FAQs:Water for Pharmaceutical and Analytical Purposes

常见问题解答：适用于制药和分析目的的水

 

1. Why are there nomicrobial requirements included in the monographs for Purified Water and Waterfor Injection? 

为什么纯化水和注水专著中没有微生物要求？

 

Because of the various usesof these waters, microbial requirements are not included in these monographssince this would unnecessarily burden some users with meaningless and/orinconsequential or inappropriate requirements, e.g. water used for manylaboratory analyses. Microbial guidelines are provided under the informationalchapter Water for Pharmaceutical Purposes <1231> whereit states that the user should establish in-house specifications or fitness foruse microbial levels above which the water is unsuitable for use.

由于这些水的用途各异，这些专著中不包括微生物要求，因为这会不必要地使一些用户背负毫无意义和/或无关紧要或不恰当的要求，例如许多用于实验室分析的水。微生物指南根据信息章节"药物用途水"<1231>其中规定，用户应建立内部标准或适合使用的微生物水平，未达到该标准的水不适合使用。

 

2. What is the purpose ofmicrobial Alert and Action Levels for Purified Water and Water for Injection?

制定纯化水和注水的微生物警戒和行动限的目的是什么？

 

Alert and Action Levels areprocess control terms and should be established at levels indicative of thewater system trending outside of its normal microbial control range. Theselevels should be established at levels no higher than, and preferably lowerthan, those listed in Water for Pharmaceutical Purposes <1231> basedon the normal microbial performance trends in your water system. The purpose ofAlert and Action Levels is to trigger additional, non-routine, rather thanroutine microbial control measures. These additional control measures shouldprevent objectionable levels and types of microorganisms from being present inthe water, based on for the water’s use.

警戒和行动限是过程控制术语，应建立在指示水系统在其正常微生物控制范围之外的趋势水平。在你的水系统，这些水平应建立在不高于，最好低于那些列在根据<1231>正常微生物性能趋势。警戒和行动限的目的是触发额外的非常规，而不是常规的微生物控制措施。基于水的用途，这些额外的控制措施应防止令人反感的水平和微生物类型存在于水中。

 

3. For off-line testing ofwater samples for Water Conductivity and Total Organic Carbon , how long can Istore samples before testing?

对于水导率和有机碳总量的水样离线测试，我可以在测试前储存样品多长时间？

 

USP issilent on a specific answer to this question. It is understood that somemanufacturers have their analyses performed by external laboratories – whichmay take several days or longer. For this reason, there is no time limit.

USP未给出这个问题的具体答案。据了解，一些制造商的分析由外部实验室进行，这可能需要几天或更长时间。因此，没有时间限制。

In general, you can wait aslong as you want – at your risk. But it is advised to test as soon as practicalfor the following reasons; 1) when stored, the water purity only degrades overtime. Since Purified Water, Water for Injection orthe sterile waters are of such high purity, the passage of time does not doanything except potentially degrade the sample due to environmental, ambient,or container factors; and 2) water is typically not produced in batches, butrather it is usually purified, produced, and consumed continuously. The watermay have had direct product impact or contact before any lab analysis isexecuted. Delays in testing only increase the amount of potential productimpact – in the event of a failed test.

一般来说，只要在你的可承受风险内，你可以放置等待。但出于以下原因，建议尽快进行实际测试：1） 储存时，水的纯度只会随着时间而下降。由于纯化水、注水或无菌水的纯度如此之高，因此随着时间的流逝，除了由于环境、环节或容器因素而可能使样品降解外，没有任何益处：和 2） 水通常不是分批生产的，而是通常连续净化、生产和使用。在执行任何实验室分析之前，水可能具有直接的产品影响或接触。如果测试失败，延迟测试只会增加潜在产品影响的数量。

 

4. For off-line testing ofwater samples for General Chapters Water Conductivity and Total Organic Carbon, how should I store the samples?

对于通则章节，水导率和有机碳总量的水样离线测试，应如何储存样品？

 

For lab analyses, samplesshould be stored in containers that do not adversely impact the test results.This is to prevent false positives and unnecessary investigations. For example,storage of water in a glass container for a few hours is usually good, butstorage for a longer time will result in a modest increase in the sampleconductivity. This is due to the leaching of sodium silicate from the glass,raising the pH and the water conductivity, and threatening to fail WaterConductivity <645>. In general, clean plastic containers are a betterchoice for long term storage of samples for Water Conductivity<645> testing. For Total Organic Carbon <643>,there is a similar rationale - many types of non-shedding plastics or glasssuffice. In general, storage at ambient or refrigerated temperatures is bestfor these chemical tests, while refrigerated storage is advised for samplesused in microbial testing. Cleanliness of any container is most critical. Dueto the very high purity of these waters, fingerprints, soaps, and otherresidues must be avoided. False positives can result.

对于实验室分析，样品应储存在不会对测试结果产生不利影响的容器中。这是为了防止误报和不必要的调查。例如，将水储存在玻璃容器中几个小时通常是可行的，但长时间储存将导致样品导电率略有增加。这是由于硅酸钠从玻璃中浸出，提高pH和水导率，并有可能导致水的电导率<645>测试不合格。一般来说，清洁塑料容器是长期储存水导率样品的更好选择，见<645>测试。对于总有机碳<643>，有一个类似的理由——用一些非脱落塑料或玻璃就足够了。一般来说，环境或冷藏温度下的储存环境最适合这些化学测试，而冷藏储存建议用于微生物测试的样品。任何容器的清洁度都是最关键的。由于这些水的纯度很高，必须避免手指印、肥皂和其他残留物。这些可能导致误报。

 

5. Can I do WaterConductivity and Total Organic Carbon testing on-line?

我可以在线进行水导率和有机碳总量测试吗？

 

These two chaptersspecifically state that these tests can be performed off-line or on-line. Thereare benefits and challenges for each approach, and they are described in moredetail in these chapters and in Water for Pharmaceutical Purposes<1231>. In general, on-line testing avoids the risk of contaminationof off-line samples by humans, containers, or the environment, and it providesimmediate analysis and direct opportunities for real-time control, decision andintervention. For example, you can continuously test and accept the water (forthese chemical attributes). Conversely, you can prevent the distribution of thewater in the event of a failed test in real time. However, for a facility withmultiple types of waters and loops, a centralized lab analysis system may offera more economical choice. In either case, the water sample must berepresentative of the water used in production.

这两章特别指出，这些测试可以离线或在线进行。每种方法都有其优点和不足，在这些章节和《药用水》<1231>中都详细描述了这些方法。一般来说，相对于离线，在线测试可避免人、容器或环境对样品污染的风险，并为实时控制、决策和干预提供即时分析和直接机会。例如，您可以持续测试和接受水（针对这些化学属性）。相反，如果测试失败，您可以实时阻止水的分配。然而，对于具有多种类型的水和循环的设施，集中式实验室分析系统可能提供更经济的选择。在这两种情况下，水样必须代表生产中使用的水。

 

6. What is the totalorganic carbon (TOC) limit for Purified Water and Water for Injection?

纯化水和注水的有机碳（TOC）总量限值是多少？

 

There is a "targetlimit response" of 500 µg of Carbon/L. The true limit is the response ofthe TOC measurement system to a 500 µg Carbon/L (prepared from sucrose)solution, Rs, corrected for the response to reagent water, Rw. This limit isequal to Rs – Rw. The actual number will vary based upon your referencestandard solution, your equipment, background carbon, etc. USP Reference Standardsare required for use.

"目标限量响应"为 500 μg 碳/升。真正的限制是TOC 测量系统对 500 μg 碳/L（从蔗糖中制备）溶液（Rs）的响应，该溶液已更正为扣除对试剂水 Rw 的反应。此限制等于 Rs -Rw。实际数字将根据您的参考标准溶液、设备、背景碳等而有所不同。同时，您需要使用USP 参考标准溶液。笔者：注意USP44的更新。

 

7. How often do I performthe system suitability test in Total Organic Carbon General Chapter?

根据总有机碳通则，我何时进行系统适用性测试？

 

USP General Chapter <643> intentionallysays nothing about how often the system suitability test (SST) should be run.The reasoning is that this frequency depends on the stability of the TotalOrganic Carbon (TOC) instrument response and other factors associated with thewater quality and risk. If the TOC of a quality water system is very low, say<20 ppb, then many opt to reduce the frequency of testing due to less risk.The stability of different TOC measurement technologies may vary over extendedperiods of time. The instrument manufacturer can advise the user on this matterand user experience can also be valuable in determining a suitable frequency.Another factor is the risk of a non-conforming system suitability test resultsince the Rs-Rw result used in this calculation is the limit response for theinstrument, the crucial pass/fail value for the TOC test. If a non-conformingsystem suitability test is obtained, it implicates the inaccuracy of all TOCtest results since the previous successful system suitability test. For thisreason, many users choose to perform the system suitability test morefrequently than the stability of the TOC instrument response might suggest,just to minimize the impact of a possibly non-conforming result. This is why atypically low TOC water system is at less risk, even with a failed SST. If theSST fails, some remediation is necessary to re-adjust the instrument, replace alamp, or some other means of instrument improvement. But even a 50% error willhave little impact on the past TOC readings (since the readings, even with thiserror, are so low relative to the Limit). On a high TOC water system, thefailure of the SST is possibly more critical. This is up to the risk the useris willing to assume, knowing the historic stability of their instrument andother factors. Therefore, the Total Organic Carbon <643> issilent on the frequency of performing the system suitability test because it isup to the user to decide what is appropriate.

USP 通则<643>故意不说何时何频率运行系统适用性测试（SST）。理由是，此频率取决于总有机碳 （TOC） 仪器响应的稳定性以及与水质和风险相关的其他因素。如果优质水系统的 TOC 非常低，比如 <20ppb，那么许多人会选择降低测试频率，因为风险较小。不同 TOC 测量技术的稳定性可能会在较长时间内有所不同。仪器制造商可以就此问题向用户提供建议，在确定合适的频率方面“用户经验”也非常有参考价值。另一个因素是系统适宜性测试结果不合格的风险，因为此计算中使用的（ Rs-Rw ）结果是仪器的极限响应，即 TOC 测试的关键通过/失败值。如果获得不合格的系统适宜性测试，则涉及自上次系统适宜性测试以来所有 TOC 测试结果的不准确的可能性。因此，相对于TOC 仪器响应的稳定性所提示的时机，为了最大限度地减少可能不符合结果的影响，许多用户选择更频繁地执行系统适宜性测试。这就是为什么一个典型的低 TOC 水系统的风险较小，即使 SST 失败也是如此。如果 SST 失败，则需要进行一些补救，以重新调整仪器、更换灯或改进仪器的其他方法。但是，即使 50% 的错误也不会对过去的 TOC 读数产生什么影响（因为读数即使有此错误，相对于极限也非常低）。在高 TOC 水系统中，SST 的失败可能更为严重。这是由用户愿意承担的风险，知道他们的仪器的历史稳定性和其他因素。因此，有机碳总量<643>对执行系统适宜性测试的频率保持沉默，因为由用户决定什么时候执行是合适的。

 

8. How long can I store andreuse reference standard solutions prepared for the Total Organic Carbon systemsuitability test?

我可以在多长时间内存储和重复使用为总有机碳系统适宜性测试准备的参考标准溶液？

 

Where USP is silent onstorage conditions and the stability of prepared Total Organic Carbon (TOC)reference standard solutions, the solutions should be 1) prepared fresh or 2)used within the expiry if procured from 3rd party supplier or 3) used within atimeframe determined by stability studies. In all cases, USP Reference Materialis specified. Several factors can influence the stability of the referencestandard solutions. These include temperature, light, oxygen, microbialdecomposition, and adsorption to the container surface. The developments ofturbidity, additional color, or performance variability relative to freshlyprepared solutions are indicators of instability. Most of the suppliers ofsolutions specify expiry dates. But as a practical matter, concentratedreference standard solutions of Sucrose last 3-6 months, and analogoussolutions of 1, 4 Benzoquinone (pBQ) last about 2 months, assuming they arestored at appropriate temperatures in appropriate containers and protected fromlight (for pBQ). It is recommended to use refrigeration since this slows downsolution degradation, and reduces microbial growth, particularly in the sucrosesolution.

如果 USP 对存储条件和已准备好的总有机碳（TOC） 参考标准溶液的稳定性不做规定，则标准溶液应为：1）新鲜准备或 2）在到期日内使用，如果从第三方供应商处采购，或在稳定性研究确定的时限内使用。在所有情况下，应使用 USP 参考品。有几个因素会影响参考标准溶液的稳定性。这些包括温度、光、氧、微生物分解和溶质吸附到容器表面。与新准备的溶液相比，浊度、额外颜色或性能变异性的变异是不稳定的指标。大多数标准溶液供应商都指定了到期日期。但作为一个实际问题，假设它们存储在适当的容器和温度下，并防止光线照射（用于 pBQ保存），高浓度蔗糖的参考标准溶液可保持 3-6 个月；1，4 -对苯醌 （pBQ）的浓溶液可保持约 2 个月。特别是蔗糖溶液，建议冷藏保存，因为这可以减缓溶液的降解，并减少微生物生长。

 

9. What is the main reasonfor KCl addition in the Water Conductivity test for pH measurement?

在pH值测量的水导率测试中增加KCl的主要原因是什么？

 

In Stage 3, a neutralelectrolyte (KCl) is added to increase the ionic strength and accuratelymeasure the pH of the solution. If the ionic strength of the solution is notincreased, the pH measurement will be highly unstable and inaccurate. So KCl isadded to make a valid pH measurement as a part of the WaterConductivity <645> - Stage 3 test. The increase in the ionicstrength is needed so that there is minimal concentration gradient across thepH electrode diaphragm/junction. A large concentration gradient results in alack of equilibrium and unstable pH response.

在第 3 阶段，添加中性电解质 （KCl） 以增加离子强度并准确测量溶液的 pH 值。如果不增加溶液的离子强度，pH值测量将非常不稳定和不准确。因此，添加KCl以进行有效的 pH 值测量，这是作为水导率<645> -第 3 阶段测试的一部分。需要提高离子强度，以便在 pH 电极隔膜/结点中实现最小的浓度梯度。大浓度梯度导致缺乏平衡和不稳定的pH响应。

 

10. Can I start at Stage 2 for Water Conductivity , or do I need to start at Stage 1?

我可以从第二阶段开始水导率，还是需要从第一阶段开始？

 

There is no need to performstages 1 and 2 in order. You can go directly to Stage 2 if offline testing inpreferred - you do not have to fail stage 1 first.

无需按顺序执行第 1 阶段和第2 阶段。如果首选的离线测试，您可以直接转到第 2 阶段 - 您不必先通过第 1 阶段。

 

11. Is the requirement forconductivity cell constant of ±2% of the nominal value?

电导率电极电导常数的要求是标称值的±2%吗?

 

The cell constant accuracymust be ±2% of the certified value, not the nominal value.

电极电导常数的恒定精度必须是校准值的±2%，而不是标称值。

 

12. What is a"suitable container" for off-line determination of conductivity?

什么是用于离线电导率测定的"合适容器"？

 

In general, any materialthat does not impact the conductivity in any appreciable way is suitable. Manyplastic containers including PTFE, HDPE, LDPE and some polycarbonates areappropriate. Glass containers for immediate testing are appropriate. Regardlessof the material, they have to be clean and free of any cleaning reagents suchas soaps. Soaps are very conductive.

一般来说，任何不以任何明显的方式影响导电性的材料都是合适的。许多塑料容器，包括PTFE，HDPE，LDPE和一些聚碳酸酯是适当的。玻璃容器可以立即进行测试。无论材料如何，它们必须清洁，并且不含肥皂等任何清洁试剂。肥皂水具有较强导电能力。

 

13. There are no tests forpH, nitrates, or heavy metals? Is this correct?

药典水没有pH、硝酸盐或重金属的测试？这是正确的吗？

 

Yes, this is correct. Therehas never been a test for nitrates for USP waters. The heavy metals test on USPwaters was deleted in 1996. The pH test was deleted in 1998. [Note - There is apH measurement (not a test) as a part of Stage 3 test for WaterConductivity <645>, but this is still a conductivity limit test].Note that you cannot fail the former pH specifications of water (pH 5.0 – 7.0)if you pass the conductivity specifications. You also cannot fail the heavymetals test or the nitrate test if you pass conductivity and your water systemstarts with water compliant with the requirements for one of the drinkingwaters specified in the monographs (for the US, EU, Japan, or WHO). In somecases, these tests may be required by other pharmacopoeia.

是的，这是正确的。USP从未要求对水的硝酸盐进行测试。USP1996年删除了对水的重金属试验。pH 测试于 1998 年被删除。[注意 - 作为水导率第 3 阶段测试的一部分，pH 值测量<645>（不是测试）仍然是为了电导率限度而进行的测试]。请注意,如果电导率符合标准，则先前水的pH标准(pH 5.0 - 7.0)必须合格。同样，如电导率测试合格，并且您的水系统的源水符合各论(针对美国、欧盟、日本或世卫组织)中指定的一种饮用水的要求，您也须确保重金属测试或硝酸盐测试合格。在某些情况下，其他药典可能要求这些检测。

 

14. May I release water foruse by performing microbial testing on water from a sample port?

我可以通过对取样端口的水进行微生物测试来放行水以供使用吗?

 

Youmay do so, but only under certain circumstances. The microbial quality of thewater within the system, as reflected by water from that sample port, may bebetter than the quality that is delivered to the point of use (POU) duringmanufacturing use. This is because of microbial contamination of the systemwater that can occur as it is transferred from the system outlets to the POU.It is the quality of water DELIVERED from the system to the POU that affectsproducts and other uses.

只有在某些情况下你才可以这样做。从取样端口的水反映系统制水质量和在生产使用期间交付到使用点(POU)的质量相比，就对系统内水的微生物质量评价而言，前者更好。这是因为系统水从系统出口转移到POU时可能发生微生物污染。影响产品和其他用途的是从系统输送到POU的水的质量。

If youhave good water use practices such that the microbial count from a sample portis essentially the same as at a POU when delivered by the manufacturing usepractice, then the risk of the sample port microbial counts falsely reflectingthe quality of the delivered water is low.

如果您有良好的水使用实践，例如，当交付到生产使用时，取样端口的微生物数量与POU的微生物数量基本相同，那么样品端口微生物数量错误反映交付的水质量的风险很低。

Generally, water releasefor use should be based on a POU sample reflecting manufacturing’s water usepractices and not on sample port data.

一般来说，水的放行应该基于反映生产用水环节的POU样品，而不是取样端口数据。

 

15. Is the outlet on thewater distribution system, sometimes called a point of use outlet, consideredto be the point of use?

分配系统上的出水口，有时称为使用点出水口，是否被认为是使用点?

 

No. The destination of thatwater where it will be used for product formulation or cleaning or where itenters a manufacturing process is the true point of use. The quality of waterat the true point of use, as delivered by manufacturing (or by a samplingprocess identical to the manufacturing water delivery process) must be known atall points of use receiving water from the system. The water quality at thetrue point of use is where the water must be “fit for use”, i.e. pass yourwater specifications.

否。水的输送目的地是用于配方生产或清洁或具体生产工艺的地方，这才是真正的使用点。在从系统接收水的所有使用点上，必须知道通过生产(或通过与生产用水相同的采样过程)交付的真正使用点上的水的质量。真正使用点的水质必须是“适合使用”的水，即符合您的水标准。

 

16. If I do not have awater microbial specification but only an Alert and Action Level, is there amicrobial level considered to be unfit for use?

如果我没有水质微生物标准，但只有一个警报和行动级别，是否只有微生物级别而无标准是不适合的?

 

Yes.Action Levels in USP <1231> (100cfu/mL for Purified Water and 10cfu/100mLfor Water for Injection) are generally considered to represent a level abovewhich the water is unfit for use. That is why an OOS investigation must beundertaken if those Action Levels are exceeded.

是的。USP1231中的行动水平(纯净水为100cfu/mL，注射用水为10cfu/100mL)通常被认为代表一个水不适合使用的情形。这就是为什么OOS调查必须在超标的情况下进行。

So whether you declaremicrobial specifications or not, they are assumed to be those “compendia actionlevel” values contained in General Chapter <1231>. To avoid everexceeding a water microbial specification, trend-based Alert and Action Levelsshould be used to monitor and control the water system so it always produceswater that is fit for use.

因此，无论你是否声明微生物指标，它们都被假定为通论1231中所包含的“总体行动水平”值。为了避免超过水的微生物标准，应该使用基于趋势的警报和行动水平来监测和控制水系统，以便它总是生产适合使用的水。

 

17. What are the mostcommon issues encountered in the WFI production systems produced under GMP.What should we look for?

在GMP条件下的WFI生产系统中遇到的最常见问题是什么？带给我们什么启示？

 

One common problem is where there is a cold WFI sub-loop off of a heated system with a large shell and tube heat exchangers used for cooling in that sub-loop. When the sub-loop is hot water sanitized, not enough contact time is allowed for the cooling heat exchangers (and their trapped chilled water)  to get them thoroughly hot and sanitized. When incompletely sanitized, any surviving biofilm will immediately reinoculate the cold sub-loop after resumed cold operation and be present as detectable micro counts.

一个常见的问题是，加热系统中有一个低温WFI 子循环，带有用于该子循环冷却的大外壳和管热交换器。当子循环是热水消毒，没有足够的接触时间，冷却热交换器（和他们被困的冷水）让他们彻底变热和消毒。当消毒不完全时，在恢复冷操作后，任何存活的生物膜会立即对冷循环环形成增殖，并被检测到微生物的存在。

Other common problems with cold WFI systems are dead legs, sometimes temporary ones that are created by open hard-piped connections to equipment that is not in use and not drawing water. The hot water during sanitization doesn’t     mix well with the trapped water in that dead leg, so the dead leg never gets sanitized. If there was any contamination that got into that side leg  during previous use, it will grow unabated in the unsanitized dead leg and continuously contaminate the loop water.

低温循环 WFI 系统的其他常见问题是死角，有时是临时的，这些死角是由打开硬管连接到未使用和不抽水的设备造成的。消毒过程中的热水与死角中被困的水不能很好地混合，所以死角永远不会得到消毒。如果在以前使用过程中有任何污染进入侧支，它会在未经消毒的死角中有增无减地生长，并持续污染循环水。

Another common problem is overwhelming the distillation purification process with a high level of endotoxin in the water going to the still (100+ EU/mL). This can happen with poor maintenance of pretreatment unit ops such as carbon beds, and also when coincident with high endotoxin levels in the     city water when they switch over to straight chlorine from chloramine for a part of a year.

另一个常见问题是蒸馏净化过程中，进入蒸馏器的水中有高浓度的内毒素(100+ EU/mL)。这种情况可能发生在预处理单元操作(如活性炭罐)维护不良的情况下，也可能发生在城市水内毒素水平高的情况下，在一年的某一段时间里，他们的消毒剂会从氯胺变成纯氯。

 

18. Do you get nucleasegeneration from biofilm and is more released during sanitization?

是否会发生从生物膜中生成核酸并且在消毒过程中被更多释放?

 

It would not be surprisingif substantial biofilm were allowed to be present from infrequently usedchemical sanitants. However, if hot water is used for sanitization, it woulddenature the nuclease enzymes, so this phenomenon might not occur with hotwater sanitized systems.

如果很少使用的化学消毒剂，那么生物膜顽固的存在于系统中，这并不奇怪。然而，如果用热水消毒，它会使核酸酶变性，所以在热水消毒系统这种现象可能不会发生。

 

19. In the new USP 1231 therecommended temperature in hot sanitizing has changed. The previousrecommendation of at least 80°C has been lowered to 65-80°C. Now temperaturesfar in excess of 80°C are explicitly deemed inadvisable. Is this correct?

在新的 USP 1231 中，热消毒建议的温度发生了变化。先前建议的至少80°C已降至65-80°C。现在温度远远超过80°C被明确认为不建议。这是正确的吗？

 

Yes. A temperature of 80˚Cis very “forgiving” of cooler locations which can still be sanitized even witha 10-15˚C temperature loss as it penetrates throughout the system by convectionand conduction, so it is very effective. Cooler temperatures (down to 65˚C) canalso be used but is “unforgiving” of yet cooler locations such as outlet valvesoff of the main loop.  So such cooler locations must be flushed with thisslightly cooler hot water in order to assure that all surfaces reach sanitizingtemperatures greater than 60˚C. Unless systems are specifically designed forthis, temperatures hotter than 80˚C can impact the longevity of systemmaterials (e.g. gaskets and diaphragms). A temperature of 80˚C is well hotenough to kill the most heat resistant biofilm organisms that will colonize awater system (D value of about 5 milliseconds).

是的。80˚C的温度对较冷的地方是非常“宽容”的，即使有10-15˚C的温度损失下仍然可以消毒，因为它通过对流和传导渗透到整个系统，所以它是非常有效的。也可以使用较低的温度(65˚C)，但对于主回路的出口阀门等温度较低的位置是“不可原谅”的。因此，这些较冷的位置必须用稍凉的热水冲洗，以确保所有表面达到60˚C以上的消毒温度。除非系统专门为此设计，否则超过80˚C的温度会影响系统材料(如垫圈和隔膜)的使用寿命。80˚C的温度足以杀死大多数将在水系统中定植的耐热生物膜(D值约为5毫秒)。

 

20. When sampling waterports should we hook up process hoses?  Is this a requirement or arecommendation?

在水口取样时，我们是否需要连接工艺软管?这是要求还是建议?

 

If the sampling is for QC “release” of the water for manufacturing use, then the outlet used by manufacturing must be sampled in EXACTLY the same fashion as it is used by manufacturing – same outlet sanitization (if any), same manufacturing hose (no matter how grungy or poorly maintained), same     pre-flushing (if any), same everything. The purpose of the sample data is to duplicate the same quality of water that manufacturing is using, so you have to duplicate in sample collection how the water is drawn from the system for use. Those procedures of water use can significantly contaminate pristine water within a water system when it exits, so that  “nasty” water is delivered to a manufacturing operation. If you sample the water differently (better) than it is used by manufacturing, you will get  lower (better) micro counts that are not representative of the water quality that is actually be used. Sampling like manufacturing water use for QC release is required by FDA to be identical. If it is not, this could earn you an FDA483 observation or worse.

如果取样是为了QC“放行”生产用的水，然后生产使用的出口必须以 与生产使用完全相同的方式取样：采用相同清洁处理措施(如有)；同样的生产软管(无论多么破旧或维护不善)；同样的预冲洗(如果有的话)，一切都一样。样品数据的目的是复制制造所用的水的相同质量，所以在样品收集中必须复制如何从系统中抽取水以供使用。这些用水程序在出水时可能会严重污染水系统内的原始水，因此“肮脏的”水被输送到生产操作中。如果你用不同的方法(更好的)对水进行采样，你会得到更低(更好的)的微生物计数，而这些计数不能代表实际使用的水质。FDA要求QC放行的生产用水取样必须相同。如果不是，这可能会让你获得FDA483的观察，甚至更糟。

If the water is being sampled for process control (PC) for the purpose of water system monitoring and systemic microbial control, it might be done through sampling ports that are not used by manufacturing. Since we know that the outlets themselves can contribute to the bioburden of the collected water,  extreme efforts can be used to assure that the outlet does not add to the microbial content of the water as it exits the system (using extreme outlet sanitization, very vigorous and thorough flushing, sterile hoses, etc.). For PC, you are interested in the quality of the water within the system behind the valve and do not want contamination in a sampling port to bias the interpretation of the data.

如果为了水系统监测和系统微生物控制的目的对水进行过程控制(PC)取样，可能会通过生产过程中未使用的取样端口进行。因为我们知道：出水口本身可能会对收集的水造成生物负担，可以尽最大努力确保出水口在离开系统时不会增加水的微生物含量(使用极端的出水口消毒，非常有力和彻底的冲洗，无菌软管等)。对于PC，您感兴趣的是阀门后的系统内的水的质量，不希望取样端口的污染影响数据的解释。

However, water collected from sampling ports (rather than manufacturing use outlets) usually cannot be used for final release (QC) of water since it is not collected in the manner it is actually used. Manufacturing does not generally use water drawn from sampling ports.

然而，从取样口(而不是生产使用口)收集的水通常不能用于水的最终放行(QC)，因为它不是以实际使用的方式收集的。生产过程中一般不使用从取样口抽取的水。

 

21. What is your risk inincreasing endotoxin levels due to the different sanitization methods?

因不同的卫生清洁处理方法而增加内毒素污染的风险有多大?

 

Endotoxin levels are typically a concern only for WFI systems. Most WFI systems are sanitized by elevated temperatures (hot water is better than steam since no special engineering is needed for hot water sanitization and it is plenty adequate), though more may employ ozone in the coming years as ambient non-distillation purification technologies become more widespread     with EP’s relaxation of the methods of preparing WFI in their WFI     monograph. Since thermal or ozone sanitization of WFI systems is typically no less frequent than weekly, that is not enough time for biofilm (with its endotoxin) to develop in the system and be released by periodic sanitization.  If the systems are much less frequently sanitized,  there is a chance that developing biofilm could release detectable endotoxin when killed by periodic sanitization.

通常只有WFI 系统关注内毒素水平。大多数 WFI 系统都因温度升高而得到消毒（热水比蒸汽好，因为热水消毒不需要特殊 工程，而且效果足够好），但随着 EP 放宽WFI 制备通则中制备WFI 的方法，系统消毒未来几年可能会使用臭氧。由于WFI系统的热水或臭氧净化通常不低于每周一次，这还不足以使生物膜（及其内毒素）在系统中发育并定期释放。如果这些系统消毒的频率要低得多，那么生物膜有可能在被定期消毒杀死前释放到系统，并检测到内毒素。

If chemical     sanitizers other than ozone are used (this would be very atypical for a     WFI system or an endotoxin-controlled Purified Water system), the     sanitizer would have to be rinsed out, which would also rinse out any     released endotoxin.

如果使用臭氧以外的化学消毒剂（对于WFI系统或需要进行内毒素控制的纯化水系统来说，这是非常不典型的），消毒剂必须冲洗掉，这也将冲洗掉任何释放的内毒素。