FAQs:Water for Pharmaceutical and Analytical Purposes

常見(jiàn)問(wèn)題解答：適用于制藥和分析目的的水

 

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

為什么純化水和注水專著中沒(méi)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.

由于這些水的用途各異，這些專著中不包括微生物要求，因?yàn)檫@會(huì)不必要地使一些用戶背負(fù)毫無(wú)意義和/或無(wú)關(guān)緊要或不恰當(dāng)?shù)囊螅缭S多用于實(shí)驗(yàn)室分析的水。微生物指南根據(jù)信息章節(jié)"藥物用途水"<1231>其中規(guī)定，用戶應(yīng)建立內(nèi)部標(biāo)準(zhǔn)或適合使用的微生物水平，未達(dá)到該標(biāo)準(zhǔn)的水不適合使用。

 

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

制定純化水和注水的微生物警戒和行動(dòng)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.

警戒和行動(dòng)限是過(guò)程控制術(shù)語(yǔ)，應(yīng)建立在指示水系統(tǒng)在其正常微生物控制范圍之外的趨勢(shì)水平。在你的水系統(tǒng)，這些水平應(yīng)建立在不高于，最好低于那些列在根據(jù)<1231>正常微生物性能趨勢(shì)。警戒和行動(dòng)限的目的是觸發(fā)額外的非常規(guī)，而不是常規(guī)的微生物控制措施。基于水的用途，這些額外的控制措施應(yīng)防止令人反感的水平和微生物類(lèi)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?

對(duì)于水導(dǎo)率和有機(jī)碳總量的水樣離線測(cè)試，我可以在測(cè)試前儲(chǔ)存樣品多長(zhǎng)時(shí)間？

 

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未給出這個(gè)問(wèn)題的具體答案。據(jù)了解，一些制造商的分析由外部實(shí)驗(yàn)室進(jìn)行，這可能需要幾天或更長(zhǎng)時(shí)間。因此，沒(méi)有時(shí)間限制。

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.

一般來(lái)說(shuō)，只要在你的可承受風(fēng)險(xiǎn)內(nèi)，你可以放置等待。但出于以下原因，建議盡快進(jìn)行實(shí)際測(cè)試：1） 儲(chǔ)存時(shí)，水的純度只會(huì)隨著時(shí)間而下降。由于純化水、注水或無(wú)菌水的純度如此之高，因此隨著時(shí)間的流逝，除了由于環(huán)境、環(huán)節(jié)或容器因素而可能使樣品降解外，沒(méi)有任何益處：和 2） 水通常不是分批生產(chǎn)的，而是通常連續(xù)凈化、生產(chǎn)和使用。在執(zhí)行任何實(shí)驗(yàn)室分析之前，水可能具有直接的產(chǎn)品影響或接觸。如果測(cè)試失敗，延遲測(cè)試只會(huì)增加潛在產(chǎn)品影響的數(shù)量。

 

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

對(duì)于通則章節(jié)，水導(dǎo)率和有機(jī)碳總量的水樣離線測(cè)試，應(yīng)如何儲(chǔ)存樣品？

 

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.

對(duì)于實(shí)驗(yàn)室分析，樣品應(yīng)儲(chǔ)存在不會(huì)對(duì)測(cè)試結(jié)果產(chǎn)生不利影響的容器中。這是為了防止誤報(bào)和不必要的調(diào)查。例如，將水儲(chǔ)存在玻璃容器中幾個(gè)小時(shí)通常是可行的，但長(zhǎng)時(shí)間儲(chǔ)存將導(dǎo)致樣品導(dǎo)電率略有增加。這是由于硅酸鈉從玻璃中浸出，提高pH和水導(dǎo)率，并有可能導(dǎo)致水的電導(dǎo)率<645>測(cè)試不合格。一般來(lái)說(shuō)，清潔塑料容器是長(zhǎng)期儲(chǔ)存水導(dǎo)率樣品的更好選擇，見(jiàn)<645>測(cè)試。對(duì)于總有機(jī)碳<643>，有一個(gè)類(lèi)似的理由——用一些非脫落塑料或玻璃就足夠了。一般來(lái)說(shuō)，環(huán)境或冷藏溫度下的儲(chǔ)存環(huán)境最適合這些化學(xué)測(cè)試，而冷藏儲(chǔ)存建議用于微生物測(cè)試的樣品。任何容器的清潔度都是最關(guān)鍵的。由于這些水的純度很高，必須避免手指印、肥皂和其他殘留物。這些可能導(dǎo)致誤報(bào)。

 

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

我可以在線進(jìn)行水導(dǎo)率和有機(jī)碳總量測(cè)試嗎？

 

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.

這兩章特別指出，這些測(cè)試可以離線或在線進(jìn)行。每種方法都有其優(yōu)點(diǎn)和不足，在這些章節(jié)和《藥用水》<1231>中都詳細(xì)描述了這些方法。一般來(lái)說(shuō)，相對(duì)于離線，在線測(cè)試可避免人、容器或環(huán)境對(duì)樣品污染的風(fēng)險(xiǎn)，并為實(shí)時(shí)控制、決策和干預(yù)提供即時(shí)分析和直接機(jī)會(huì)。例如，您可以持續(xù)測(cè)試和接受水（針對(duì)這些化學(xué)屬性）。相反，如果測(cè)試失敗，您可以實(shí)時(shí)阻止水的分配。然而，對(duì)于具有多種類(lèi)型的水和循環(huán)的設(shè)施，集中式實(shí)驗(yàn)室分析系統(tǒng)可能提供更經(jīng)濟(jì)的選擇。在這兩種情況下，水樣必須代表生產(chǎn)中使用的水。

 

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

純化水和注水的有機(jī)碳（TOC）總量限值是多少？

 

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.

"目標(biāo)限量響應(yīng)"為 500 μg 碳/升。真正的限制是TOC 測(cè)量系統(tǒng)對(duì) 500 μg 碳/L（從蔗糖中制備）溶液（Rs）的響應(yīng)，該溶液已更正為扣除對(duì)試劑水 Rw 的反應(yīng)。此限制等于 Rs -Rw。實(shí)際數(shù)字將根據(jù)您的參考標(biāo)準(zhǔn)溶液、設(shè)備、背景碳等而有所不同。同時(shí)，您需要使用USP 參考標(biāo)準(zhǔn)溶液。筆者：注意USP44的更新。

 

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

根據(jù)總有機(jī)碳通則，我何時(shí)進(jìn)行系統(tǒng)適用性測(cè)試？

 

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 通則<643>故意不說(shuō)何時(shí)何頻率運(yùn)行系統(tǒng)適用性測(cè)試（SST）。理由是，此頻率取決于總有機(jī)碳 （TOC） 儀器響應(yīng)的穩(wěn)定性以及與水質(zhì)和風(fēng)險(xiǎn)相關(guān)的其他因素。如果優(yōu)質(zhì)水系統(tǒng)的 TOC 非常低，比如 <20ppb，那么許多人會(huì)選擇降低測(cè)試頻率，因?yàn)轱L(fēng)險(xiǎn)較小。不同 TOC 測(cè)量技術(shù)的穩(wěn)定性可能會(huì)在較長(zhǎng)時(shí)間內(nèi)有所不同。儀器制造商可以就此問(wèn)題向用戶提供建議，在確定合適的頻率方面“用戶經(jīng)驗(yàn)”也非常有參考價(jià)值。另一個(gè)因素是系統(tǒng)適宜性測(cè)試結(jié)果不合格的風(fēng)險(xiǎn)，因?yàn)榇擞?jì)算中使用的（ Rs-Rw ）結(jié)果是儀器的極限響應(yīng)，即 TOC 測(cè)試的關(guān)鍵通過(guò)/失敗值。如果獲得不合格的系統(tǒng)適宜性測(cè)試，則涉及自上次系統(tǒng)適宜性測(cè)試以來(lái)所有 TOC 測(cè)試結(jié)果的不準(zhǔn)確的可能性。因此，相對(duì)于TOC 儀器響應(yīng)的穩(wěn)定性所提示的時(shí)機(jī)，為了最大限度地減少可能不符合結(jié)果的影響，許多用戶選擇更頻繁地執(zhí)行系統(tǒng)適宜性測(cè)試。這就是為什么一個(gè)典型的低 TOC 水系統(tǒng)的風(fēng)險(xiǎn)較小，即使 SST 失敗也是如此。如果 SST 失敗，則需要進(jìn)行一些補(bǔ)救，以重新調(diào)整儀器、更換燈或改進(jìn)儀器的其他方法。但是，即使 50% 的錯(cuò)誤也不會(huì)對(duì)過(guò)去的 TOC 讀數(shù)產(chǎn)生什么影響（因?yàn)樽x數(shù)即使有此錯(cuò)誤，相對(duì)于極限也非常低）。在高 TOC 水系統(tǒng)中，SST 的失敗可能更為嚴(yán)重。這是由用戶愿意承擔(dān)的風(fēng)險(xiǎn)，知道他們的儀器的歷史穩(wěn)定性和其他因素。因此，有機(jī)碳總量<643>對(duì)執(zhí)行系統(tǒng)適宜性測(cè)試的頻率保持沉默，因?yàn)橛捎脩魶Q定什么時(shí)候執(zhí)行是合適的。

 

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

我可以在多長(zhǎng)時(shí)間內(nèi)存儲(chǔ)和重復(fù)使用為總有機(jī)碳系統(tǒng)適宜性測(cè)試準(zhǔn)備的參考標(biāo)準(zhǔn)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 對(duì)存儲(chǔ)條件和已準(zhǔn)備好的總有機(jī)碳（TOC） 參考標(biāo)準(zhǔn)溶液的穩(wěn)定性不做規(guī)定，則標(biāo)準(zhǔn)溶液應(yīng)為：1）新鮮準(zhǔn)備或 2）在到期日內(nèi)使用，如果從第三方供應(yīng)商處采購(gòu)，或在穩(wěn)定性研究確定的時(shí)限內(nèi)使用。在所有情況下，應(yīng)使用 USP 參考品。有幾個(gè)因素會(huì)影響參考標(biāo)準(zhǔn)溶液的穩(wěn)定性。這些包括溫度、光、氧、微生物分解和溶質(zhì)吸附到容器表面。與新準(zhǔn)備的溶液相比，濁度、額外顏色或性能變異性的變異是不穩(wěn)定的指標(biāo)。大多數(shù)標(biāo)準(zhǔn)溶液供應(yīng)商都指定了到期日期。但作為一個(gè)實(shí)際問(wèn)題，假設(shè)它們存儲(chǔ)在適當(dāng)?shù)娜萜骱蜏囟认拢⒎乐构饩€照射（用于 pBQ保存），高濃度蔗糖的參考標(biāo)準(zhǔn)溶液可保持 3-6 個(gè)月；1，4 -對(duì)苯醌 （pBQ）的濃溶液可保持約 2 個(gè)月。特別是蔗糖溶液，建議冷藏保存，因?yàn)檫@可以減緩溶液的降解，并減少微生物生長(zhǎng)。

 

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

在pH值測(cè)量的水導(dǎo)率測(cè)試中增加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 階段，添加中性電解質(zhì) （KCl） 以增加離子強(qiáng)度并準(zhǔn)確測(cè)量溶液的 pH 值。如果不增加溶液的離子強(qiáng)度，pH值測(cè)量將非常不穩(wěn)定和不準(zhǔn)確。因此，添加KCl以進(jìn)行有效的 pH 值測(cè)量，這是作為水導(dǎo)率<645> -第 3 階段測(cè)試的一部分。需要提高離子強(qiáng)度，以便在 pH 電極隔膜/結(jié)點(diǎn)中實(shí)現(xiàn)最小的濃度梯度。大濃度梯度導(dǎo)致缺乏平衡和不穩(wěn)定的pH響應(yīng)。

 

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

我可以從第二階段開(kāi)始水導(dǎo)率，還是需要從第一階段開(kāi)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.

無(wú)需按順序執(zhí)行第 1 階段和第2 階段。如果首選的離線測(cè)試，您可以直接轉(zhuǎn)到第 2 階段 - 您不必先通過(guò)第 1 階段。

 

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

電導(dǎo)率電極電導(dǎo)常數(shù)的要求是標(biāo)稱值的±2%嗎?

 

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

電極電導(dǎo)常數(shù)的恒定精度必須是校準(zhǔn)值的±2%，而不是標(biāo)稱值。

 

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

什么是用于離線電導(dǎo)率測(cè)定的"合適容器"？

 

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.

一般來(lái)說(shuō)，任何不以任何明顯的方式影響導(dǎo)電性的材料都是合適的。許多塑料容器，包括PTFE，HDPE，LDPE和一些聚碳酸酯是適當(dāng)?shù)摹２Ａ萜骺梢粤⒓催M(jìn)行測(cè)試。無(wú)論材料如何，它們必須清潔，并且不含肥皂等任何清潔試劑。肥皂水具有較強(qiáng)導(dǎo)電能力。

 

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

藥典水沒(méi)有pH、硝酸鹽或重金屬的測(cè)試？這是正確的嗎？

 

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，這是正確的。USP從未要求對(duì)水的硝酸鹽進(jìn)行測(cè)試。USP1996年刪除了對(duì)水的重金屬試驗(yàn)。pH 測(cè)試于 1998 年被刪除。[注意 - 作為水導(dǎo)率第 3 階段測(cè)試的一部分，pH 值測(cè)量<645>（不是測(cè)試）仍然是為了電導(dǎo)率限度而進(jìn)行的測(cè)試]。請(qǐng)注意,如果電導(dǎo)率符合標(biāo)準(zhǔn)，則先前水的pH標(biāo)準(zhǔn)(pH 5.0 - 7.0)必須合格。同樣，如電導(dǎo)率測(cè)試合格，并且您的水系統(tǒng)的源水符合各論(針對(duì)美國(guó)、歐盟、日本或世衛(wèi)組織)中指定的一種飲用水的要求，您也須確保重金屬測(cè)試或硝酸鹽測(cè)試合格。在某些情況下，其他藥典可能要求這些檢測(cè)。

 

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

我可以通過(guò)對(duì)取樣端口的水進(jìn)行微生物測(cè)試來(lái)放行水以供使用嗎?

 

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.

只有在某些情況下你才可以這樣做。從取樣端口的水反映系統(tǒng)制水質(zhì)量和在生產(chǎn)使用期間交付到使用點(diǎn)(POU)的質(zhì)量相比，就對(duì)系統(tǒng)內(nèi)水的微生物質(zhì)量評(píng)價(jià)而言，前者更好。這是因?yàn)橄到y(tǒng)水從系統(tǒng)出口轉(zhuǎn)移到POU時(shí)可能發(fā)生微生物污染。影響產(chǎn)品和其他用途的是從系統(tǒng)輸送到POU的水的質(zhì)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實(shí)踐，例如，當(dāng)交付到生產(chǎn)使用時(shí)，取樣端口的微生物數(shù)量與POU的微生物數(shù)量基本相同，那么樣品端口微生物數(shù)量錯(cuò)誤反映交付的水質(zhì)量的風(fēng)險(xiǎn)很低。

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

一般來(lái)說(shuō)，水的放行應(yīng)該基于反映生產(chǎn)用水環(huán)節(jié)的POU樣品，而不是取樣端口數(shù)據(jù)。

 

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

分配系統(tǒng)上的出水口，有時(shí)稱為使用點(diǎn)出水口，是否被認(rèn)為是使用點(diǎn)?

 

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。水的輸送目的地是用于配方生產(chǎn)或清潔或具體生產(chǎn)工藝的地方，這才是真正的使用點(diǎn)。在從系統(tǒng)接收水的所有使用點(diǎn)上，必須知道通過(guò)生產(chǎn)(或通過(guò)與生產(chǎn)用水相同的采樣過(guò)程)交付的真正使用點(diǎn)上的水的質(zhì)量。真正使用點(diǎn)的水質(zhì)必須是“適合使用”的水，即符合您的水標(biāo)準(zhǔn)。

 

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?

如果我沒(méi)有水質(zhì)微生物標(biāo)準(zhǔn)，但只有一個(gè)警報(bào)和行動(dòng)級(jí)別，是否只有微生物級(jí)別而無(wú)標(biāo)準(zhǔn)是不適合的?

 

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中的行動(dòng)水平(純凈水為100cfu/mL，注射用水為10cfu/100mL)通常被認(rèn)為代表一個(gè)水不適合使用的情形。這就是為什么OOS調(diào)查必須在超標(biāo)的情況下進(jìn)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，無(wú)論你是否聲明微生物指標(biāo)，它們都被假定為通論1231中所包含的“總體行動(dòng)水平”值。為了避免超過(guò)水的微生物標(biāo)準(zhǔn)，應(yīng)該使用基于趨勢(shì)的警報(bào)和行動(dòng)水平來(lái)監(jiān)測(cè)和控制水系統(tǒng)，以便它總是生產(chǎn)適合使用的水。

 

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

在GMP條件下的WFI生產(chǎn)系統(tǒng)中遇到的最常見(jiàn)問(wèn)題是什么？帶給我們什么啟示？

 

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.

一個(gè)常見(jiàn)的問(wèn)題是，加熱系統(tǒng)中有一個(gè)低溫WFI 子循環(huán)，帶有用于該子循環(huán)冷卻的大外殼和管熱交換器。當(dāng)子循環(huán)是熱水消毒，沒(méi)有足夠的接觸時(shí)間，冷卻熱交換器（和他們被困的冷水）讓他們徹底變熱和消毒。當(dāng)消毒不完全時(shí)，在恢復(fù)冷操作后，任何存活的生物膜會(huì)立即對(duì)冷循環(huán)環(huán)形成增殖，并被檢測(cè)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.

低溫循環(huán) WFI 系統(tǒng)的其他常見(jiàn)問(wèn)題是死角，有時(shí)是臨時(shí)的，這些死角是由打開(kāi)硬管連接到未使用和不抽水的設(shè)備造成的。消毒過(guò)程中的熱水與死角中被困的水不能很好地混合，所以死角永遠(yuǎn)不會(huì)得到消毒。如果在以前使用過(guò)程中有任何污染進(jìn)入側(cè)支，它會(huì)在未經(jīng)消毒的死角中有增無(wú)減地生長(zhǎng)，并持續(xù)污染循環(huán)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.

另一個(gè)常見(jiàn)問(wèn)題是蒸餾凈化過(guò)程中，進(jìn)入蒸餾器的水中有高濃度的內(nèi)毒素(100+ EU/mL)。這種情況可能發(fā)生在預(yù)處理單元操作(如活性炭罐)維護(hù)不良的情況下，也可能發(fā)生在城市水內(nèi)毒素水平高的情況下，在一年的某一段時(shí)間里，他們的消毒劑會(huì)從氯胺變成純氯。

 

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

是否會(huì)發(fā)生從生物膜中生成核酸并且在消毒過(guò)程中被更多釋放?

 

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.

如果很少使用的化學(xué)消毒劑，那么生物膜頑固的存在于系統(tǒng)中，這并不奇怪。然而，如果用熱水消毒，它會(huì)使核酸酶變性，所以在熱水消毒系統(tǒng)這種現(xiàn)象可能不會(huì)發(fā)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，熱消毒建議的溫度發(fā)生了變化。先前建議的至少80°C已降至65-80°C。現(xiàn)在溫度遠(yuǎn)遠(yuǎn)超過(guò)80°C被明確認(rèn)為不建議。這是正確的嗎？

 

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的溫度對(duì)較冷的地方是非常“寬容”的，即使有10-15?C的溫度損失下仍然可以消毒，因?yàn)樗ㄟ^(guò)對(duì)流和傳導(dǎo)滲透到整個(gè)系統(tǒng)，所以它是非常有效的。也可以使用較低的溫度(65?C)，但對(duì)于主回路的出口閥門(mén)等溫度較低的位置是“不可原諒”的。因此，這些較冷的位置必須用稍涼的熱水沖洗，以確保所有表面達(dá)到60?C以上的消毒溫度。除非系統(tǒng)專門(mén)為此設(shè)計(jì)，否則超過(guò)80?C的溫度會(huì)影響系統(tǒng)材料(如墊圈和隔膜)的使用壽命。80?C的溫度足以殺死大多數(shù)將在水系統(tǒng)中定植的耐熱生物膜(D值約為5毫秒)。

 

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

在水口取樣時(shí)，我們是否需要連接工藝軟管?這是要求還是建議?

 

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.

如果取樣是為了QC“放行”生產(chǎn)用的水，然后生產(chǎn)使用的出口必須以 與生產(chǎn)使用完全相同的方式取樣：采用相同清潔處理措施(如有)；同樣的生產(chǎn)軟管(無(wú)論多么破舊或維護(hù)不善)；同樣的預(yù)沖洗(如果有的話)，一切都一樣。樣品數(shù)據(jù)的目的是復(fù)制制造所用的水的相同質(zhì)量，所以在樣品收集中必須復(fù)制如何從系統(tǒng)中抽取水以供使用。這些用水程序在出水時(shí)可能會(huì)嚴(yán)重污染水系統(tǒng)內(nèi)的原始水，因此“骯臟的”水被輸送到生產(chǎn)操作中。如果你用不同的方法(更好的)對(duì)水進(jìn)行采樣，你會(huì)得到更低(更好的)的微生物計(jì)數(shù)，而這些計(jì)數(shù)不能代表實(shí)際使用的水質(zhì)。FDA要求QC放行的生產(chǎn)用水取樣必須相同。如果不是，這可能會(huì)讓你獲得FDA483的觀察，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.

如果為了水系統(tǒng)監(jiān)測(cè)和系統(tǒng)微生物控制的目的對(duì)水進(jìn)行過(guò)程控制(PC)取樣，可能會(huì)通過(guò)生產(chǎn)過(guò)程中未使用的取樣端口進(jìn)行。因?yàn)槲覀冎溃撼鏊诒旧砜赡軙?huì)對(duì)收集的水造成生物負(fù)擔(dān)，可以盡最大努力確保出水口在離開(kāi)系統(tǒng)時(shí)不會(huì)增加水的微生物含量(使用極端的出水口消毒，非常有力和徹底的沖洗，無(wú)菌軟管等)。對(duì)于PC，您感興趣的是閥門(mén)后的系統(tǒng)內(nèi)的水的質(zhì)量，不希望取樣端口的污染影響數(shù)據(jù)的解釋。

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，從取樣口(而不是生產(chǎn)使用口)收集的水通常不能用于水的最終放行(QC)，因?yàn)樗皇且詫?shí)際使用的方式收集的。生產(chǎn)過(guò)程中一般不使用從取樣口抽取的水。

 

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

因不同的衛(wèi)生清潔處理方法而增加內(nèi)毒素污染的風(fēng)險(xiǎn)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 系統(tǒng)關(guān)注內(nèi)毒素水平。大多數(shù) WFI 系統(tǒng)都因溫度升高而得到消毒（熱水比蒸汽好，因?yàn)闊崴静恍枰厥?工程，而且效果足夠好），但隨著 EP 放寬WFI 制備通則中制備WFI 的方法，系統(tǒng)消毒未來(lái)幾年可能會(huì)使用臭氧。由于WFI系統(tǒng)的熱水或臭氧凈化通常不低于每周一次，這還不足以使生物膜（及其內(nèi)毒素）在系統(tǒng)中發(fā)育并定期釋放。如果這些系統(tǒng)消毒的頻率要低得多，那么生物膜有可能在被定期消毒殺死前釋放到系統(tǒng)，并檢測(cè)到內(nèi)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學(xué)消毒劑（對(duì)于WFI系統(tǒng)或需要進(jìn)行內(nèi)毒素控制的純化水系統(tǒng)來(lái)說(shuō)，這是非常不典型的），消毒劑必須沖洗掉，這也將沖洗掉任何釋放的內(nèi)毒素。