USP制药用水和分析用水21问.docx

USP制药用水和分析用水21问2017-08-24Julia法规翻译USP制药和分析用水21问/frequently-asked-questions/water-pharmaceutical-and-analytical-purposesFAQs: Water for Pharmaceutical and AnalyticalPurposes1. Why are there no microbial requirements included inthe monographs for Purified Water and Water for Injection?为什么在纯化水和注射水各论中没有微生物要求？Because of the various uses of these waters, microbialrequirements are not included in these monographs since this would unnecessarilyburden some users with meaningless and/or inconsequential or inappropriaterequirements, e.g. water used for many laboratory analyses. Microbialguidelines are provided under the informational chapterWater forPharmaceutical Purposes where it states that the user shouldestablish in-house specifications or fitness for use microbial levels abovewhich the water is unsuitable for use.因为这些水有不同用途，而将微生物要求放在各论中会给一些用户带来不必要的负担，增加了无意义和/或无效果并且不恰当的要求，例如，用于一些化验室分析的水。在参考章节“药用水”里有给出微生物指南，其中讲了用户应建立内控标准或用途适当性，当水中微生物水平高于该限度时则不适合该用途。2. What is the purpose of microbial Alert and ActionLevels for Purified Water and Water for Injection? 纯化水和注射水的微生物警戒限和行动限目的是什么？Alert and Action Levels are process control terms andshould be established at levels indicative of the water system trending outsideof its normal microbial control range. These levels should be established atlevels no higher than, and preferably lower than, those listed inWater forPharmaceutical Purposes based on the normal microbialperformance trends in your water system. The purpose of Alert and Action Levelsis to trigger additional, non-routine, rather than routine microbial controlmeasures. These additional control measures should prevent objectionable levelsand types of microorganisms from being present in the water, based on for thewaters use.警戒限和行动限是过程控制的术语，其水平应反映出超出正常微生物控制范围时的水系统趋势。警戒限和行动限水平应基于你的水系统中常规微生物性能趋势制订，其水平应不高于（最好是低于）“制药用水”中所列限度。警戒限和行动限的目的是激活更多的非常规动作，而不仅是进行日常的微生物测量。这些额外的控制措施应依据水的用途防止水中出现的微生物种类及其不良水平。3. For off-line testing of water samples for WaterConductivity and Total Organic Carbon , how long can Istore samples before testing?对于水电导率与总有机碳的离线检测，样品在检测前可以存放多久？USP is silent on a specific answer to this question.It is understood that some manufacturers have their analyses performed byexternal laboratories which may take several days or longer. For this reason,there is no time limit.USP对此问题上没有专门解释。大家知道，有些厂家是委托外部实验室检测的，这样可能就会耗费几天甚至更长。基于这类原因，未设置时间限制。In general, you can wait as long as you want at yourrisk. But it is advised to test as soon as practical for the following reasons;1) when stored, the water purity only degrades over time. SincePurifiedWater,Water for Injectionor the sterile waters are of such highpurity, the passage of time does not do anything except potentially degrade thesample due to environmental, ambient, or container factors; and 2) water istypically not produced in batches, but rather it is usually purified, produced,and consumed continuously. The water may have had direct product impact orcontact before any lab analysis is executed. Delays in testing only increasethe amount of potential product impact in the event of a failed test.通常，在你可接受风险范围内，厂家可以放置任意时长。不过，仍建议尽快检测，原因如下：1.样品在放置时，水质会随着时间推移而变差。因为纯化水、注射用水或无菌水的纯度较高，放置时间只会有周围的环境、室温、储存的容器等因素使样品质量变差，而没有任何好处。2.纯化水一般不是按批制成，通常是连续纯化、制备和使用的。在化验室进行分析之前，水样可能已经对产品产生直接影响或有过直接接触，延迟检测只会增加潜在产品影响的数量-如果检测不合格的话。4. For off-line testing of water samples for GeneralChapters Water Conductivity and Total Organic Carbon ,how should I store the samples?在水电导率和总有机碳章节中，检测离线水样时，如何保存水样？For lab analyses, samples should be stored incontainers that do not adversely impact the test results. This is to preventfalse positives and unnecessary investigations. For example, storage of waterin a glass container for a few hours is usually good, but storage for a longertime will result in a modest increase in the sample conductivity. This is dueto the leaching of sodium silicate from the glass, raising the pH and the waterconductivity, and threatening to failWater Conductivity . Ingeneral, clean plastic containers are a better choice for long term storage ofsamples forWater Conductivity testing. ForTotal OrganicCarbon , there is a similar rationale - many types ofnon-shedding plastics or glass suffice. In general, storage at ambient orrefrigerated temperatures is best for these chemical tests, while refrigeratedstorage is advised for samples used in microbial testing. Cleanliness of anycontainer is most critical. Due to the very high purity of these waters,fingerprints, soaps, and other residues must be avoided. False positives canresult.在实验室分析中，样品应贮存于不会对检测结果产生不良影响的容器中。这是为了防止错误的阳性结果以及不必要的调查。例如，水在玻璃容器中贮存几个小时通常是没有问题的，但是放置更长时间则会导致样品电导率缓慢上升。这是因为玻璃中的硅酸钠溶出，使水中的pH和电导率升高，可能导致电导率检测不通过。通常来说，长期存贮后检测电导率时宜使用洁净在塑料容器。对于总有机碳检测，存在类似的原理-有许多不脱落的塑料或者玻璃材质满足要求。一般来说，检测化学指标时，最好将样品存贮于室温或冷藏温度下，微生物检测用样品则建议冷藏存贮。容器的清洁时最关键的。由于这些类别的纯度非常之高，因此应避免指印、肥皂或者其他残留，否则可能导致假性不合格。5. Can I do Water Conductivity and TotalOrganic Carbon testing on-line?电导率和总有机碳可以在线检测吗？These two chapters specifically state that these testscan be performed off-line or on-line. There are benefits and challenges foreach approach, and they are described in more detail in these chapters and inWaterfor Pharmaceutical Purposes . In general, on-line testingavoids the risk of contamination of off-line samples by humans, containers, orthe environment, and it provides immediate analysis and direct opportunitiesfor real-time control, decision and intervention. For example, you cancontinuously test and accept the water (for these chemical attributes).Conversely, you can prevent the distribution of the water in the event of afailed test in real time. However, for a facility with multiple types of watersand loops, a centralized lab analysis system may offer a more economicalchoice. In either case, the water sample must be representative of the waterused in production.这两个章节专门描述了这两个检测可以离线或者在线进行，两个方法各有利弊，在这两个章节中以及“制药用水”中有详细阐述。通常来说，在线检测避免了由于人为原因、容器原因和环境原因对离线样品带来的污染风险，实现了实时检测，提供了实时控制、决策和干预的直接机会。例如，可以连续检测放行水（基于这些化学属性）。反过来说，你可以在实时检测不合格时防止水进入循环。但是，如果一个工厂有多种水多个循环回路，中央化验室分析系统则可以提供更为经济的选择。不管是何种情况，水样都必须可以代表生产用水。6. What is the total organic carbon (TOC) limit forPurified Water and Water for Injection?纯化水和注射水的总有机碳（TOC）限度是多少？There is a target limit response of 500 gof Carbon/L. The true limit is the response of the TOC measurement system to a500 g Carbon/L (prepared from sucrose) solution, Rs, corrected for theresponse to reagent water, Rw. This limit is equal to Rs Rw. The actualnumber will vary based upon your reference standard solution, your equipment,background carbon, etc. USP Reference Standards are required for use.这里有一个500g/L的“目标限度响应”，它是TOC测量系统对500g碳/L的（以蔗糖制备）溶液（RS）在扣除试剂水响应（RW）之后的响应的真实限度。该限制等于RS-RW。实际值随着对照液、设备、背景碳等不同而波动。检测中需要使用USP对照品。7. How often do I perform the system suitability testin Total Organic Carbon General Chapter ?有机碳总检测时系统适应性试验要求频次是多少？USP General Chapterintentionallysays 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, say20 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 factoris the risk of a non-conforming system suitability test result since the Rs-Rwresult used in this calculation is the limit response for the instrument, thecrucial pass/fail value for the TOC test. If a non-conforming systemsuitability test is obtained, it implicates the inaccuracy of all TOC testresults since the previous successful system suitability test.For this reason, many users choose to perform thesystem suitability test more frequently than the stability of the TOCinstrument response might suggest, just to minimize the impact of a possiblynon-conforming result. This is why a typically low TOC water system is at lessrisk, even with a failed SST. If the SST fails, some remediation is necessaryto re-adjust the instrument, replace a lamp, or some other means of instrumentimprovement. But even a 50% error will have little impact on the past TOCreadings (since the readings, even with this error, are so low relative to theLimit). On a high TOC water system, the failure of the SST is possibly morecritical. This is up to the risk the user is willing to assume, knowing thehistoric stability of their instrument and other factors. Therefore, theTotalOrganic Carbon is silent on the frequency of performing thesystem suitability test because it is up to the user to decide what isappropriate.USP通则无意指定系统适应性试验（SST）的运行频次，因为该频次取决于总有机碳（TOC）仪器的响应和其他与水质和风险的稳定有关的因素。如果一个水系统的TOC非常低，比如说20ppb，因为风险较小那么很多人选择降低检测频次。不同的TOC测量技术的稳定性可能在较长期时间段内有所不同。仪器生产商可以对用户在此方面提出建议，用户的经验在确定适当的频次时也很有价值。由于在此计算中所使用的RS-RW结果是仪器的一个限度响应值，TOC检测中关键的合格/不合格，因此另一个因素是SST结果不合格时的风险。如果SST结果不合格，则表示自上次SST合格之后所有的TOC检测结果均是不准确的。因此，许多用户会选择使用TOC仪器响应稳定性所需的SST频次更高的频次，只是为了减少可能的不合格SST结果所带来的影响。这就是为什么一般即使SST不合格，仍能保持低TOC水系统风险较低。如果SST不合格，则必须采取补救措施，对仪器重新调、替换灯泡，或其它一些改善仪器的方法。但即使有50%的误差仍会对过去的TOC读数结果产生微小影响（因为这些读数，即使有错误，相对于限度也还是很低的）。对于TOC值较高的水系统，SST不合格可能会更严重。这取决于用户愿意假定的风险、对其仪器历史稳定性的了解以及其它因素。因此，总有机碳对于SST的执行频次保持沉默，因为要由用户来决定怎样做是合适的。8. How long can I store and reuse reference standardsolutions prepared for the Total Organic Carbon system suitabilitytest?TOC系统的标准适用性试验所用的标准溶液的存放和重复使用时间有多长？Where USP is silent on storage conditions and thestability of prepared Total Organic Carbon (TOC) reference standard solutions,the solutions should be 1) prepared fresh or 2) used within the expiry ifprocured from 3rd party supplier or 3) used within a timeframe determined bystability studies. In all cases, USP Reference Material is specified. Severalfactors can influence the stability of the reference standard solutions. Theseinclude temperature, light, oxygen, microbial decomposition, and adsorption tothe container surface. The developments of turbidity, additional color, orperformance variability relative to freshly prepared solutions are indicatorsof instability. Most of the suppliers of solutions specify expiry dates. But asa practical matter, concentrated reference standard solutions of Sucrose last3-6 months, and analogous solutions of 1, 4 Benzoquinone (pBQ) last about 2months, assuming they are stored at appropriate temperatures in appropriatecontainers and protected from light (for pBQ). It is recommended to userefrigeration since this slows down solution degradation, and reduces microbialgrowth, particularly in the sucrose solution.如果USP没有给出TOC对照液的存贮条件和稳定性，应采用以下方案解决：1）即用即配；2）如果在第三方供应商处购买，则在有效期内使用；3）用稳定性研究确定有效期，在该有效期内使用。所有情形下均需要使用USP对照品。对照液稳定性会受到几个因素的影响。不稳定的指征有混浊、颜色加深、相对新配溶液其性能波动。大多溶液供应商会指明有效期。不过作为常规要求，假定存贮在适当容器适当温度下，蔗糖浓对照液有效期3-6个月，1，4-苯醌（PBQ）对照液避光有效期2个月。建议冷藏保存，因为这样能减慢溶液降解，减少微生物滋生，尤其是蔗糖溶液。9. What is the main reason for KCl addition in theWater Conductivity test for pH measurement?在电导率试验中加入KCl测量pH值的主要原因是什么？In Stage 3, a neutral electrolyte (KCl) is added toincrease the ionic strength and accurately measure the pH of the solution. Ifthe ionic strength of the solution is not increased, the pH measurement will behighly unstable and inaccurate. So KCl is added to make a valid pH measurementas a part of theWater Conductivity -Stage 3 test. Theincrease in the ionic strength is needed so that there is minimal concentrationgradient across the pH electrode diaphragm/junction. A large concentrationgradient results in a lack of equilibrium and unstable pH response.在第3阶段中，要求加入中性电解质（KCl）增加离子强度，准确地测量溶液的pH值。如果不增加溶液的离子强度，则pH测量结果会高度不稳定不准确。因此，添加KCl是为了使pH值测量有效，它是的第3阶段测试的一部分。增加离子强度是为了减少pH电极隔膜/接头间的浓缩梯度。浓缩梯度过大会导致平衡缺失，pH响应不稳定。10. Can I start at Stage 2 for Water Conductivity, or do I need to start at Stage 1?检测电导率时，是否可以从第二阶段测试开始还是需要从第一阶段开始？There is no need to perform stages 1 and 2 in order.You can go directly to Stage 2 if offline testing in preferred - you do nothave to fail stage 1 first.不需要按照顺序执行第1阶段和第2阶段测试。如果你更倾向于离线测试，你可以直接进入第2阶段-不必先等着第1阶段检测不合格。11. Is the requirement for conductivity cell constantof 2% of the nominal value?电导池常数是否需要在名义值的+/-2%范围内？The cell constant accuracy must be 2% of thecertified value, not the nominal value.电导池常数的精度必须是测得标准值的+/-2%，而名义值。12. What is a suitable container foroff-line determination of conductivity?离线检测电导率时“合适的容器”指什么？In general, any material that does not impact theconductivity in any appreciable way is suitable. Many plastic containersincluding PTFE, HDPE, LDPE and some polycarbonates are appropriate. Glasscontainers for immediate testing are appropriate. Regardless of the material,they have to be clean and free of any cleaning reagents such as soaps. Soapsare very conductive.一般来说，任何不会以可检出程度影响电导率的材料都是合适的。许多塑料容器包括聚四氟乙烯、聚乙烯、LDPE（低密度聚乙烯）和聚碳酸酯都是合适的。立即检测时也可以使用玻璃容器。不管是何材料，容器均必须清洁，不残留任何清洁剂如肥皂。肥皂导电性很强。13. There are no tests for pH, nitrates, or heavymetals? Is this correct?各论没有pH值、硝酸盐和重金属项目？这个正确吗？Yes, this is correct. There has never been a test fornitrates for USP waters. The heavy metals test on USP waters was deleted in1996. The pH test was deleted in 1998. Note - There is a pH measurement (not atest) as a part of Stage 3 test forWater Conductivity , butthis is still a conductivity limit test. Note that you cannot fail the formerpH specifications of water (pH 5.0 7.0) if you pass the conductivityspecifications. You also cannot fail the heavy metals test or the nitrate testif you pass conductivity and your water system starts with water compliant withthe requirements for one of the drinking waters specified in the monographs(for the US, EU, Japan, or WHO). In some cases, these tests may be required byother pharmacopoeia.是的，这是正确的。USP水中从未检测硝酸盐，重金属检测是1996年删除的，pH检测是在1998年删除的。【注：在水电导率的第3阶段测试中有一部分是pH值测量（不是测试），但它仍然是一个电导率限度测试。请注意，如果你在通过电导率测试】。注意，如果你的电导率结果合格，就肯定会符合之前的pH标准（pH 5.0 7.0）。如果你的电导率合格，并且你的原水符合各论中饮用水的要求之一（US、EU、日本或WHO），你也不可能重金属或硝酸盐不合格。在有些情形下，其它药典可能会要求这些测试。14. May I release water for use by performingmicrobial testing on water from a sample port?我可以通过完成测试水样的微生物来放行水吗？You may do so, but only under certain circumstances.The microbial quality of the water within the system, as reflected by waterfrom that sample port, may be better than the quality that is delivered to thepoint of use (POU) during manufacturing use. This is because of microbialcontamination of the system water that can occur as it is transferred from thesystem outlets to the POU. It is the quality of water DELIVERED from the systemto the POU that affects products and other uses.你可以这样做，但只有在特定情形下才可以。如果是检测了取样点，则其检测结果所反映出的水系统的微生物质量可能会优于生产使用中传送至使用点（POU）的水质。这是因为系统水的微生物污染可能是在水从系统出口传送至POU的过程中发生的，而影响产品和其它用途的水质正是传送之后的水。If you have good water use practices such that themicrobial count from a sample port is essentially the same as at a POU whendelivered by the manufacturing use practice, then the risk of the sample portmicrobial counts falsely reflecting the quality of the delivered water is low.如果你有良好用水规范，使得取样口处的微生物结果与遵守生产使用规范传送至POU处的基本相同，则取样口处微生物结果虚假反映传送之后的水质的风险就会很低。Generally, water release for use should be based on aPOU sample reflecting manufacturings water use practices and not on sampleport data.一般来说，用水放行应基于反映生产用水规范的POU样本，而不是基于取样口的数据。15. Is the outlet on the water distribution system,sometimes called a point of use outlet, considered to be the point of use?是否认为水循环系统的总出口，有时称为使用点出口，是使用点？No. The destination of that water where it will beused for product formulation or cleaning or where it enters a manufacturingprocess is the true point of use. The quality of water at the true point ofuse, as delivered by manufacturing (or by a sampling process identical to themanufacturing water delivery process) must be known at all points of usereceiving water from the system. The water quality at the true point of use iswhere the water must be “fit for use”, i.e. pass your water specifications.不。用于药品配方或清洁或进入生产流程的水的目标点才被是实际使用点。所有从系统传送（指生产过程中传送；如果取样过程与生产用水传送过程相同的话，也可以是取样点）达到的使用点，即实际使用点的水质均应知晓。在真正的使用点的水质是必须“适合使用”，即符合你的水质量标准。16. If I do not have a water microbial specificationbut only an Alert and Action Level, is there a microbial level considered to beunfit for use?如果我没有给水制订微生物标准，仅只有警戒限和行动限，那么是否有某个微生物限度是不适合使用的？Yes. Action Levels in USP (100cfu/mL forPurified Water and 10cfu/100mL for Water for Injection) are generallyconsidered to represent a level above which the water is unfit for use. That iswhy an OOS investigation must be undertaken if those Action Levels areexceeded.是的。美国药典中规定的行动限（纯化水100CFU/ML，注射用水10CFU/100ML）通常表示如果水超过该水平即不适合使用。这就是为什么如果超出行动限则必须进行OOS调查。So whether you declare microbial specifications ornot, they are assumed to be those “compendia action level” values contained inGeneral Chapter . To avoid ever exceeding a water microbialspecification, trend-based Alert and Action Levels should be used to monitorand control the water system so it always produces water that is fit for use.因此，无论你是否将其订为微生物标准，上述标准都被认为是通则中的“药典行动限”。为了避免超出水的微生物标准，应基于警戒限和行动限进行趋势分析，以对水系统进行监控，从而保证其持续生产出符合用途的水。17. What are the most common issues encountered in theWFI production systems produced under GMP. What should we look for?GMP要求下注射用水制备系统最常见问题是什么？我们应该找些什么？1.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 sur