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7.CHEMICAL EVALUATIONS 化学评估
7.1Chemical Tests for Bulk Waters
The chemical attributes of Purified Water and Water for Injection that were in effect prior to USP 23 were specified by a series of chemistry tests for various specific and nonspecific attributes with the intent of detecting chemical species indicative of incomplete or inadequate purification. Although these methods could have been considered barely adequate to control the quality of these waters, they nevertheless stood the test of time. This was partly because the operation of water systems was, and still is, based on on-line conductivity measurements and specifications generally thought to preclude the failure of these archaic chemistry attribute tests.
USP 23之前，有效的纯化水和注射用水的化学属性，通过一系列化学测试来确定各种特异性和非特异性属性，目的是检测表明纯化不完全或不充分的化学物质。虽然这些方法被认为几乎不足以控制这些水的质量，但它们仍然经受住了时间的考验。部分原因是，水系统的运行过去是，现在依然是，基于在线电导率测量，并且规格标准通常被认为是排除这些陈旧的化学属性测试的失败。
In 1996, USP moved away from these chemical attribute tests, switching to contemporary analytical technologies for the bulk waters Purified Water and Water for Injection. The intent was to upgrade the analytical technologies without tightening the quality requirements. The two contemporary analytical technologies employed were TOC and conductivity. The TOC test replaced the test for Oxidizable Substances that primarily targeted organic contaminants. A multi-staged conductivity test that detects ionic (mostly inorganic) contaminants replaced, with the exception of the test for Heavy Metals, all of the inorganic chemical tests (i.e., Ammonia, Calcium, Carbon Dioxide, Chloride, Sulfate).
1996年，USP放弃了这些化学属性测试，转而采用散装水纯化水和注射用水的现代分析技术。其目的是在不加强质量要求的情况下升级分析技术。采用的两种当代分析技术是TOC和电导率。TOC测试取代了主要针对有机污染物的可氧化物质测试。一种检测离子(主要是无机)污染物的多级电导率测试取代了除重金属测试外的所有无机化学测试(即氨、钙、二氧化碳、氯化物、硫酸盐)。
Replacing the heavy metals attribute was considered unnecessary because 1) the source water specifications (found in the
U.S. EPA’s NPDWR) for individual heavy metals were tighter than the approximate limit of detection of the Heavy Metals test for USP XXII Water for Injection and Purified Water (approximately 0.1 ppm), 2) contemporary water system construction materials do not leach heavy metal contaminants, and 3) test results for this attribute have uniformly been negative; there has not been a confirmed occurrence of a singular test failure (failure of only the Heavy Metals test with all other attributes passing) since the current heavy metal drinking water standards have been in place.
更换重金属属性被认为是不必要的，因为：1)水源水对单个重金属的规格(在美国环保署的NPDWR中发现)比USP XXII注入水和纯化水的重金属测试的近似检测极限(约0.1 ppm)更严格；2)现代水系构筑材料不浸出重金属污染物；和3) 自现行重金属饮用水标准出台以来，该属性的测试结果均为阴性且没有确认发生单一测试失败(只有重金属测试失败，其他所有属性通过)。
Total Solids and pH were the only tests not covered by conductivity testing. The test for Total Solids was considered redundant because the nonselective tests of conductivity and TOC could detect most chemical species other than silica, which could remain undetected in its colloidal form. Colloidal silica in Purified Water and Water for Injection is easily removed by most water pretreatment steps, and even if present in the water, it constitutes no medical or functional hazard except in extreme and rare situations. In such extreme situations, other attribute extremes are also likely to be detected. It is, however, the user’s responsibility to ensure fitness for use. If silica is a significant component in the source water, and the purification unit operations could fail and selectively allow silica to be released into the finished water (in the absence of co-contaminants detectable by conductivity), then either silica-specific testing or a total-solids type testing should be utilized to monitor for and control this rare problem.
总固体和pH是电导率测试不包括的唯一测试。总固体的测试被认为是多余的，因为电导率和TOC的非选择性测试可以检测除二氧化硅之外的大多数化学物质，尽管二氧化硅以胶体形式存在时，可以不被上述方法检测到。纯化水和注射用水中的胶体二氧化硅很容易被大多数水预处理步骤去除，即使存在于水中，也不会构成医疗或功能危害，除非在极端和罕见的情况下。在这种极端情况下，还可能检测到其他极端属性。然而，确保适合使用是用户的责任。如果二氧化硅是水源水中的重要组成部分，而净化装置的操作可能会失败，并选择性地允许二氧化硅释放到成品水中(在没有通过电导率检测到共污染物的情况下)，那么应采用二氧化硅特异性测试或总固体类型测试来监测和控制这一罕见的问题。
The pH attribute was eventually recognized to be redundant to the conductivity test (which included pH as an aspect of the test and specification); therefore, pH was discontinued as a separate attribute test.
相较于电导率测试，pH属性为测试和规格的一个方面，最终被认为是多余的;因此，pH被停止作为单独的属性测试。
The rationale used by USP to establish its Purified Water and Water for Injection conductivity specifications took into consideration the conductivity contributed by the two least-conductive former attributes of Chloride and Ammonia, thereby precluding their failure had those wet chemistry tests been performed. In essence, the Stage 3 conductivity specifications (see Water Conductivity 645, Bulk Water, Procedure, Stage 3) were established from the sum of the conductivities of the limit concentrations of chloride ions (from pH 5.0 to 6.2) and ammonia ions (from pH 6.3 to 7.0), plus the unavoidable contribution of other conductivity-contributing ions from water (H+ and OH–), dissolved atmospheric carbon dioxide (as HCO3–), and an electro-balancing quantity of either sodium (Na+) or chlorine (Cl–), depending on the pH-induced ionic imbalance (see Table 1). The Stage 2 conductivity specification is the lowest value in this table, 2.1 µS/cm. The Stage 1 specifications, designed primarily for on-line measurements, were derived by essentially summing the lowest values in individual (H+, OH−, HCO3−) and group (Cl−, Na+, NH4+) of contributing ion columns for each of a series of tables similar to Table 1, created for each 5° increment between 0° and 100°. For example purposes, the italicized values in Table 1, the conductivity data table for 25°, were summed to yield a conservative value of 1.3 µS/cm, the Stage 1 specification for a nontemperature-compensated, nonatmosphere-equilibrated water sample that actually had a measured temperature of 25°–29°. Each 5° increment in the table was similarly treated to yield the individual values listed in the table of Stage 1 specifications (see Water Conductivity 645, Bulk Water).
USP用于确定其电导率规格的理由考虑了两个模型中氯化物和氨的最低导电率时的电导率,从而排除了它们在进行这些湿化学测试时失败的可能性。从本质上讲，第三阶段电导率规范(参见 USP 645 水电导率，散装水，程序，阶段3)是由氯离子(pH 5.0 ~ 6.2)和氨离子(pH 6.3 ~ 7.0)的限度浓度电导率之和，加上不可避免的贡献，其他电导率贡献离子来自水(H+和OH -)，溶解的大气二氧化碳(HCO3 -)，以及钠(Na+)或氯(Cl -)的电平衡离子量，这取决于ph诱导的离子活度(见表1)。阶段二电导率标准为本表中最低值2.1µS/cm。阶段1规格主要为在线测量设计，基本上是通过对贡献离子列的单个(H+， OH -， HCO3 -)和组(Cl -， Na+， NH4+)的最低值求和得出；对于与表1相似的一系列表中的每个表，它为0°到100°之间的每5°增量创建。例如，表1中斜体的值，即25°的电导率数据表，加起来得到1.3µS/cm的保守值，这是第1阶段对实际测量温度为25°-29°的非温度补偿、非大气平衡水样的规范。对表中的每个5°增量进行类似处理，以产生阶段1规格表中列出的各个值(参见水电导率645，散装水)。
As stated above, this rather radical change to utilizing a conductivity attribute as well as the inclusion of a TOC attribute allowed for on-line measurements. This was a major philosophical change and allowed industry to realize substantial savings. The TOC and conductivity tests can also be performed off-line in the laboratories using collected samples, although sample collection tends to introduce opportunities for adventitious contamination that can cause false high readings. The collection of on-line data is not, however, without challenges. The continuous readings tend to create voluminous amounts of data, where previously only a single data point was available. As stated in 6. Sampling, continuous in-process data are excellent for understanding how a water system performs during all of its various usage and maintenance events in real time, but this is too much data for QC purposes. Therefore, for example, one can use a justifiable portion of the data (at a designated daily time or at the time of batch manufacturing) or the highest value in a given period as a worst case representation of the overall water quality for that period. Data averaging is generally discouraged because of its ability to obscure short-lived extreme quality events.
如上所述，这种使用电导率属性以及包含TOC属性的革命性变化允许在线测量。这是一个重大的哲学转变，使工业实现了大量的节约。TOC和电导率测试也可以在实验室使用收集的样品离线进行，尽管样品收集往往会引入可能导致假高读数的偶然污染的机会。然而，联机数据的收集并非没有挑战。连续的读数往往会产生大量的数据，而以前只有一个数据点可用。如6所述。采样、连续的过程中数据对于实时了解水系统在各种使用和维护事件中的表现非常好，但对于QC目的来说，这是太多的数据了。因此，例如，可以使用合理部分的数据(在指定的每日时间或批量生产时)或给定时期的最高值作为该时期整体水质的最坏情况表示。数据取平均值通常不被鼓励，因为它能够掩盖短期的极端质量事件。
7.2Chemical Tests for Sterile Waters
Packaged/sterile waters present a particular dilemma relative to the attributes of conductivity and TOC. The package itself is the major source of chemicals (inorganics and organics) that leach over time into the packaged water and can easily be detected by the conductivity and TOC tests. The irony of organic leaching from plastic packaging is that before the advent of bulk water TOC testing, when the Oxidizable Substances test was the only “organic purity” test for both bulk and packaged/ sterile water monographs in USP, the insensitivity of that test to many of the organic leachables from plastic and elastomeric packaging materials was largely unrecognized, allowing organic levels in packaged/sterile water to be quite high (possibly many times the TOC specification for bulk water).
相对于电导率和TOC的属性，包装的/无菌的水呈现一个特殊的麻烦。包装本身是随时间渗入包装水中的化学品(无机和有机物)的主要来源，通过电导率和TOC测试可以很容易地检测到这些化学品。具有讽刺意味的是，在散装水TOC测试出现之前，当“可氧化物质测试”是USP中散装水和包装/无菌水专论的唯一“有机纯度”测试时，该测试对从塑料和弹性体包装材料中许多有机浸出物的不敏感性在很大程度上未被认识到，使包装水/无菌水中的有机含量相当高(可能是散装水TOC规格的许多倍)。
Similarly, glass containers can also leach inorganics, such as sodium, which are easily detected by conductivity but poorly detected by the former wet chemistry attribute tests. Most of these leachables are considered harmless based on current perceptions and standards at the rather significant concentrations present. Nevertheless, they effectively degrade the quality of the high-purity waters placed into these packaging systems. Some packaging materials contain more leachables than others and may not be as suitable for holding water and maintaining its purity.
同样，玻璃容器也会滤出无机物质，如钠，这类物质很容易通过电导率检测到，但以前的湿化学属性测试很难检测到。根据目前的看法和标准，这些无机可浸出物在一定的浓度下被认为是无害的。然而，它们有效地降低了放入这些包装系统的高纯度水的质量。一些包装材料含有更多的可浸出物，可能不适合保持水的纯度。
The attributes of conductivity and TOC tend to reveal more about the packaging leachables than they do about the water’s original purity. These currently “allowed” leachables could render the sterile packaged versions of originally equivalent bulk water essentially unsuitable for many uses where the bulk waters are perfectly adequate.
电导率和TOC的属性往往更多地揭示了包装可浸出物，而不是水的原始纯度。这些目前“允许的”可浸出物可能使原本等效的散装水的无菌包装版本基本上不适合许多散装水完全充足的用途。
Therefore, to better control the ionic packaging leachables, 645 is divided into two sections. The first, Water Conductivity
645, Bulk Water, applies to Purified Water, Water for Injection, Water for Hemodialysis, and Pure Steam, and includes the three-stage conductivity testing instructions and specifications. The second, Water Conductivity 645, Sterile Water, applies to
Sterile Purified Water, Sterile Water for Injection, Sterile Water for Inhalation, and Sterile Water for Irrigation. The Sterile Water section includes conductivity specifications similar to the Water Conductivity 645, Bulk Water, Procedure, Stage 2 testing approach because it is intended as a laboratory test, and these sterile waters were made from bulk water that already complied with the three-stage conductivity test. In essence, packaging leachables are the primary target analytes of the conductivity specifications in Water Conductivity 645, Sterile Water. The effect on potential leachables from different container sizes is the rationale for having two different specifications, one for small packages containing nominal volumes of 10 mL or less and another for larger packages. These conductivity specifications are harmonized with the European Pharmacopoeia conductivity specifications for Sterile Water for Injection. All monographed waters, except Bacteriostatic Water for Injection, have a conductivity specification that directs the user to either the Bulk Water or the Sterile Water section. For the sterile packaged water monographs, this water conductivity specification replaces the redundant wet chemistry limit tests intended for inorganic contaminants that had previously been specified in these monographs.
因此，为了更好地控制离子包装可浸出物，645被分为两段。第一，水电导率645，散装水，适用于纯化水，注射用水，血液透析用水，纯蒸汽，包括三级电导率测试说明和规范。二、电导率645，无菌水，适用于无菌纯化水、无菌注射水、无菌吸入水、无菌冲洗水。无菌水部分包括类似于水电导率645，散装水，程序，阶段2测试方法的电导率规格，因为它是作为一个实验室测试，这些无菌水是由散装水制成的，已经符合三级电导率测试。本质上，包装可浸出物是《水电导率 645，无菌水》中电导率规范的主要目标分析物。不同容器尺寸对潜在可浸出物的影响是采用两种不同规格的基本原理，一种用于标称体积≤10 mL的小包装，另一种用于大包装。这些电导率规范与欧洲药典的无菌注射用水电导率规范一致。除抑菌注射水，所有的专论水，有一个电导率规范，用于指导用户对散装水或无菌水的管控。对于无菌包装水的各论，本水电导率规范取代了先前在这些各论中规定的针对无机污染物的多余的湿化学限度测试。
Controlling the organic purity of these sterile packaged waters, particularly those in plastic packaging, is more challenging.
Although the TOC test can better detect these impurities and therefore can be better used to monitor and control these impurities than the current Oxidizable Substances test, the latter has a history of use for many decades and has the flexibility to test a variety of packaging types and volumes that are applicable to these sterile packaged waters. Nevertheless, TOC testing of these currently allowed sterile, plastic-packaged waters reveals substantial levels of plastic-derived organic leachables that render the water perhaps orders of magnitude less organically pure than is typically achieved with bulk waters. Therefore, usage of these packaged waters for analytical, manufacturing, and cleaning applications should only be exercised after the purity of the water for the application has been confirmed as suitable.
控制这些无菌包装水的有机纯度，特别是塑料包装的水，更具挑战性。虽然TOC测试可以更好地检测这些杂质，因此可以比当前的可氧化物质测试更好地用于监测和控制这些杂质，但后者已有几十年的使用历史，并且可以灵活地测试适用于这些无菌包装水的各种包装类型和体积。尽管如此，对目前允许使用的无菌、塑料包装水进行的TOC检测显示，这些水中有大量的塑料衍生有机可浸出物，这使得水的有机纯度可能比散装水低几个数量级。因此，只有在确认用于分析、制造和清洗的水的纯度合适之后，才可以使用这些包装水。【除非必要，包装水不受待见】
▲7.3 Storage and Hold Times for Chemical Tests
Due to the homogeneous nature of chemical impurities in water, unlike the challenges of microbial impurities, the storage requirements and impact of holding times are very practically determined. In general, the chemical purity of high-purity water samples can only degrade over time, possibly generating a failed result of the sample that would have passed if it were tested immediately or on-line. The general fact is that the longer samples are stored, the greater the potential to be adversely impacted by containers or conditions.
由于水中化学杂质的同质性，不同于微生物杂质的挑战，储存要求和保存时间的影响是非常实际的确定的。一般来说，高纯水样品的化学纯度只会随着时间的推移而下降，可能会产生一个失败的结果，如果立即或在线测试，就会通过。一般的事实是，样品储存的时间越长，受到容器或环境不利影响的可能性就越大。
For off-line chemical tests of waters, there are no compendial requirements for storage time and conditions. However, the general recommendation is to perform testing as soon as practical to avoid false adverse results. Where possible, store cool and measure as quickly as practical. This reduces the chances that a water sample gets contaminated over time, and this would reduce unwarranted and unnecessary investigations of false positives.
对于水的离线化学试验，药典对储存时间和条件没有要求。然而，一般的建议是尽快进行测试，以避免错误的不良结果。在可能的情况下，保持凉爽并尽可能快地测量。这降低了随着时间的推移水样被污染的几率，并将减少对假阳性的无根据和不必要的调查。
7.3.1CONTAINERS
When sampling water for off-line analysis, the selection and cleanliness of the container play a significant part in obtaining accurate data. For samples to be tested for chemical impurities according to 645 and Total Organic Carbon 643, the proper container should be one that does not contaminate the sample during the storage/hold time. For example, the use and preparation of glass containers could be very acceptable for storing samples for TOC testing, but some glass containers do leach ions over time (hours and days), and they can adversely impact a conductivity test by creating a false positive result—if the storage time is too long. Likewise, there are some polymer materials that can adversely impact the TOC chemical impurity in water. However, many polymer materials are very inert.
在进行脱机分析的水采样时，容器的选择和清洁度对获得准确的数据起着重要的作用。对于要根据 电导率 645 和 总有机碳643检测化学杂质的样品，适当的容器应该是在储存/保存期间不会污染样品的容器。例如，玻璃容器的使用和制备可以很好地用于储存TOC测试的样品，但一些玻璃容器会随着时间的推移(数小时和数天)沥滤离子，如果储存时间过长，它们会产生假阳性结果，从而对电导率测试产生不利影响。同样，有些聚合物材料会对水中的TOC化学杂质产生不利影响。然而，许多聚合物材料是非常惰性的。
In any case, cleanliness of the container is crucial because trace quantities of soaps and fingerprints will adversely impact the chemical purity of the water. Properly cleaned containers are acceptable because chemical impurities are easily rinsed away. Extensive chemical cleaning methods such as acid or caustic rinsing should never be needed. If they are needed, consider replacing the containers.
无论如何，容器的清洁是至关重要的，因为微量的肥皂和指纹会对水的化学纯度产生不利影响。适当清洁的容器是可以接受的，因为化学杂质很容易被冲洗掉。不应该使用通用的化学清洗方法，如酸或腐蚀性冲洗。如果需要，请考虑更换容器。
7.3.2STORAGE TIME AND CONDITIONS
There are no specific recommendations for storage of samples for water analyses. If there is some trace interaction of the container and water, then generally colder and shorter storage times are better than warmer and longer storage times. Chemical dissolution and reactivity are usually enhanced by increased temperature. Furthermore, time is always an element because the water sample can only get worse in a container, and it never gets better with time.
对于水分析样品的储存没有特别的建议。如果容器和水有一些微量的相互作用，那么一般来说，较冷和较短的储存时间优于较热和较长的储存时间。化学溶解和反应性通常因温度升高而增强。此外，时间总是一个因素，因为水样在容器中只会变差，而不会随着时间的推移而变好。
7.4 Elemental Impurities in Pharmaceutical Waters制药用水中的元素杂质
Elemental impurities (EI) have the most restrictive limits for Water for Injection used in manufacturing parenterals, in particular large-volume injections (see Injections and Implanted Drug Products 1 for a definition of large-volume injections) because of the large dose. The most restrictive permissible daily exposure (PDE) of EI resides with lead, mercury, cadmium, and arsenic. Other EI listed in 232 permit a substantially higher PDE, and are therefore less restrictive.
由于剂量大，元素杂质(EI)对用于生产非肠道药物的注射用水的限制最严格，特别是大容量注射剂(大容量注射剂的定义见注射剂和植入性药物制品1)。EI最受限制的允许日暴露量(PDE)为铅、汞、镉和砷。232中列出的其他EI允许更高的PDE，因此限制较少。
Water that meets U.S. EPA National Primary Drinking Water Regulations or WHO Drinking Water Guidelines that has been purified by conventional technologies used to produce Water for Injection can comply with 232 for parenterals. 符合美国环境保护局国家一级饮用水条例或世界卫生组织饮用水指南的水，经用于生产注射用水的传统技术净化后，用于注射用途时应符合 通则232。
Table 2 shows that source water that meets US EPA NPDWR or WHO Drinking Water Guidelines has maximum contaminant levels (concentration) for lead, mercury, cadmium, and arsenic that are NMT 10 times (1-log) higher than the EI limits for
parenterals, based on a daily dose of 2000 mL. For a smaller volume injection, the allowed parenteral daily dose of EI is correspondingly higher. The purification technologies needed to produce Water for Injection that reduce the impurities by a factor of 100 to 1000 will assure compliance with 232, provided there are no elemental impurities added during processing, packaging, delivery, or storage.
表2显示符合美国EPA NPDWR或WHO饮用水指南的水源水，其铅、汞、镉和砷的最大污染物水平(浓度)是注射用途EI限值的10倍(1-log)(以日剂量2000 mL为基础)。对于较小的注射体积，肠外EI的允许日剂量相应较高。生产注入水所需的净化技术可以将杂质减少100到1000倍，确保符合232标准，前提是在加工、包装、运输或存储过程中没有添加元素杂质。
Chemical purification technologies for Purified Water are similarly efficient in removing EI as those for Water for Injection production. Because all sterile waters are prepared from Purified Water or Water for Injection, the assurance of compliance to
232 extends to sterile waters, provided there are no elemental impurities added during processing, packaging, delivery, or storage.
纯化水的化学净化技术在去除EI方面与注射用水生产的化学净化技术同样有效。因为所有的无菌水都是从纯化水或注射用水中制备的，如果在加工、包装、运送或储存过程中没有添加元素杂质，那么符合USP 232的保证也延伸到无菌水。
Further discussion can be found in Pharmacopeial Forum [see Bevilacqua A, Soli TC, USP Chemical Analysis Expert Committee.
Elemental impurities in pharmaceutical waters. Pharm Forum. 2013;39(1)].
进一步的讨论可以在药典论坛找到[见Bevilacqua A, Soli TC, USP化学分析专家委员会]。制药用水中的元素杂质，药典论坛。
两个表就不放了，跨页，不好整，需要的可以看张功臣老师的 制药用水 那本书，或者看原版。
