time is an expression of how much air is supplied per unit time速度乘以以面积（平方英尺或平方英尺等）为单位测量的进入管道的面积，给出一个数字，现在以体积单位除以时间单位表示每单位时间供应多少空气If this figure is then divided by the volume of the cleanroom measured in(say)m3 or ft3 you get the number of air changes per hour如果这个数字除以洁净室的体积（例如）m3或ft3，你会得到每小时的换气次数Cl
20、eanrooms have a clean-up time.洁净室有一个“清理”时间This the time taken for a room to return to a set level of particles in the air after it has been used for an activity.This is required to take place within 20 minutes of the room last being used.这是房间用于活动后返回空气中颗粒水平所需的时间。这需要在最后一次使用房间的20分钟内进行This is an optiona
21、l test for cleanrooms,although one often undertaken for new facilities(in ISO 14644).这是洁净室的“可选”测试，尽管通常用于新设施（ISO 14644）。First of all imagine you have a room full of“clean”air首先想象你有一个充满首先想象你有一个充满“干净干净”空气的房间空气的房间Then imagine that you have free access to this room from a surrounding area containing norm
22、al environmental air然后想象您可以从包含正常环境空气的周边区域自由进入然后想象您可以从包含正常环境空气的周边区域自由进入这个房间这个房间What happens next?接下来发生什么接下来发生什么？We make sure that the“dirty”air does not enter the clean room by ensuring that there is always a flow of air in an outward direction我们确保“脏”空气不会进入洁净室，确保始终有向外流动的空气流The way in which the“dirty”
23、air is prevented from entering the clean room is by ensuring a very high rate of air supply to the clean room thus keeping it at a higher pressure than its surroundings防止防止“脏脏”空气进入洁净室的方式是确保洁净室的空气供应速度非常空气进入洁净室的方式是确保洁净室的空气供应速度非常快，从而使其保持在比周围环境更高的压力下快，从而使其保持在比周围环境更高的压力下If there is contact with“outside”a
24、ir,any mixing of the two types of air takes place outside the clean room because the direction of air flow is from the clean to the dirty area如果与如果与“外部外部”空气接触，则两种类型空气的混合发生在洁净室外，因为空气接触，则两种类型空气的混合发生在洁净室外，因为气流的方向是从清洁区域到脏区域气流的方向是从清洁区域到脏区域This directional air flow is measured and monitored through pressu
25、re differentials air will always move from an area where it is at a high pressure to one where there is a low pressure its a Law of Physics通过压差测量和监测这种定向气流通过压差测量和监测这种定向气流-空气总是从高压区域移动到低压空气总是从高压区域移动到低压区域区域-这是一个物理定律这是一个物理定律Particles and microorganisms cannot“swim upstream”against a directional air flow颗
26、粒和微生物不能对着定向气流颗粒和微生物不能对着定向气流“游向上游游向上游”Air locks are placed over the access and exit doors of clean rooms to make sure that the high pressure within the clean room is not lost too easily 空气锁放置在洁净室的入口和出口门上方，以确保洁净室内的空气锁放置在洁净室的入口和出口门上方，以确保洁净室内的高压不会太容易丢失高压不会太容易丢失EU GMP Annex 1 states that air locks:欧盟欧盟GM
27、P附件附件1规定空气锁：规定空气锁：Both air-lock doors should not open simultaneously(Annex 1.52)两个气闸门不应同时打开（附件两个气闸门不应同时打开（附件1.52）An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time(Annex 1.52)应操作联锁系统或视觉和应操作联锁系统或视觉和/或声音警告系统，以防止一次打
28、开多个门（附件或声音警告系统，以防止一次打开多个门（附件1.52）Changing rooms should be designed as airlocks(Annex 1.51)更衣室应设计为气闸（附件更衣室应设计为气闸（附件1.51）PPPThis is called a pressure differential“cascade”这被称为压差这被称为压差“级联级联”Outward air flows from areas which require serious levels of protection from contamination to less critical areas
29、 helps to maintain the integrity of the areas of the cleaner environments从需要严重保护的从需要严重保护的区域向外流动的空区域向外流动的空气不受污染到不太气不受污染到不太关键的区域有助于关键的区域有助于保持清洁环境区域保持清洁环境区域的完整性的完整性Filling RoomPersonnel Entry(Filling)Materials EntryPersonnel Access(Support)Filled Product“Hatch”TunnelPersonnel Exit(Filling)PPPPPPPPAir p
30、ressure cascade:Annex 1.31:Indicators of pressure difference should be fitted between areas where these differences are important.These pressure differences should be recorded regularly or otherwise documentedIn aseptic manufacture,we are trying to avoid contamination particularly contamination of p
31、roduct and equipment.在无菌生产中，我们正在努力避免污染在无菌生产中，我们正在努力避免污染-特别是产品和设备的特别是产品和设备的污染。污染。For product or equipment to be contaminated from air-borne microorganisms,they have to settle out of the air onto whatever you are trying to protect.对于被空气传播的微生物污染的产品或设备，它们必须从空气对于被空气传播的微生物污染的产品或设备，它们必须从空气中沉淀到您想要保护的任何物质上。中
32、沉淀到您想要保护的任何物质上。It is an important principle to understand that as long as particles and microorganisms stay suspended in the air they are not really a problem it is only when they settle out that they become an actual cause of contamination了解一个重要的原则是，只要颗粒和微生物悬浮在空气中，它们就不是真正的问题-只有当他们落下安家时，他们才会成为污染的真正原
33、因Consider these Grade B results:考虑这些B级结果：Active air samples:活动空气样本Median count 0 cfu/m3计数 0 cfu/m3Settle plates沉降碟Median count 0 cfu/4hours计数 0 cfu/4小时Is the data OK?数据好吗？Consider these Grade B results:考虑这些B级结果Active air samples:活动空气样本Median count 3 cfu/m3计数 3 cfu/m3Settle plates沉降碟Median count 0 cf
34、u/4hours计数 0 cfu/4小时Is the data OK?数据好吗？Consider these Grade B results:考虑这些B级结果Active air samples:活动空气样本Median count 3 cfu/m3计数 3 cfu/m3Settle plates沉降碟Median count 3 cfu/4hours计数 3 cfu/4小时Is the data OK?数据好吗？In aseptic manufacture,we are trying to avoid contamination particularly contamination of p
35、roduct and equipment.在无菌生产中，我们正在努力避免污染在无菌生产中，我们正在努力避免污染-特别是产品和设备的特别是产品和设备的污染污染For product or equipment to be contaminated from air-borne microorganisms,they have to settle out of the air onto whatever you are trying to protect.对于被空气传播的微生物污染的产品或设备，它们必须从空气对于被空气传播的微生物污染的产品或设备，它们必须从空气中沉淀到您想要保护的任何物质上。中沉淀
36、到您想要保护的任何物质上。We use the principle of air movement in two beneficial ways in clean rooms:我们在洁净室中以两种有益的方式使用空气流动原理：Turbulent air flow湍流气流湍流气流Unidirectional air flow(UDAF)单向气流（单向气流（UDAF）Most European clean rooms are of the turbulent air flow type大多数欧洲洁净室属于湍流气流类型大多数欧洲洁净室属于湍流气流类型Air is driven in through g
37、rilles and ducts at ceiling height and removed through low level ducts,and while it is in the room its initial supply velocity is sufficient to keep it in constant turbulence therefore particles and microorganisms do not settle out空气通过格栅和管道在天花板高度驱动，并通过低水平管道移除，空气通过格栅和管道在天花板高度驱动，并通过低水平管道移除，当它在室内时，其初始供
38、应速度足以使其保持恒定的湍流当它在室内时，其初始供应速度足以使其保持恒定的湍流-因此因此颗粒和微生物不会沉淀出来颗粒和微生物不会沉淀出来Of course this is an“ideal”and you may get dead air beneath tables etc,当然这是一个当然这是一个“理想理想”，你可能会在桌子下面等空气，你可能会在桌子下面等空气，We need to know about these dead areas,and if we cant engineer them out,we have to be careful around them because th
39、ats where contamination may occur(and consider targeting monitoring at these locations)我们需要了解这些死区，如果我们无法解决这些问题，我们必须小心谨慎，因为这可能会发生污染（并考虑在这些位置进行监控）In the USA there are some Unidirectional Air Flow Clean Rooms but in Europe we usually only see Unidirectional Air Flow providing localised protection over
40、benches and in B-F-S in the air shower at point of fill.在美国有一些单向气流洁净室，但在欧洲，我们通常只能看在美国有一些单向气流洁净室，但在欧洲，我们通常只能看到单向气流在长凳上提供局部保护，在填充点的空气淋浴中到单向气流在长凳上提供局部保护，在填充点的空气淋浴中提供提供B-F-S。The idea of unidirectional air flow is that if air is supplied at a very high velocity through specially designed grilles it will
41、flow for quite a distance in straight lines单向气流的想法是，如果通过特殊设计的格栅以非常高的速单向气流的想法是，如果通过特殊设计的格栅以非常高的速度供应空气，它将以直线流动相当远的距离度供应空气，它将以直线流动相当远的距离Unidirectional air flow blows away all the contamination and particles that come into its path单向气流吹走了进入其路径的所有污染物和颗粒单向气流吹走了进入其路径的所有污染物和颗粒Unidirectional air flow is capa
42、ble of sweeping up microorganisms that are sitting on surfaces and thereby cleaning the surfaces up单向气流能够清扫坐在表面上的微生物，从而清洁表面单向气流能够清扫坐在表面上的微生物，从而清洁表面When the pressure cascade is balanced in a facility the outward air flow(although indicated by positive Ps)should be confirmed by smoke tests and recorde
43、d on video.It is important that the smoke is visible and can be recorded on VCR or DVD.当压力级联在设施中平衡时，外部气流（尽管由正P表示）应通过烟雾测试确认并记录在视频中。重要的是烟雾是可见的并且可以记录在VCR或DVD上。The smoke test is the only effective way of determining if air flow is turbulent or unidirectional and also its direction in relation to protect
44、ing the product while personnel are operational in the areas烟雾测试是确定气流是湍流还是单向的唯一有效方法，也是确保人员在该区域运行时保护产品的方向These airflow visualisations are expected for aseptic filling.这些“气流可视化”预计用于无菌灌装。Re-circulating airTerminal HEPA Filter 高效Extract duct回风管道UDAF单向流PPPPLAFClean roomMaybe a Change RoomMaybe a Material
45、s EntryMaybe a Corridor with Viewing Windows into the Clean Room也许一个带有观察窗进入洁净室的走廊Terminal HEPA filter in ceilingExtract duct at low levelPressure differentialsThese are typically 10-15 Pascals(EU GMP states 12.5 as the recommended target)压差压差这些通常为这些通常为10-15帕斯卡（欧帕斯卡（欧盟盟GMP规定规定12.5为推荐目标）为推荐目标）Air is a
46、 source of microbiological contamination in aseptic manufacturing facilities空气是无菌生产设施中微生物污染的来源It is also a means of controlling contamination它也是控制污染的一种手段But its velocity is important to ensure it moves in the correct direction and the means of filtration must ensure that the main supply of air to pharmaceutical clean rooms has a very low particle count and bioburden但其速度对于确保其向正确方向移动非常重要，过滤方式必须确保制药洁净室的主要空气供应具有非常低的颗粒数和生物负载
