2. Example pharmaceutical water
例如水系统The firstvariation already arises in the case of a water system. In the course of the(first) qualification the terms qualification and validation become blurred. Usually,so-called dry runs are carried out during the performance qualification (PQ).This means that the equipment is operated with a substitute materialinstead of the product. Often the substitute material is water. The realproduct has to be used in the subsequent validation at the latest. In a watersystem, the product manufactured naturally is water. Therefore, the PQ, atleast the later part, also is considered to be a validation. In this case, thequalification in three steps described by the FDA already many years ago, isindustry standard. But the single phases differ as concerns the frequency ofsampling and the number of sampling points. The complete qualification lasts upto one year in order to prove that seasonal fluctuations of the feed water'squality as well as different operating conditions don't influence the qualityof the produced water.
在水系统（首次）确认过程中，术语“确认”和“验证”变得模糊不清。通常，在性能确认期间开展所谓的“空运行”。这意味着设备使用替代物料代替产品运行。通常替代物料是水。至少需要在随后的验证中使用实际产品。在水系统，生产的产品自然是水。所以，它的PQ，至少在后期阶段，也应该被认为是一个验证。在这种情况下，FDA很多年前描述的三个步骤的确认就是行业标准了。但单个阶段关于采样频率和采样点的数量存在差异。为了证实原水质量和运行条件的季节性波动不影响所产水的质量，完整的确认需要持续一年A requalificationhas to be carried out after changes have taken place at the water systeminsofar as the change can influence the qualified state of the water system.The risk analysis carried out in the context of qualification shoulddemonstrate if this is the case. This decision making process should be carriedout by means of the change control system in order to be able to understandalso at a later date why for example no qualification tests were necessary orwhy which requalification tests had been determined.
水系统发生变更后，如果该变更可能会影响该水系统的确认状态的，应该进行再确认。在确认背景下进行的风险分析应该证实这一点。为了在日后便于理解为什么可以没有确认测试的或者为什么采取那种再确认测试，这个决策流程必须通过使用变更控制体系来进行。
As a general rule, requalification then consists of thetests that have demonstrated already during the first qualification for therelevant part of the equipment that the equipment was operatingcorrectly. Should there be a risk for the whole systemthe qualification has to be repeated. Then quality assurance has to decidewhether all phases really have to be carried out. The exchange of the watertank with a tank of another size will probably affect thewhole system - the installation of an additional valve presumably only thepart of the water system that is concerned. It has to be assessed ona case by case basis whether seasonal effects are to be expected.
一般地，再确认由那些在首次确认期间已经证实设备相关部件的测试组成，证明设备得到正确的运行。确认是否需要重复进行？质量保证需要决定是否所有阶段都需要被实施。水箱更换另一种规格将可能影响整个系统——一个额外的阀门的安装。是否季节性效果需要被预期的评估需要具体情况具体分析评估
As alreadymentioned, the periodically recurring requalification should include the changes, deviations andlogbook considerations as well as an overview of the quality data:microbiology, TOC, conductivity etc.
如上文讲到的，周期性重复的再确认应该包括变更、偏差和日志的考虑，和质量数据的综述如微生物、TOC、电导率等。
The monitoring partly takes place continuously (forexample in the case of online TOC and conductibility measurements) ordiscontinuously by means of sampling at defined sampling points with the help ofa sampling plan (such as microbiology or TOC) if there is no continuousmeasurement in the system).
监测可以部分持续地进行（如在线TOC和电导率测试仪）或如果没有持续监测装置的话，在采样计划的帮助下不连续地在规定采样点采样监测（如微生物、TOC）。
3. Example clean room
例如洁净室
In the case ofclean rooms qualification also takes place after construction orreconstruction. A qualification is carried out for the HVAC system as well asfor the premises themselves (for example verification of surfaces of the walls,lighting etc.). As a rule qualification of the HVAC system is much moreextensive. Qualification of the HVAC system is also extended over alonger period, again in order to cover seasonal fluctuations(temperature/humidity/number of particles in the intake air). Constructionalchanges also require a requalification insofar as they may influence thequality or the qualified state.
洁净室的确认一般在它完成施工或者改造后进行。用于确认HVAC系统和他们的厂房（如墙面、照明的核实等等）。一般来说HVAC系统的确认是非常广泛的。为了覆盖季节性的波动（温度、湿度、进入通风系统的粒子数等）HVAC系统的确认也需要耗费较长的时间。结构性的变更也需要进行再确认的，因为他们可能影响系统的质量或者确认状态。
In the PQ at thelatest a further term is added: classification . Classification is part of thequalification and is supposed to show that the clean zones as defined in Annex1 with regard to the number of particles in the air are actually met inoperation as well as at rest. The classification which is also part of theacceptance test has to be carried out according to ISO 14664-1, the particlenumber limit is defined by Annex 1. Further qualification tests are for examplethe recovery time, filter leakage tests or the air speed in laminar grade Azones. For the GMP environment Annex 1 always is the binding document. Shouldthere be contradictory statements Annex 1 prevails over statements from the ISOstandards. Another part of the qualification is the microbiological examinationof surfaces and of the microbial concentration in the air as concernscompliance with the specifications according to Annex 1 - quasi amicrobiological classification. But the requirements of Annex 1 are onlybinding for the production of sterile dosage forms, that is for zones A-D.
在PQ洁净级别是确认的一部分，并且应该显示的洁净区在动态条件下和静态条件下都切实符合附录1中定义的空气中粒子浓度要求。根据ISO14644-1，洁净级别同时也是接受性测试的一部分，粒子浓度标准规定在附录一中。更进一步的确认测试如恢复时间、过滤泄漏率和A级层流的气流流速。在GMP环境，附录一同样具有约束力。附录一中的规定要比ISO中的规定更具约束力呢？
根据附录一的标准，另一个确认的项目是表面微生物和空气中的微生物浓度测试——类似一个微生物的级别划分。但是附录1只对无菌药品（即A-D级）具备约束力。
It is often askedwhich of the measurements have to be repeated regularly, respectively how oftenand to which extent requalification has to take place. As already explained inChapter 1 a requalification is required. It does not necessitate a repetitionof measurements however, but can be carried out by means of an evaluation ofoperation or monitoring data - excluding, of course, a requalification afterchanges. But, other than in the case of water (see 2) recurring measurements certainlyare required in clean room areas (analogously to qualification). Suchinformation can be found in ISO 14644-1-3 or rather in the annexes:classification of rooms (according to zones) for example has to be repeatedevery 12 months, the leakage tests after 24 months at the latest and therecovery test as well. Since Annex 1 requires the application of ISO 14644,strictly speaking, these requirements are valid only for sterile areas (zonesA-D). Problems arise, when these recurring tests are termed. In the ISOenvironment the terms used are qualification or requalification measurements.But this is not quiet correct since then there ought to exist a qualificationprotocol as is customary in the GMP environment, with an analogous releaseprocedure such as in the original qualification. Sometimes, at this point, theterms 'monitoring' even better 'technical monitoring' are used. But it wouldalso be possible to talk about verification or revision. The term"periodic performance evaluation" also is used. Maybe the review ofAnnex 15 could be optimised by giving clear definitions.
经常会问哪些措施需要定期重复地进行？多久进行一次？再确认需要进行到哪种程度？第一章解释了再确认是必要的。然而它不是需要一个重复的测试，而是可以通过一个对运行和监测数据的评价来实现，变更后的再确认除外。但是不同于水系统（见2）的情况，对于洁净区是需要一些重复的测试的（类似于确认）。这些信息可以在ISO14644-1~3中找到，或者更准确的说，在附录：例如每12个月进行一次洁净室的级别确认，每24个月进行一次泄漏率和恢复测试等等。自从附录一要求使用ISO14644，严格的说，这些要求只对无菌产品（级别A~D级）有效。问题来了，这些重复的测试怎么定义？在ISO环境，进行这些测试被称为确认或者再确认测试。自此，GMP环境中惯有的做法是跟初始确认一样应该有一个确认方案，有一个类似于放行的程序，但是这不是非常准确的。有时，在这点上，使用“监测”或者更准确的“技术监测”更好。但是也可能被称为核实或者修正。术语“周期性的性能评价”也可以使用。也许在更新附录15中可以给出更清洗的定义。
Monitoring of clean rooms is rather extensive. Apartfrom the obvious values such as particle concentration in the air andmicrobiology of the surfaces and the air, differential pressures betweendifferent clean room zones, the temperature and if necessary, relative airhumidity and the air speed under laminar flow (A) areas are monitored, too.Monitoring can take place continuously or discontinuously. A permanentmonitoring is required only for particles in clean room zones A and B. This hasto be carried out according to ISO 14644-2. Monitoring of the air pressuredifferential between two different cleanliness classes has to take placecontinuously, at least in the zones for the manufacture of sterile productsclassified according to Annex 1. For solid pharmaceutical production (tablets)for example, there are no defined requirements. They have to be defined by themanufacturer himself. Microbiological monitoring only is possible offline,whereas it is carried out quasi continuously for example by means of so-calledsettle plates during the filling process in grade A. It is not sufficientlypossible to use particle measurement values of the air to assess themicrobiological quality.
洁净室的监测更为广泛。除了空气中的粒子浓度和表面和空气微生物，不同洁净室之间的压差、温度和空气相对湿度（如需要）、层流罩气流流速也需要监测。监测可以间断或不间断地进行。只有A、B级需要对悬浮粒子进行持续监测。这需要根据ISO14644-2进行。根据附录1，不同洁净级别之间的空气压差监测需要持续进行，至少在无菌产品生产的区域需要这样。对于固体产品（如片剂），没有规定的要求。这些需要生产者制剂制定。微生物监测只可能离线进行。然而它似乎可以被持续监测，如在A级分装过程使用所谓的沉降菌监测。使用空气粒子监测数值来评价微生物质量是不充分的。
编者：这是ECA之前发布的一篇GMP新闻，阐述了在GMP环境下术语“确认（qualification）”、“再确认（requalification）”和“监测（monitoring）”的区别。因不久前看到蒲公英激烈的讨论“硬件再确认是否必须”这个话题，特地找出来以便大家理解GMP对“再确认”的定义，避免混淆。
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发表于 2016-4-6 09:36:07
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