美国药典USP31 71 无菌检查法 双语版

美国药典USP31-NF26无菌检查法《71》.doc

71 STERILITY TESTS 无菌检查法

Portions of this general chapter have been harmonized with the corresponding texts of the European Pharmacopeia and/or the Japanese Pharmacopeia. Those portions that are not harmonized are marked with symbols () to specify this fact.

此通则的各部分已经与欧洲药典和/或日本药典的对应部分做了协调。不一致的部分用符号（）来标明。

The following procedures are applicable for determining whether a Pharmacopeial article purporting to be sterile complies with the requirements set forth in the individual monograph with respect to the test for sterility. Pharmacopeial articles are to be tested by the Membrane Filtration method under Test for Sterility of the Product to be Examined where the nature of the product permits. If the membrane filtration technique is unsuitable, use the Direct Inoculation of the Culture Medium method under Test for Sterility of the Product to be Examined. All devices, with the exception of Devices with Pathways Labeled Sterile, are tested using the Direct Inoculation of the Culture Medium method. Provisions for retesting are included under Observation and Interpretation of Results.

下面这些步骤适用于测定是否某个用于无菌用途的药品是否符合其具体的各论中关于无菌检查的要求。只要其性质许可，这些药品将使用供试产品无菌检查法项下的膜过滤法来检测。如果膜过滤技术是不适合的，则使用在供试产品无菌检查法项下的培养基直接接种法。除了具有标记为无菌通道的设备之外，所有的设备均须使用培养基直接接种法进行检测。在结果的观测与理解项下包含了复验的规定。

Because sterility testing is a very exacting procedure, where asepsis of the procedure must be ensured for a correct interpretation of results, it is important that personnel be properly trained and qualified. The test for sterility is carried out under aseptic conditions. In order to achieve such conditions, the test environment has to be adapted to the way in which the sterility test is performed. The precautions taken to avoid contamination are such that they do not affect any microorganisms that are to be revealed in the test. The working conditions in which the tests are performed are monitored regularly by appropriate sampling of the working area and by carrying out appropriate controls.

由于无菌检查法是一个非常精确的程序，在此过程中程序的无菌状态必须得到确保以实现对结果的正确理解，因此人员经过适当的培训并取得资质是非常重要的。无菌检查在无菌条件下进行。为了实现这样的条件，试验环境必须调整到适合进行无菌检查的方式。为避免污染而采取的特定预防措施应不会对任何试图在检查中发现的微生物产生影响。通过在工作区域作适当取样并进行适当控制，来定期监测进行此试验的工作条件。

These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process or of the aseptic processing procedures.

这些药典规定程序自身的设计不能确保一批产品无菌或已经灭菌。这主要是通过灭菌工艺或者无菌操作程序的验证来完成。

When evidence of microbial contamination in the article is obtained by the appropriate Pharmacopeial method, the result so obtained is conclusive evidence of failure of the article to meet the requirements of the test for sterility, even if a different result is obtained by an alternative procedure. For additional information on sterility testing, see Sterilization and Sterility Assurance of Compendial Articles 1211 .

当通过适当的药典方法获得了某物品中微生物污染的证据，这样获得的结果是该物品未能达到无菌检验要求的结论性证据，即便使用替代程序得到了不同的结果也无法否定此结果。如要获得关于无菌检验的其他信息，见药品的灭菌和无菌保证<1211>

MEDIA 培养基

Prepare media for the tests as described below, or dehydrated formulations may be used provided that, when reconstituted as directed by the manufacturer or distributor, they meet the requirements of the Growth Promotion Test of Aerobes, Anaerobes, and Fungi. Media are sterilized using a validated process.

按照下面描述的方法配制实验用培养基；或者使用脱水培养基，只要根据其制造商或者分销商说明进行恢复之后，其能够符合好氧菌、厌氧菌、霉菌生长促进试验的要求即可。使用经过验证的工艺对培养基进行灭菌操作。

The following culture media have been found to be suitable for the test for sterility. Fluid Thioglycollate Medium is primarily intended for the culture of anaerobic bacteria. However, it will also detect aerobic bacteria. Soybean–Casein Digest Medium is suitable for the culture of both fungi and aerobic bacteria.

下面的培养基已经被证实适合进行无菌检查。巯基醋酸盐液体培养基主要用于厌氧菌的培养。但其也用于检测好氧菌。大豆酪蛋白消化物培养基适合于培养霉菌和好氧菌。

Fluid Thioglycollate Medium 巯基醋酸盐液体培养基

Mix the L-cystine, sodium chloride, dextrose, yeast extract, and pancreatic digest of casein with the purified water, and heat until solution is effected. Dissolve the sodium thioglycollate or thioglycolic acid in the solution and, if necessary, add 1 N sodium hydroxide so that, after sterilization, the solution will have a pH of 7.1 ± 0.2. If filtration is necessary, heat the solution again without boiling, and filter while hot through moistened filter paper. Add the resazurin sodium solution, mix, and place the medium in suitable vessels that provide a ratio of surface to depth of medium such that not more than the upper half of the medium has undergone a color change indicative of oxygen uptake at the end of the incubation period. Sterilize using a validated process. If the medium is stored, store at a temperature between 2 and 25 in a sterile, airtight container. If more than the upper one-third of the medium has acquired a pink color, the medium may be restored once by heating the containers in a water-bath or in free-flowing steam until the pink color disappears and by cooling quickly, taking care to prevent the introduction of nonsterile air into the container.

将L-胱氨酸、氯化钠、葡萄糖、酵母提取物、酪蛋白胰酶消化物与纯净水混合，并加热至实现溶解。将巯基乙酸钠或者巯基乙酸溶解于该溶液，如果需要可再加入1N氢氧化钠，以便在灭菌后该溶液呈pH值7.1 ± 0.2。如需要则过滤，再次加热该溶液但不得煮沸，并趁热以湿润滤纸将该溶液过滤。加入刃天青钠溶液，混匀，并将该培养基置于适当容器中，该容器应为培养基提供特定的面积－深度比，以使在培养期末表明氧气摄入的变色部分不超过培养基的上半部分。使用经过验证的工艺进行灭菌。如果需要储存该培养基，将其置于无菌、气密容器中，在2 至25 之间储藏。如果超过上部三分之一的培养基已经呈粉色，可以用以下方法恢复该培养基一次：在水浴锅中或者自由流动蒸气中加热该容器，直至粉色消失，并迅速放凉，须小心防止非无菌空气进入到容器中。

Fluid Thioglycollate Medium is to be incubated at 32.5 ± 2.5 .

巯基醋酸盐液体培养基将在32.5 ± 2.5 条件下进行培养。

Alternative Thioglycollate Medium 替代巯基醋酸盐培养基

Prepare a mixture having the same composition as that of the Fluid Thioglycollate Medium, but omitting the agar and the resazurin sodium solution, sterilize as directed above, and allow to cool prior to use. The pH after sterilization is 7.1 ± 0.2. Incubate under anaerobic conditions for the duration of the incubation period.

配制与巯基醋酸盐液体培养基成分相同，但省略了琼脂和刃天青钠溶液的混合物，按上述方法灭菌，并在使用前静置至凉。灭菌后pH值为7.1 ± 0.2。在厌氧条件下培养，培养时间同培养期。

Alternative Fluid Thioglycollate Medium is to be incubated at 32.5 ± 2.5 .

替代性巯基醋酸盐培养基将在32.5 ± 2.5 条件下进行培养。

Soybean–Casein Digest Medium 大豆-酪蛋白消化物培养基

Dissolve the solids in the Purified Water, heating slightly to effect a solution. Cool the solution to room temperature, and adjust the pH with 1 N sodium hydroxide so that, after sterilization, it will have a pH of 7.3 ± 0.2. Filter, if necessary to clarify, dispense into suitable containers, and sterilize using a validated procedure. Store at a temperature between 2 and 25 in a sterile

well-closed container, unless it is intended for immediate use.

将固体物质溶解于纯净水，轻微加热以实现溶解。放凉溶液至室温，并用1N氢氧化钠调整pH值，以便在灭菌后其pH值呈7.3 ± 0.2。过滤，如需要则使之澄清，分装入适合的容器，

并用经过验证的程序消毒。如果不立刻使用，则在2 到25 之间以无菌且密闭良好的容器保存。

Soybean–Casein Digest Medium is to be incubated at 22.5 ± 2.5 .

大豆-酪蛋白消化物培养基将在22.5 ± 2.5 条件下培养。

Media for Penicillins or Cephalosporins 用于青霉素和头孢菌素的培养基

Where sterility test media are to be used in the Direct Inoculation of the Culture Medium method under Test for Sterility of the Product to be Examined, modify the preparation of Fluid Thioglycollate Medium and the Soybean–Casein Digest Medium as follows. To the containers of each medium, transfer aseptically a quantity of -lactamase sufficient to inactivate the amount of antibiotic in the specimen under test. Determine the quantity of -lactamase required to inactivate the antibiotic by using a -lactamase preparation that has been assayed previously for its penicillin- or cephalosporin-inactivating power. [NOTE—Supplemented -lactamase media can also be used in the membrane filtration test.]

当无菌检查培养基用于供试产品无菌检查项下的培养基直接接种法时，按如下内容变更巯基醋酸盐液体培养基和大豆-酪蛋白消化物培养基的制备方法。向每一种培养基的容器中，以无菌操作转移足够灭活供试样品中所存在抗生素的-内酰胺酶。使用此前已经对其青霉素或头孢菌素灭活能力进行了测定的-内酰胺酶配制品，来测定灭活该抗生素所必需的-内酰胺酶数量。[注意：补充的-内酰胺酶培养基也可以用于膜过滤试验]

Alternatively (in an area completely separate from that used for sterility testing), confirm that an appropriate amount of -lactamase is incorporated into the medium, following either method under Validation Test, using less than 100 colony-forming units (cfu) of Staphylococcus aureus (see Table 1) as the challenge. Typical microbial growth of the inoculated culture must be observed as a confirmation that the -lactamase concentration is appropriate.

或者（在与无菌试验所用场所彻底隔离的区域中），按照验证试验项下的任意一种方法，使用少于100个菌落（cfu）的金黄色葡萄球菌（见表1）作为验证菌，来确认适当数量的-内酰胺酶已经被整合到该培养基中。必须观测到接种后培养物中出现典型微生物生长，才能确认-内酰胺酶浓度是适当的。

Table 1. Strains of the Test Microorganisms Suitable for Use in the Growth Promotion Test and

the

Validation Test

表1 适合用于生长促进试验和验证试验中的试验微生物的菌株

Suitability Tests 适合性试验

The media used comply with the following tests, carried out before, or in parallel, with the test on the product to be examined.

所使用的培养基须符合下列试验，这些试验应在检验供试产品之前或者同时进行。

STERILITY 无菌状态

Confirm the sterility of each sterilized batch of medium by incubating a portion of the media at the specified incubation temperature for 14 days. No growth of microorganisms occurs.

通过在指定培养温度下将一部分培养基培养14天，来确认每一批已灭菌培养基的无菌状态。不得出现微生物生长。

GROWTH PROMOTION TEST OF AEROBES, ANAEROBES, and FUNGI

好氧菌、厌氧菌、霉菌的生长促进试验

Test each lot of ready-prepared medium and each batch of medium prepared either from dehydrated medium or from ingredients1 . Suitable strains of microorganisms are indicated in Table 1.

检查每一批已经配制好的培养基和每一批用脱水培养基或配料制备的培养基1。适当微生物菌株见表1。

Inoculate portions of Fluid Thioglycollate Medium with a small number (not more than 100 cfu)

of the following microorganisms, using a separate portion of medium for each of the following species of microorganism: Clostridium sporogenes, Pseudomonas aeruginosa, and Staphylococcus aureus. Inoculate portions of Alternative Fluid Thioglycollate Medium with a small number (not more than 100 cfu) of Clostridium sporogenes.Inoculate portions of

Soybean–Casein Digest Medium with a small number (not more than 100 cfu) of the following microorganisms, using a separate portion of medium for each of the following species of microorganism: Aspergillus niger, Bacillus subtilis, and Candida albicans. Incubate for not more than 3 days in the case of bacteria and not more than 5 days in the case of fungi.

在部分巯基醋酸盐液体培养基上接种少量（不超过100cfu）下列微生物，每一种微生物均使用单独一部分培养基：产芽胞梭状芽胞杆菌、绿脓杆菌、金黄色葡萄球菌。在部分替代巯基醋酸盐液体培养基上接种少量（不超过100cfu）产芽胞梭状芽胞杆菌。在部分大豆-酪蛋白消化物培养基上接种少量（不超过100cfu）下列微生物，每一种微生物均使用单独一部分的培养基：黑曲霉、枯草芽孢杆菌、白色念珠菌。细菌培养时间不超过3天，霉菌培养时间不超过5天。

The media are suitable if a clearly visible growth of the microorganisms occurs.

如果出现清晰可见的微生物生长，则该培养基是适合的。

STORAGE 保存

If prepared media are stored in unsealed containers, they can be used for 1 month, provided that they are tested for growth promotion within 2 weeks of the time of use and that color indicator requirements are met. If stored in tight containers, the media can be used for 1 year, provided that they are tested for growth promotion within 3 months of the time of use and that the color indicator requirements are met.

如果配制好的培养基保存于未密闭的容器中，只要在使用时间的2周内对其进行了生长促进试验并且符合颜色指示剂的要求，它们就可以使用1个月。如果保存在密闭的容器中，只要在使用时间的3个月内对其进行了生长促进试验并且符合颜色指示剂的要求，则该培养基可以使用1年。

DILUTING AND RINSING FLUIDS FOR MEMBRANE FILTRATION

用于膜过滤的稀释和冲洗液

Fluid A 液体A

PREPARATION 配制品

Dissolve 1 g of peptic digest of animal tissue in water to make 1 L, filter or centrifuge to clarify, if necessary, and adjust to a pH of 7.1 ± 0.2. Dispense into containers, and sterilize using a validated process.

将1g动物组织胃蛋白酶消化物溶于1L水中，如果需要则通过滤或离心使其澄清，再调节pH值至7.1 ± 0.2。分装入容器中，并用经过验证的工艺灭菌。

PREPARATION FOR PENICILLINS OR CEPHALOSPORINS

用于青霉素或头孢菌素的配制品

Aseptically add to the above Preparation, if necessary, a quantity of sterile -lactamase sufficient to inactivate any residual antibiotic activity on the membranes after the solution of the test specimen has been filtered (see Media for Penicillins or Cephalosporins).

在供试样品溶液已经过滤（见用于青霉素或头孢菌素的培养基）之后，如果需要，向上述配制品中，以无菌操作加入数量足够灭活滤膜上残余抗生素活性的-内酰胺酶。

Fluid D 液体D

To each L of Fluid A add 1 mL of polysorbate 80, adjust to a pH of 7.1 ± 0.2, dispense into containers, and sterilize using a validated process. Use this fluid for articles containing lecithin or oil, or for devices labeled as ―sterile pathway.‖

向每升液体A中，加入1mL聚山梨酯80，调节pH值至7.1 ± 0.2，分装入容器中，并使用经过验证的工艺灭菌。此液体用于含有卵磷脂或油脂的物品，或用于标为―无菌通道‖的设备。

Fluid K 液体K

Dissolve 5.0 g of peptic digest of animal tissue, 3.0 g of beef extract, and 10.0 g of polysorbate 80 in water to make 1 L. Adjust the pH to obtain, after sterilization, a pH of 6.9 ± 0.2. Dispense into containers, and sterilize using a validated process.

将5.0g动物组织胃蛋白酶消化物、3.0g牛肉提取物、10.0g聚山梨酯80溶解于1L水中。调节pH值，以便使pH值在灭菌后呈6.9 ± 0.2。分装入容器中，并使用经过验证的工艺灭菌。

VALIDATION TEST验证试验

Carry out a test as described below under Test for Sterility of the Product to be Examined using exactly the same methods, except for the following modifications.

按照下面供试产品无菌检查项下的描述，使用除了下面变更之外完全相同的方法，进行试验。

Membrane Filtration 膜过滤

After transferring the content of the container or containers to be tested to the membrane, add an inoculum of a small number of viable microorganisms (not more than 100 cfu) to the final portion of sterile diluent used to rinse the filter.

在将一个或多个供试容器中的内容物转移到滤膜之后，在最后一次的冲洗液中加入少量（不超过100cfu）试验菌.

Direct Inoculation 直接接种

After transferring the contents of the container or containers to be tested (for catgut and other surgical sutures for veterinary use: strands) to the culture medium, add an inoculum of a small number of viable microorganisms (not more than 100 cfu) to the medium.

在将一个或多个供试容器（对于兽医的肠线和其他外科缝合用线：若干股线）中的内容物转移至培养基之后，将少量试验菌（不超过100cfu）加入至培养基中。

In both cases use the same microorganisms as those described above under Growth Promotion Test of Aerobes, Anaerobes, and Fungi. Perform a growth promotion test as a positive control. Incubate all the containers containing medium for not more than 5 days.

在这两种情况中，均按照上述好氧菌、厌氧菌、霉菌生长促进试验项下的描述，使用同样的微生物。进行一个生长促进试验作为阳性对照。培养所有含有培养基的容器，培养时间不超过5天。

If clearly visible growth of microorganisms is obtained after the incubation, visually comparable

to that in the control vessel without product, either the product possesses no antimicrobial activity under the conditions of the test or such activity has been satisfactorily eliminated. The test for sterility may then be carried out without further modification.

如果在培养后得到清晰可见的微生物生长，看起来与没有产品的对照容器中的生长类似，则该产品在此试验条件下没有任何抗微生物活性，或者此活性已经被令人满意地消除了。然后，无菌试验可以进行，而无需进一步的变更。

If clearly visible growth is not obtained in the presence of the product to be tested, visually comparable to that in the control vessels without product, the product possesses antimicrobial activity that has not been satisfactorily eliminated under the conditions of the test. Modify the conditions in order to eliminate the antimicrobial activity, and repeat the validation test.

如果用肉眼与没有产品的对照容器比较，无法在存在供试产品的情况下得到清晰可见的生长，则该产品在试验条件下所具有的抗微生物活性尚未令人满意地消除。变更条件以便消除抗微生物活性，并重复验证试验。

This validation is performed (a) when the test for sterility has to be carried out on a new product; and (b) whenever there is a change in the experimental conditions of the test. The validation may be performed simultaneously with the Test for Sterility of the Product to be Examined.

当(a)一个新产品必须进行无菌试验时，和(b)无论何时该试验的试验条件发生改变时，则需进行此验证试验。该验证可以与供试产品的无菌试验同时进行。

TEST FOR STERILITY OF THE PRODUCT TO BE EXAMINED

供试产品的无菌检查

Number of Articles to Be Tested 供试物品数量

Unless otherwise specified elsewhere in this chapter or in the individual monograph, test the number of articles specified in Table 3. If the contents of each article are of sufficient quantity (see Table 2), they may be divided so that equal appropriate portions are added to each of the specified media. [NOTE—Perform sterility testing employing two or more of the specified media.] If each article does not contain sufficient quantities for each medium, use twice the number of articles indicated in Table 3.

除非在此章节的其他位置或在具体的各论中另有规定，供试物品的数量遵照表3中的规定。如果每个物品的内容物有足够数量（见表2），可以将其分成若干等份，将适当的等份加入到每个指定的培养基。[注意：使用两个或更多指定培养基，来进行无菌试验。]如果每个物品内容物的数量不够每个培养基的用量，使用表3中所规定物品数量的2倍。

Table 2. Minimum Quantity to be Used for Each Medium

表2：用于每个培养基的最小数量

Table 3. Minimum Number of Articles to be Tested in Relation to the Number of Articles in the Batch 表3：与物品批量相关的最小供试物品数量

The test may be carried out using the technique of Membrane Filtration or by Direct Inoculation of the Culture Medium with the product to be examined. Appropriate negative controls are included. The technique of membrane filtration is used whenever the nature of the product permits; that is, for filterable aqueous preparations, for alcoholic or oily preparations, and for preparations miscible with, or soluble in, aqueous or oily solvents, provided these solvents do not have an antimicrobial effect in the conditions of the test.

此试验可以使用膜过滤法或培养基直接接种法进行。应包括多个适当的阴性对照。只要该产品的性质许可，就应使用膜过滤法；这些性质是，可过滤的水溶性配制品、酒精或油性配制品、易混合或溶解于水或油性溶剂的配制品，只要这些溶剂在试验条件下没有抗生素效果。

Membrane Filtration 膜过滤

Use membrane filters having a nominal pore size not greater than 0.45 μm whose effectiveness to retain microorganisms has been established. Cellulose nitrate filters, for example, are used for aqueous, oily, and weakly alcoholic solutions; and cellulose acetate filters, for example, are used for strongly alcoholic solutions. Specially adapted filters may be needed for certain products (e.g., for antibiotics).

使用标称孔径不大于0.45 μm的膜过滤器，此孔径已知能够有效截留微生物。例如，硝酸纤维素过滤器可用于水、油、稀醇溶液；而醋酸纤维素可用于浓醇溶液。特定产品（例如，抗生素）可能需要特别改造过的过滤器。

The technique described below assumes that membranes about 50 mm in diameter will be used. If filters of a different diameter are used, the volumes of the dilutions and the washings should be adjusted accordingly. The filtration apparatus and membrane are sterilized by appropriate means. The apparatus is designed so that the solution to be examined can be introduced and filtered under aseptic conditions: it permits the aseptic removal of the membrane for transfer to the medium, or it is suitable for carrying out the incubation after adding the medium to the apparatus itself.

下面描述的方法所使用直径约50mm的滤膜。如果使用不同直径的过滤器，稀释液和洗液的体积应当作相应调节。以适当方法将过滤设备和滤膜灭菌。该设备设计用于在无菌条件下加入和过滤供试溶液：其使得在无菌状态下将滤膜摘掉转移至培养基成为可能，或者其适合于将培养基加入该设备自身之中，并进行培养。

AQUEOUS SOLUTIONS 水性溶液

If appropriate, transfer a small quantity of a suitable, sterile diluent such as Fluid A (see Diluting and Rinsing Fluids for Membrane Filtration)onto the membrane in the apparatus and filter. The diluent may contain suitable neutralizing substances and/or appropriate inactivating substances, for example, in the case of antibiotics.

如果适当，将少量适当的无菌稀释剂，例如液体A（见用于膜过滤的稀释和冲洗液），转移至设备中的滤膜上并过滤。该稀释剂可以含有适当的中和物质和/或适当的灭活物质，例如针对抗生素。

Transfer the contents of the container or containers to be tested to the membrane or membranes, if necessary, after diluting to the volume used in the Validation Test with the chosen sterile diluent, but using not less than the quantities of the product to be examined prescribed in Tables 2 and 3. Filter immediately. If the product has antimicrobial properties, wash the membrane not less than three times by filtering through it each time the volume of the chosen sterile diluent used in the Validation Test. Do not exceed a washing cycle of 5 times 200 mL, even if during validation it has been demonstrated that such a cycle does not fully eliminate the antimicrobial activity. Transfer the whole membrane to the culture medium or cut it aseptically into two equal parts, and transfer one half to each of two suitable media. Use the same volume of each medium as in the Validation Test. Alternatively, transfer the medium onto the membrane in the apparatus. Incubate the media for not less than 14 days.

将一个或多个供试容器的内容物转移到滤膜，如需要可先使用选定的无菌稀释剂稀释至验证试验中所用体积，但须使用不少于表2和3中规定的供试产品数量。立即过滤。如果该产品具有抗微生物特性，冲洗滤膜不少于3次，每次均将验证试验中所使用的无菌稀释剂体积滤过该滤膜。即便验证中显示5次200mL的冲洗循环没有完全消除抗微生物活性，也不要超越这样一个循环。转移整个滤膜至培养基，或以无菌操作将其切开至相等的2部分，并将每一部分转移至适当的培养基中。每个培养基的体积与验证试验所用的一样。或者，将培养基转移至设备中的滤膜上。培养该培养基，不少于14天。

SOLUBLE SOLIDS (other than antibiotics) 可溶固体（非抗生素）

Use for each medium not less than the quantity prescribed in Tables 2 and 3 of the product dissolved in a suitable solvent, such as Fluid A (Diluting and Rinsing Fluids for Membrane Filtration),and proceed with the test as described above for Aqueous Solutions using a membrane appropriate to the chosen solvent.

在每个培养基中，使用不少于表2和3规定的产品数量溶于适当溶剂，例如溶液A（用于膜过滤的稀释和冲洗液），并按照上述关于水性溶液的描述，使用适合所选溶剂的滤膜，继续进行该试验。

OILS and OILY SOLUTIONS 油和油性溶液

Use for each medium not less than the quantity of the product prescribed in Tables 2 and 3. Oils and oily solutions of sufficiently low viscosity may be filtered without dilution through a dry membrane. Viscous oils may be diluted as necessary with a suitable sterile diluent such as isopropyl myristate shown not to have antimicrobial activity in the conditions of the test. Allow the oil to penetrate the membrane by its own weight, and then filter, applying the pressure or suction gradually. Wash the membrane at least three times by filtering through it each time about 100 mL of a suitable sterile solution such as Fluid A (see Diluting and Rinsing Fluids for Membrane Filtration)containing a suitable emulsifying agent at a concentration shown to be appropriate in the validation of the test, for example polysorbate 80 at a concentration of 10 g per L (Fluid K). Transfer the membrane or membranes to the culture medium or media, or vice versa, as described above for Aqueous Solutions, and incubate at the same temperatures and for the same times.

在每个培养基中，使用不少于表2和3中描述的产品用量。粘性足够低的油和油性溶液可能在不经稀释的情况下滤过干燥滤膜。如需要，粘稠油质可以用适合的无菌稀释剂进行稀释，例如已证实在该试验条件下不具有抗微生物活性的豆蔻酸异丙酯。使该油质依靠其自身的重量穿过滤膜，然后逐渐应用压力或抽吸过滤。每次过滤约100mL适当的无菌溶液，例如液体A（见用于膜过滤的稀释和冲洗液），并含有适当乳化剂且其浓度已证实适用于该试验的验证，例如浓度为10克每升的聚山梨酯80（液体K）。将一个或多个滤膜转移到一个或多个培养基，或反之，如上面关于水性溶液的描述，并在相同温度下培养同样的时间。

OINTMENTS and CREAMS 油膏和乳膏

Use for each medium not less than the quantities of the product prescribed in Tables 2 and 3. Ointments in a fatty base and emulsions of the water-in-oil type may be diluted to 1% in isopropyl myristate as described above, by heating, if necessary, to not more than 40 . In exceptional cases it may be necessary to heat to not more than 44 . Filter as rapidly as possible, and proceed as described above for Oils and Oily Solutions.

在每个培养基中，使用不少于表2和3中描述的产品用量。脂肪状的油膏和水在油中形态乳化剂可以按照上面所述，在豆蔻酸异丙酯中稀释至1%，如需要可加热至不高于40 。在特别情况下，其可能必须加热到不超过44 。尽可能迅速地过滤，并按照上面针对油和油性溶液所述内容继续操作。

PREFILLED SYRINGES 预装填的注射器

For prefilled syringes without attached sterile needles, expel the contents of each syringe into one or two separate membrane filter funnels or into separate pooling vessels prior to transfer. If a separate sterile needle is attached, directly expel the syringe contents as indicated above, and proceed as directed for Aqueous Solutions. Test the sterility of the needle, using Direct Inoculation under Validation Test.

对于没有附无菌针头的预装填注射器，在转移之前，将每个注射器的内容物排出至一个或两个单独的膜过滤器漏斗，或至若干单独的合并容器。如果附了单独的灭菌针头，直接按照上面的规定将注射器内容物直接排出，并按照关于水性溶液的规定继续进行。使用验证试验项下的直接接种，检查针头的无菌情况。

SOLIDS FOR INJECTION OTHER THAN ANTIBIOTICS 除了抗生素之外的注射用固体

Constitute the test articles as directed on the label, and proceed as directed for Aqueous Solutions or Oils and Oily Solutions, whichever applies. [NOTE—If necessary, excess diluent can be added to aid in the constitution and filtration of the constituted test article.]

按照其标签上的规定配制供试物品，并按照适用的关于水性溶液或油和油性溶液的规定继续进行。[注意：如需要，可以加入额外的稀释剂以帮助对已配制的供试物品进行再配制和过滤]

ANTIBIOTIC SOLIDS FOR INJECTION 用于注射的抗生素

Pharmacy Bulk Packages, < 5 g— From each of 20 containers, aseptically transfer about 300 mg of solids, into a sterile 500-mL conical flask, dissolve in about 200 mL of Fluid A (see Diluting and Rinsing Fluids for Membrane Filtration), and mix; or constitute, as directed in the labeling, each of 20 containers and transfer a quantity of liquid or suspension, equivalent to about 300 mg

of solids, into a sterile 500-mL conical flask, dissolve in about 200 mL of Fluid A, and mix. Proceed as directed for Aqueous Solutions or Oils and Oily Solutions, whichever applies.

药房散装< 5 g：取20个容器，每个容器均以无菌操作将约300mg固体转移至一个无菌的500mL锥形烧瓶，溶解于约200mL液体A中（见用于膜过滤的稀释和冲洗液），并混匀；或取20个容器，每个容器均按照标签上的规定配制，并将相当于大约300mg固体的液体或悬浮液转移至一个无菌的500mL锥形烧瓶，溶解于约200mL液体A中，并混匀。按照适合的关于水性溶液或油和油性溶液的规定，继续操作。

Pharmacy Bulk Packages, 5 g— From each of 6 containers, aseptically transfer about 1 g of solids into a sterile 500-mL conical flask, dissolve in about 200 mL of Fluid A, and mix; or constitute, as directed in the labeling, each of 6 containers and transfer a quantity of liquid, equivalent to about 1 g of solids, into a sterile 500-mL conical flask, dissolve in about 200 mL of Fluid A, and mix. Proceed as directed for Aqueous Solutions.

药方散装5 g：取6个容器，每个均以无菌操作将大约1克的固体转移至一个无菌的500mL 锥形烧瓶，溶解于约200mL液体A中，并混匀；或取6个容器，每个均按照标签的规定配制，将相当于1g固体的液体转移至一个无菌的500mL锥形烧瓶，溶解于200mL液体A中，并混匀。按照关于水性溶液的规定，继续操作。

ANTIBIOTIC SOLIDS, BULKS, and BLENDS 抗生素固体、散装品、混合品

Aseptically remove a sufficient quantity of solids from the appropriate amount of containers (see Table 2), mix to obtain a composite, equivalent to about 6 g of solids, and transfer to a sterile

500-mL conical flask. Dissolve in about 200 mL of Fluid A, and mix. Proceed as directed for Aqueous Solutions.

以无菌操作从适当数量的容器中（见表2）取出足够数量的固体，混匀以获得等同于6g固体的混合物，转移至一个无菌的500mL锥形烧瓶。溶解于约200mL液体A中，并混匀。按照关于水性溶液的规定，继续进行。

STERILE AEROSOL PRODUCTS 无菌气(喷)雾剂产品

For fluid products in pressurized aerosol form, freeze the containers in an alcohol-dry ice mixture at least at –20 for about 1 hour. If feasible, allow the propellant to escape before aseptically

opening the container, and transfer the contents to a sterile pooling vessel. Add 100 mL of Fluid D to the pooling vessel, and mix gently. Proceed as directed for Aqueous Solutions or Oils and Oily Solutions, whichever applies.

对于以加压气(喷)雾剂形式存在的液体产品，在大约–20 的酒精－干冰混合物中冷冻容器约1小时。如果可行，在以无菌操作打开容器之前使推进剂散发掉，并将内容物转移至一个无菌的合并容器。加入100mL液体D至该合并容器，并轻轻混匀。按照适合的关于水性溶液或油和油性溶液的规定，继续进行。

DEVICES WITH PATHWAYS LABELED STERILE 具有导管的医疗器具供试品

Aseptically pass not less than 10 pathway volumes of Fluid D through each device tested. Collect the fluids in an appropriate sterile vessel, and proceed as directed for Aqueous Solutions or Oils and Oily Solutions, whichever applies.

以无菌操作用10个通道体积的液体D通过供试设备。在适当的无菌容器中收集冲洗液，并按照适合的关于水性溶液或油和油性溶液的规定，继续进行。

In the case of sterile, empty syringes, draw sterile diluent into the barrel through the sterile needle, if attached, or th, rough a sterile needle attached for the purpose of the test, and express the contents into a sterile pooling vessel. Proceed as directed above.

对于无菌的空注射器，如果附有无菌针头，通过其将无菌稀释剂吸取至管中，或者使用一个专为此试验准备的无菌针头，并将内容物压出至合并容器中。按照上述内容继续进行。

Direct Inoculation of the Culture Medium 培养基的直接接种

Transfer the quantity of the preparation to be examined prescribed in Tables 2 and 3 directly into the culture medium so that the volume of the product is not more than 10% of the volume of the medium, unless otherwise prescribed.

If the product to be examined has antimicrobial activity, carry out the test after neutralizing this with a suitable neutralizing substance or by dilution in a sufficient quantity of culture medium. When it is necessary to use a large volume of the product, it may be preferable to use a concentrated culture medium prepared in such a way that it takes into account the subsequent dilution. Where appropriate, the concentrated medium may be added directly to the product in its container.

按照表2和3规定的供试配制品的数量，将该配制品直接转移到培养基中，除非另有规定，产品体积不得超过该培养基体积的10%。如果该供试产品具有抗微生物活性，通过使用适

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á233? ELEMENTAL IMPURITIES—PROCEDURES INTRODUCTION This chapter describes two analytical procedures (Procedures 1 and 2) for the evaluation of the levels of the elemental impuri-ties. The chapter also describes criteria for acceptable alternative procedures. By means of validation studies, analysts will confirm that the analytical procedures described herein are suitable for use on specified material. Use of Alternative Procedures The chapter also describes criteria for acceptable alternative procedures. Alternative procedures that meet the validation re-quirements herein may be used in accordance with General Notices and Requirements 6.30, Alternative and Harmonized Meth-ods and Procedures . Information on the Requirements for Alternate Procedure Validation is provided later in this chapter.Speciation The determination of the oxidation state, organic complex, or combination is termed speciation . 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The selection of the appropriate sample preparation depends on the material under test and is the responsibil-ity of the analyst. When a sample preparation is not indicated in the monograph, an analyst may use any of the following appropriately validated preparation procedures. In cases where spiking of a material under test is necessary to provide an acceptable signal intensity, the blank should be spiked with the same Target elements , and where possible, using the same spiking solution. Standard solutions may contain multiple Target elements . [N OTE —All liquid samples should be weighed.]Neat:Used for liquids or alternative procedures that allow the examination of unsolvated samples. Direct aqueous solution:Used when the sample is soluble in an aqueous solvent. Direct organic solution:Used where the sample is soluble in an organic solvent. Indirect solution:Used when a material is not directly soluble in aqueous or organic solvents. Total metal extraction is the preferred sample preparation approach to obtain an Indirect solution . Digest the sample using the Closed vessel diges-tion procedure provided below or one similar to it. The sample preparation scheme should yield sufficient sample to allow quantification of each element at the limit specified in the corresponding monograph or chapter. Closed vessel digestion:This sample preparation procedure is designed for samples that must be digested in a Concen-trated acid using a closed vessel digestion apparatus. Closed vessel digestion minimizes the loss of volatile impurities. The choice of a Concentrated acid depends on the sample matrix. The use of any of the Concentrated acids may be appropri-ate, but each introduces inherent safety risks. Therefore, appropriate safety precautions should be used at all times. [N OTE —Weights and volumes provided may be adjusted to meet the requirements of the digestion apparatus used.] An example procedure that has been shown to have broad applicability is the following. Dehydrate and predigest 0.5 g of primary sample in 5 mL of freshly prepared Concentrated acid . Allow to sit loosely covered for 30 min in a fume hood.Add an additional 10 mL of Concentrated acid , and digest, using a closed vessel technique, until digestion or extraction is complete. Repeat, if necessary, by adding an additional 5 mL of Concentrated acid . [N OTE —Where closed vessel digestion is necessary, follow the manufacturer’s recommended procedures to ensure safe use.] Alternatively, leachate extraction may be appropriate with justification following scientifically validated metal disposition studies, which may include animal studies, speciation, or other means of studying disposition of the specific metal in the drug product. Reagents:All reagents used for the preparation of sample and standard solutions should be free of elemental impurities,in accordance with Plasma Spectrochemistry á730?. ? P ROCEDURE 1: ICP–OES Standardization solution 1: 1.5J of the Target element(s) in a Matched matrix Standardization solution 2:0.5J of the Target element(s) in a Matched matrix Sample stock solution:Proceed as directed in Sample preparation above. Allow the sample to cool, if necessary. For mer-cury determination, add an appropriate stabilizer. Sample solution:Dilute the Sample stock solution with an appropriate solvent to obtain a final concentration of the Target elements at NMT 1.5J . Blank: Matched matrix 298 á233? Elemental Impurities—Procedures / Chemical Tests USP 40

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美国药典USP气相色谱柱对照表 L62 C30硅胶键合于完全多孔球状硅胶，粒径3~15μm。 G48 Highly polar, partially cross-linked cyanopolysiloxane. Rt-2560 G46 14% 氰丙基苯基- 86% 甲基聚硅氧烷 CB-1701MXT?-1701Rtx?-1701VF-1701ms OV-1701CBX-1701DB-1701DB-1701P G43 6% 氰丙基苯基- 94% 二甲基聚硅氧烷 MXT?-624DB-624MXT?-Volatiles CBX-1301 MXT?-1301OV-1301CB-624Rtx?-1301 VF-624ms/VF-1301ms Rtx?-624CB-1301CBX-624 G42 35% 苯基- 65% 二甲基乙烯聚硅氧烷 DB-35Rtx?-35MXT?-35CBX-35 HP-35DB-35MS G38 固定相G1 加减尾剂 MXT-1Rtx?-1MS Rtx?-1 G36 1% 乙烯基- 5% 苯基甲基聚硅氧烷 Rtx?-5MS Rtx?-5CBX-5MXT?-5 G35 聚乙二醇和硝基对苯二甲酸二乙二醇酯 DB-FFAP HP-FFAP CB-FFAP G32 20% Phenylmethyl-80% dimethylpolysiloxane. MXT?-20 G27 5% 苯基- 95% 甲基聚硅氧烷 CB-5XTI?-5Rtx?-5SIL MS VF-5ms Rtx?-5PONA HP-5MS HP-5DB-5MS SE-52DB-5SE-54 G25 聚乙二醇TPA（Carbowax 20M 对苯二酸） FFAP CBX-FFAP G19 25% 苯基- 25% 氰丙基甲基聚硅氧烷 OV-225Rtx?-225VF-23ms CBX-225 G17 75% 苯基- 25% 甲基聚硅氧烷 MXT?-65 G16 聚乙二醇（平均分子量15,000） DB-WAX CBX-Wax CB-WAX Stabilwax?PEG-20M Stabilwax?-DB Stabilwax?-DA MXT?-WAX

美国药典USP40-左氧氟沙星API

USP 40 Official Monographs / Levofloxacin 4831 Acceptance criteria: See Table 1. Sample solution: 1mg/mL of Levofloxacin in Mobile phase Chromatographic system Table 1(See Chromatography ?621?, System Suitability .)Relative Relative Acceptance Mode: LC Retention Response Criteria,Detector: UV 360 nm Name Time Factor NMT (%) Column: 4.6-mm × 25-cm; 5-μm packing L1Levodopa related Column temperature: 45°compound A 0.90.830.1Flow rate: 0.8mL/min Injection size: 25μL Levodopa 1.0——System suitability Levodopa related Sample: Standard solution compound B 2.8 0.83 0.5 Suitability requirements 5,6-Dihydroxy-in-Tailing factor: 0.5–1.5 dole-2-carboxylic Relative standard deviation: NMT 1.0%acid 6.0 2.5 0.1Analysis 0.1Samples: Standard solution and Sample solution individual Calculate the percentage of levofloxacin (C 18H 20FN 3O 4)— 0.3 total in the portion of Levofloxacin taken: Unknown impurities 1.0unknown Total impurities — — 1.1 Result = (r U /r S ) × (C S /C U ) × 100 r U = peak response of levofloxacin from the Sample ADDITIONAL REQUIREMENTS solution ?P ACKAGING AND S TORAGE : Preserve in tight, light-resistant r S = peak response of levofloxacin from the containers, in a dry place, and prevent exposure to ex-Standard solution cessive heat. C S = concentration of USP Levofloxacin RS in the ?USP R EFERENCE S TANDARDS ?11?Standard solution (mg/mL) USP Levodopa RS C U = concentration of Levofloxacin in the Sample USP Levodopa Related Compound A RS solution (mg/mL) 3-(3,4,6-Trihydroxyphenyl)alanine.Acceptance criteria: 98.0%–102.0% on the anhydrous C 9H 11NO 5213.19 basis USP Levodopa Related Compound B RS 3-Methoxytyrosine.IMPURITIES C 10H 13NO 4211.22 ?R ESIDUE ON I GNITION ?281?: NMT 0.2%. Use a platinum crucible. Delete the following: Levofloxacin ??H EAVY M ETALS , Method II ?231?: NMT 10ppm ?(Official 1-Jan-2018) ?O RGANIC I MPURITIES , P ROCEDURE 1 [N OTE —Procedure 1 is recommended if levofloxacin N -ox-ide is a potential organic impurity. Procedure 2 and Pro-cedure 3 are recommended if levofloxacin related com-pound B is a potential organic impurity.] Solution A, Mobile phase, Sample solution, and Chro-matographic system: Proceed as directed in the C 18H 20FN 3O 4·1/2H 2O 370.38Assay . 7H -Pyrido[1,2,3-de ]-1,4-benzoxazine-6-carboxylic acid, System suitability solution: 1mg/mL of USP Levoflox-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-acin RS in Mobile phase 7-oxo-hydrate (2:1), (S )-; Sensitivity solution: 0.3μg/mL of USP Levofloxacin RS (?)-(S )-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piper-in Mobile phase azinyl)-7-oxo-7H -pyrido[1,2,3-de ]-1,4-benzoxazine-6-car-System suitability boxylic acid, hemihydrate [138199-71-0].Samples: System suitability solution and Sensitivity Anhydrous [100986-85-41]. solution Suitability requirements DEFINITION Relative standard deviation: NMT 1.0%, System suit-Levofloxacin contains NLT 98.0% and NMT 102.0% of ability solution C 18H 20FN 3O 4, calculated on the anhydrous basis.Signal-to-noise ratio: NLT 10, Sensitivity solution IDENTIFICATION Analysis ?A . I NFRARED A BSORPTION ?197K ? Sample: Sample solution ?B . The retention time of the major peak of the Sample Calculate the percentage of each individual impurity in solution corresponds to that of the Standard solution , as the portion of Levofloxacin taken: obtained in the Assay.Result = (r U /r S ) × (1/F ) × 100 ASSAY ?P ROCEDURE r U = peak response of each impurity Buffer: 8.5g/L of ammonium acetate, 1.25g/L of cu-r S = peak response of levofloxacin pric sulfate, pentahydrate, and 1.3g/L of L -isoleucine in F = relative response factor (see Table 1)water Acceptance criteria: See Table 1. Mobile phase: Methanol and Buffer (3:7) Standard solution: 1mg/mL of USP Levofloxacin RS in Mobile phase USP Monographs