usp36 467溶剂残留

<467> 溶剂残留

简介：INTRODUCTION

This general chapter applies to existing drug substances, excipients, and products. All substances and products are subject to relevant control of solvents likely to be present in a substance or product.

本章节适用于现有的原料药，辅料和制剂。应对原料药或制剂产品中可能存在溶剂的所有原料及制剂产品进行控制。

Where the limits to be applied comply with those given below, tests for residual solvents are not generally mentioned in specific monographs, because the solvents employed may vary from one manufacturer to another.

当限值与下面提供的数值相符合，残留溶剂的测试方法一般不会在专论中特别，因为不同制造商所使用的溶剂不同。

The objective of this general chapter is to provide acceptable amounts of residual solvents in pharmaceuticals for the safety of the patient. The chapter recommends the use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.

本指导原则旨在介绍药物中残留溶剂在保证人体安全条件下的可接受量，指导原则建议使用低毒的溶剂，提出了一些残留溶剂毒理学上的可接受水平。

For pharmacopeial purposes, residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The residual solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of a drug substance or an excipient may enhance the yield, or determine characteristics such as crystal form, purity, and

solubility. Therefore, the solvent may sometimes be a critical element in the synthetic process. This general chapter does not address solvents deliberately used as excipients, nor does it address solvates. However, the content of solvents in such products should be evaluated and justified.

药物中的残留溶剂在此定义为在原料药或辅料的生产中，以及在制剂制备过程中产生或使用的有机挥发性化合物，它们在工艺中不能完全除尽。在合成原料药中选择适当的溶剂可提高产量或决定药物的性质，如结晶型、纯度和溶解度。因此有时溶剂是合成中非常关键的因素。通用章节中并没有将溶剂作为辅料或溶剂化物。然而在这些制剂中的溶剂含量也应进行评估和判定。

Because residual solvents do not provide therapeutic benefit, they should be removed, to the extent possible, to meet ingredient and product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Solvents that are known to cause unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Solvents associated with less severe toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, Table 3) should be used where practical. The complete list of solvents included in this general chapter is given in Appendix 1. These tables and the list are not exhaustive. For the purposes of this Pharmacopeia, when a manufacturer has received approval from a competent regulatory authority for the use of a new solvent not currently listed in this general chapter, it is the responsibility of that manufacturer to notify the USP regarding the identity of this solvent, the approved residual solvent limit in the article, and the appropriate test procedure for this residual solvent in the article. The USP will then address this topic in the individual monograph. When a new solvent has been approved

through the ICH process, this new solvent will be added to the appropriate list in this general chapter. At that time, consideration will be given for removal of the specific solvent test requirement in the individual monograph.

出于残留溶剂没有疗效，故所有残留溶剂均应尽可能去以符合产品规范、GMP或其他基本的质量要求。制剂所含残留溶剂的水平不能高于安全值。已知能引起不可接受毒性的溶剂（第一类，表1）应避免在原料、辅料、制剂生产中使用，除非其使用在风险效益评估下得到强力的证明。一些毒性不太大的溶剂（第二类，表2）应限制使用，以防止病人潜在的不良反应。使用低毒溶剂（第三类，表3）较为理想。附录1中列出了指导原则中的全部溶剂。表中所列溶剂并非详尽无遗，其他可能使用的溶剂有待日后补充列入。第一、二类溶剂的建议限度或溶剂的分类会随着新的安全性资料的获得而调整。出于药典目的，当一供应商从主管当局获得未收集在本章列表中的新溶剂批准时，厂家有责任通报美国药典关于此残留溶剂的特性和可接受限度及检查方法。美国药典将在个别专论解决此主题。当一个新的溶剂通过了ICH指南，该溶剂会被添加到本章节适当目录上。到那时将考虑在个别专论中去除专门的溶剂测试要求。

Testing of drug substances, excipients, and drug products for residual solvents should be performed when production or purification processes are known to result in the presence of such residual solvents. It is only necessary to test for residual solvents that are used or produced in the manufacture or purification of drug substances, excipients, or products.

指导原则范围包括原料药、辅料或制剂中所含残留溶剂，因此，当生产或纯化过程中会出现这些溶剂时，应进行残留溶剂的检验。也只有在上述情况下，才有必要作溶剂的检查。

Although manufacturers may choose to test the drug product, a cumulative procedure may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used to produce the

drug product. If the calculation results in a level equal to or below that provided in this general chapter, no testing of the drug product for residual solvents need be considered. If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount. A drug product should also be tested if a residual solvent is used during its manufacture.

虽然生产商可以选择性地测定制剂，但也可以从制剂中各成分的残留溶剂水平来累积计算制剂中的残留溶剂。如果计算结果等于或低于本原则的建议水平，该制剂可考虑不检查残留溶剂，但如果计算结果高于建议水平则应进行检测，以确定制剂制备过程中是否降低了有关溶剂的量以达到可接受水平。如果制剂生产中用到某种溶剂，也应进行测定。

For the purposes of this Pharmacopeia, when a manufacturer has received approval from a competent regulatory authority for a higher level of residual solvent, it is the responsibility of that manufacturer to notify the USP regarding the identity of this solvent and the approved residual solvent limit in the article. The USP will then address this topic in the individual monograph.

该药典指出，当一个制造商从一个权威机构通过一个残留溶剂更高水平的批准，该制造商有责任告知美国药典关于该溶剂的鉴别及残留溶剂限度，美国药典将会在个别专论中解决此主题。

See Appendix 2 for additional background information related to residual solvents.

有关残留溶剂的背景附加说明见附录2。

CLASSIFICATION OF RESIDUAL SOLVENTS BY RISK ASSESSMENT

根据危害程度对残留溶剂分类

The term tolerable daily intake (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals, and the term acceptable daily intake (ADI) is used by the World Health Organization (WHO) and other national and international health authorities and institutes. The term permitted daily exposure (PDE) is defined as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADIs of the same substance.

“可耐受的日摄人量”（TDI）是国际化学品安全纲要（IPCS）用于描述毒性化合物接触限度的术语。“可接受的日摄入量”（ADI）是WHO及一些国家和国际卫生组织所用的术语。新术语“允许的日接触量”（PDE）是本指导原则中用于定义药物中可接受的有机溶剂摄入量，以避免与同一物质的ADI混淆。

Residual solvents assessed in this general chapter are listed in Appendix 1 by common names and structures. They were evaluated for their possible risk to human health and placed into one of three classes as follows:

本原则中残留溶剂的评价以通用名和结构列于附录1，根据它们对人体可能造成的危害分为以下三类；

（1）第一类溶剂：应避免的溶剂

为人体致癌物、疑为人体致癌物或环境危害物。 （2）第二类溶剂。应限制的溶剂

非遗传毒性动物致癌或可能导致其他不可逆毒性测神经毒性或

致畸性）的试剂。

可能具其他严重的但可逆毒性的溶剂。 （3）第三类溶剂：低毒性溶剂

*对人体低毒的溶剂，无须制定接触限度；第三类溶剂的PDE为每天50mg或50mg以上(*PDE为每天50mg以上的残留溶剂，详见第三类溶剂的讨论章节)。

METHODS FOR ESTABLISHING EXPOSURE LIMITS

建立接触限度的方法

The method used to establish PDEs for residual solvents is presented in Appendix 3.

用于建立残留溶剂的PDE方法见附录3。

For articles that are designated ―for veterinary use only‖, higher levels for the PDE and concentration limit may be justified in exceptional cases based upon the actual daily dose, actual target species, and relevant toxicological data and considering consumer safety impact. For the purpose of this Pharmacopeia, when a manufacturer has received approval from a competent regulatory authority for a higher limit, it is the responsibility of that manufacturer to notify the USP regarding the approved residual solvent limit in the article and the justification. The USP will then address this topic in the individual monograph.

对于指定是―只供兽用‖的药品，根据实际日剂量，实际的目标物种，以及相关的毒理学数据，并考虑消费者的安全影响，认为更高水平的允许的日接触量(PDE)及浓度限度在特殊情况下是合理的。本药典旨在，当一个制造商从一个权威管理机构得到一个更高的限度，该制造商有责任通知美国药典关于对该产品所批准的残留溶剂限度及理由，美国药典将会在单独专论中解决此主题。

OPTIONS FOR DESCRIBING LIMITS OF CLASS 2 RESIDUAL

SOLVENTS

第二类溶剂限度的选择方法

Two options are available when setting limits for Class 2 residual solvents.

制定第二类溶剂的限度时有两种选择。

Option 1

The concentration limits in ppm stated in Table 2 are used. They were calculated using the equation below by assuming a product weight of 10 g administered daily.

Concentration (ppm) = (1000 μg/mg x PDE)/dose

方法1: 使用表 2中以 ppm为单位的浓度限度，假定日给药量为10g，以方程(1)计算。

1000(μg/mg)×PDE 方程(1) C(ppm)=

剂量

Here, PDE is given in terms of mg per day, and dose is given in g per day.

PDE：mg／天 剂量：g／天

These limits are considered acceptable for all drug substances, excipients, and drug products. Therefore, this option may be applied if the daily dose is not known or fixed. If all drug substances and excipients in a formulation meet the limits given in Option 1, these components may be used in any proportion. No further calculation is necessary, provided that the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day are to be considered under Option 2.

这些限度对所有原料药、辅料和制剂均适用。因此，这一方法可用于日剂量未知或未定的情况、只要在处方中所有的辅料和原料药都

符合方法1给定的限度，就可以以任何比例用于制剂。只要日剂量不超过10g，就无须进一步计算。服用剂量超过 10g／天，应考虑用方法 2。

Option 2

It is not necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg per day as stated in Table 2 can be used with the known maximum daily dose and the equation above to determine the concentration of residual solvent allowed in a drug product. Such limits are considered acceptable, provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, and reasonable variation in the manufacturing process. The limits should also reflect contemporary manufacturing standards.

方法2：制剂中的每一种成分不必符合方法1的限度。药物中允许的残留溶剂限度水平，可根据表2中 PDE mg／天及已知最大日剂量，用方程（1）来计算。只要证明已降低至实际最低水平，便可以认为这种限度是可接受的、该限度能说明分析方法的精度、生产能力和生产工艺的合理变异，并能反映当前生产的标准水平。

Option 2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.

应用方法2时可将药物制剂的每种成分中残留溶剂叠加起来，每天的总溶剂量应低于PDE给定的值。

Consider an example of the application of Option 1 and Option 2 to acetonitrile concentration in a drug product. The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm. The maximum administered daily weight of a drug product is 5.0 g, and the

drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the following table.

下面举例说明如何用方法l和2来考虑制剂中的乙腈限度。乙腈的允许日接触量是4.1 mg／天，因此由方法1算出限度是410PPm；如现在日最大给药量是5.0g，制剂中含两种辅料，制剂中的成分和计算得到的最大残留乙睛量见下表：

成分 处方量(g) 乙腈量(ppm) 日(摄人)量(mg) 原料药 0.3g 800ppm 0.24mg 辅料一 0.9g 400ppm 0.36mg 辅料二 3.8g 800PPm 3.04mg 药物制剂 5.0g 728ppm 3.64mg

Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the drug product meets the Option 2 limit of 4.1 mg per day and thus conforms to the acceptance criteria in this general chapter.

辅料1符合方法1限度，但原料、辅料2和药物制剂不符合方法1限度，而制剂符合方法2规定的4.1mg／天，故符合本指导原则的建议值。

Consider another example, using acetonitrile as the residual solvent. The maximum administered daily weight of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are

given in the following table.

乙睛作为残留溶剂的另一例子，日最大给药量5.0g，制剂中含两种辅料，各组分及计算得到的最大残留的乙腈最见下表：

成分 处方量 乙腈量 日（摄人）量 原料药 0.3g 800ppm 0.24mg 辅料1 0.9g 2000ppm 1.80mg 辅料2 3.8g 800ppm 3.04mg 药物制剂 5.0g 1016ppm 5.08mg

In this example, the drug product meets neither the Option 1 nor the Option 2 limit according to this summation. The manufacturer could test the drug product to determine whether the formulation process reduced the level of acetonitrile. If the level of acetonitrile was not reduced to the allowed limit during formulation, the product fails to meet the solvent limits as described in this chapter, and the manufacturer of the drug product should take other steps to reduce the amount of acetonitrile in the drug product. In some instances the manufacturer may have received approval from a competent regulatory authority for such a higher level of residual solvent. If this is the case, it is the responsibility of that manufacturer to notify the USP regarding the identity of this solvent and the approved residual solvent limit in the article. The USP will then address this topic in the individual monograph.

此例制剂中乙腈限度总量既不符合方法1也不符合方法2。生产厂可先测定制剂，以确定在处方工艺中能否降低乙腈水平，如果不能将乙腈水平降至允许范围，生产厂应采取措施降低制剂中的乙腈量；

若所有措施均不能降低残留溶剂的水平，厂方应提供其尝试降低残留溶剂以符合指导原则所做工作的总结报告，并以利弊分析报告证明允许该制剂存在的较高水平的残留溶剂。

ANALYTICAL PROCEDURES

Residual solvents are typically determined using chromatographic techniques such as gas chromatography. Compendial methods for testing for residual solvent content are described under the section Identification, Control, and Quantification of Residual Solvents in this general chapter. The General Notices discuss the use of other methods in special circumstances (see 6.30. Alternative and Harmonized Methods and Procedures). If Class 3 solvents are present, a nonspecific method such as loss on drying may be used.

分析方法

残留溶剂通常用色谱技术，如用GC法测定。药典规定对该章节检测的残留溶剂含量需要进行鉴别控制和定量。通则规定在特殊情况下使用其他方法（见6.30.替换统一方法和操作步骤）。若仅存在第三类溶剂；可用非专属性的方法如干燥失重来检查。

REPORTING LEVELS OF RESIDUAL SOLVENTS

残留溶剂的报告水平

Manufacturers of pharmaceutical products need certain information about the content of residual solvents in drug substances or excipients in order to meet the criteria of this general chapter. The following statements are given as acceptable examples of the information that could be provided from a supplier of drug substances or excipients to a pharmaceutical manufacturer. The supplier might choose one of the following as appropriate:

医药产品生产商需要了解有关药物或辅料中残留溶剂含量的信息，以符合本指导原则的标准。以下阐述了药物或辅料供应商应提供给制剂生产商的信息的一些例子。供应商应选择以下一项：

〃Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.

〃Only Class 2 solvents X, Y, ... are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, ...)

〃Only Class 2 solvents X, Y, ... and Class 3 solvents are likely to be present. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.

〃仅可能存在第三类溶剂，干燥失重小于0.5％。 〃仅可能存在第二类溶剂，X、Y……

全部应低于方法1的限度。（这里供应商应将第二类溶剂用X、Y……来表示）

〃仅可能存在第二类溶剂X、Y……和第三类溶剂，残留的第三

类溶剂低于方法1的限度，残留的第三类溶剂低于0.5％。

The phrase ―likely to be present‖ as used in the above examples refers to the solvent used or produced in the final manufacturing step and to solvents that are used or produced in earlier manufacturing steps and not removed consistently by a validated process.

If Class 1 solvents are likely to be present, they should be identified and quantified. If solvents of Class 2 or 3 are present at greater than their Option 1 limits or 0.5%, respectively, they should be identified and quantified.

上述例子中的“可能存在”系指最后一步工艺使用或产生的溶剂和较前几步工艺使用或产生的溶剂经验证不能全部除尽。 如果可能存在第一类溶剂，应进行鉴定并定量。如果第二类溶剂高于方法1的限度或第三类溶剂高于0.5％，应鉴定并定量。

LIMITS OF RESIDUAL SOLVENTS

残留溶剂的限度

Class 1 (solvents to be avoided) 1类(应避免的溶剂)

Class 1 residual solvents (Table 1) should not be employed in the manufacture of drug substances, excipients, and drug products because of the unacceptable toxicities or deleterious environmental effects of these residual solvents. However, if their use in order to produce a medicinal product with a significant therapeutic advance is unavoidable, their levels should be restricted as shown in Table 1, unless otherwise stated in the individual monograph. The solvent 1,1,1-trichloroethane is included in Table 1 because it is an environmental hazard. The stated limit of 1500 ppm is based on a review of safety data.

1类残留溶剂(表1)因其具有不可接受的毒性或对环境造成公害，第一类溶剂在原料药、辅料及制剂生产中不应该使用。但是，为了生产一种有特殊疗效的药品而不得不使用时，除非经过其他论证，否则应按表1控制，1，1，1－三氯乙烷因会造成环境公害列入表1，其限度1500ppm是基于安全性数据而定的。

When Class 1 residual solvents are used or produced in the manufacture or purification of a drug substance, excipient, or drug product and are not removed by the process, these solvents should be identified and quantified. The procedures described in the section Identification, Control, and Quantification of Residual Solvents in this general chapter are to be applied wherever possible. Otherwise an appropriate validated procedure is to be employed.

当1类残留溶剂被使用或在原料药，辅料，制剂的生产、精制中产生且在生产过程中没有去除，这些溶剂应被鉴别并确认。描述于本章节残留溶剂的鉴别、控制及量化中的方法适用于任何可能的情况下。否则一个适当的验证程序将被使用。

Table 1. Class 1 Residual Solvents (solvents that should be avoided)

表1 药物制剂中含第一类溶剂的限度（应避免使用）

溶剂 浓度限度（ppm） 备注 苯 2 致癌物 四氯化碳 4 毒性及环境公害 1,2－二氯乙烷 5 毒性 1,1－二氯乙烷 8 毒性 1,1,1－三氯乙烷 1500 环境公害

Class 2

Class 2 residual solvents (Table 2) should be limited in drug substances, excipients, and drug products because of the inherent toxicities of the residual solvents. PDEs are given to the nearest 0.1 mg per day, and concentrations are given to the nearest 10 ppm. The stated values do not reflect the necessary analytical precision of the determination procedure. Precision should be determined as part of the procedure validation.

2类

2类残留溶剂(表2) 应限制的溶剂，由于其具毒性，在制剂中应予限制，规定 PDE约 0.1mg／天，浓度约10ppm。所列值不能反映测定所必需的分析精度，精度应为方法论证的一部分。

If Class 2 residual solvents are present at greater than their Option 1 limits, they should be identified and quantified. The procedures described in the section Identification, Control, and Quantification of Residual

Solvents in this general chapter are to be applied wherever possible. Otherwise an appropriate validated procedure is to be employed.

如果2类溶剂比方法1的限度高，这些溶剂应被鉴别并定量分析。描述于本章节残留溶剂的鉴别、控制及量化中的方法适用于任何可能的情况下。否则一个适当的验证程序将被使用。

[Note—The following Class 2 residual solvents are not readily detected by the headspace injection conditions described in the section Identification, Control, and Quantification of Residual Solvents in this general chapter: formamide, 2-ethoxyethanol, 2-methoxyethanol, ethylene glycol, N-methylpyrrolidone, and sulfolane. Other appropriate validated procedures are to be employed for the quantification of these residual solvents. Such procedures shall be submitted to the USP for review and possible inclusion in the relevant individual monograph. In addition, USP Residual Solvent Class 2—Mixture C RS can be used to develop an alternative procedure. ]

[注释-下面的2类残留溶剂不易被描述于本章节中的残留溶剂的鉴别、控制及量化中的顶空进样条件所检测：甲酰胺，2－乙氧基乙醇，2－甲氧基乙醇，乙二醇，N-甲基吡咯烷酮及二氧噻吩烷。其它合适的验证方法将被用于这些残留溶剂的量化。这些方法应递交给美国药典审核并可能包含于相关的个别专论中。此外，USP第2类残留溶剂- CRS混匀物可以用于发展替代程序。]

表2 药品中第二类溶剂Table 2. Class 2 Residual Solvents

溶剂 PDE（mg/天） 浓度限度（ppm）

乙晴 4.1 410 氯苯 3.6 360 氯仿 0.6 60 环己烷 38.8 3880 1,2－二氯乙烯 18.7 1870 二氯甲烷 6.0 600 1,2－二甲亚砜 1.0 100 N,N－二甲乙酰胺 10.9 1090 N,N－二甲基甲酰胺 8.8 880 1,4－二恶烷 3.8 380 2－乙氧基乙醇 1.6 160 乙二醇 6.2 620 甲酰胺 2.2 220 正己烷 2.9 290 甲醇 30.0 3000 2－甲氧基乙醇 0.5 50 甲基丁酮 0.5 50 甲基环己烷 11.8 1180 二氯甲烷 6.0 600 N-甲基吡咯烷酮 5.3 530 硝基甲烷 0.5 50 吡啶 2.0 200 二氧噻吩烷 1.6 160 四氢呋喃 7.2 720 四氢萘 1.0 100 甲苯 8.9 890 1,1,2-三氯乙烯 0.8 80 二甲苯* 21.7 2170 *通常为60% m-二甲苯，14% p-二甲苯，9% o-二甲苯和17%乙基苯。

Class 3

Class 3 residual solvents (Table 3) may be regarded as less toxic and of lower risk to human health than Class 1 and Class 2 residual solvents. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the residual solvents in Class 3. Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. 第3类

第3类残留溶剂(表3)可被视为低毒并较第1类和第2类残留溶剂对人体健康的危害风险更小。第三类溶剂包括人们认为在药物中以一般量存在时对人体无害的溶剂，但该类溶剂中许多尚未进行长期毒性或致癌研究。现有数据表明，它们在急性或短期研究和阴性遗传毒性研究中表现为低毒。

It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification. Higher amounts may also be acceptable, provided that they are realistic in relation to manufacturing capability and good manufacturing practice. For the purposes of this Pharmacopeia, when a manufacturer has received approval from a competent regulatory authority for such a higher level of residual solvent, it is the responsibility of that manufacturer to notify the USP regarding the identity of this solvent and the approved residual solvent limit in the article. The USP will then address this topic in the individual monograph. If a Class 3 solvent limit in an individual monograph is greater than 50 mg per day, that residual solvent should be identified and quantified. The procedures described in the section Identification, Control, and Quantification of Residual Solvents in this general chapter, with appropriate modifications to the standard solutions, are to be applied wherever possible. Otherwise an appropriate validated procedure is to be employed.

据认为，每日50mg或更少的残留溶剂量无须论证即可接受（用方法１计算。即5000ppm或0.5％）。如果能够反映生产能力和GMP的实际情况，更大的量也可接受。该药典旨在，当一个制造商从一个权

威管理机构通过一个更高的限度，该制造商有责任通知美国药典关于对该产品所批准的的残留溶剂限度及理由。美国药典将会在个别专论中解决此主题。如有一个三类溶剂在个别专论的限度大于每天50mg，该残留溶剂应被鉴别并量化。在本章节残留溶剂鉴别，控制及量化中所述的方法，对标准溶液作合适的修改，将被尽可能地应用，否则一个适当的验证方法将被使用。

Acetic acid 乙酸 Heptane庚烷

Acetone 丙酮 Isobutyl acetate乙酸异丁酯 Anisole苯甲醚 Isopropyl acetate乙酸异丙酯 1-Butanol 1-丁醇 Methyl acetate乙酸甲酯 2-Butanol 2-丁醇 3-Methyl-1-butanol 3-甲基-1-丁醇 Butyl acetate乙酸丁酯 Methylethylketone甲乙酮

tert-Butylmethyl ether甲基叔丁基醚 Methylisobutylketone甲基异丁酮 Cumene异丙苯 2-Methyl-1-propanol 2-甲基-1-丙醇 Dimethyl sulfoxide二甲基亚砜 Pentane戊烷 Ethanol 乙醇 1-Pentanol 1-戊醇 Ethyl acetate 乙酸乙酯 1-Propanol 1-丙醇 Ethyl ether 乙醚 2-Propanol 2-丙醇 Ethyl formate甲酸乙酯 Propyl acetate乙酸丙酯 Formic acid甲酸

Other Residual Solvents

The residual solvents listed in Table 4 may also be of interest to manufacturers of drug substances, excipients, or drug products. However, no adequate toxicological data on which to base a PDE was found Table 4. Other Residual Solvents

(for which no adequate toxicological data was found) 其他残留溶剂

以下溶剂在表4中列出，在辅料、原料药和制剂生产中也许会被生产商采用，但尚无足够的毒理学数据，故无PDE值。 表4 无足够毒理学数据的溶剂

1,1-二乙氧基丙烷 甲基异丙酮 1,1-二甲氧基甲烷 甲基四氢呋喃 2,2-二甲氧基丙烷 石油醚 异辛烷 三氯乙酸 异丙醚 三氟乙酸 IDENTIFICATION, CONTROL, AND QUANTIFICATION OF RESIDUAL SOLVENTS

Whenever possible, the substance under test needs to be dissolved to release the residual solvent. Because the USP deals with drug products, as well as active ingredients and excipients, it may be acceptable that in some cases, some of the components of the formulation will not dissolve completely. In those cases, the drug product may first need to be pulverized into a fine powder so that any residual solvent that may be present can be released. This operation should be performed as fast as

possible to prevent the loss of volatile solvents during the procedure. 残留溶剂的鉴别，控制和量化

只要有可能，待测品需要被溶解以释放残留溶剂。因USP涉及制剂，原料药成分及辅料，因此处方中一些成分不能完全溶解的情况是可以接受的。在这种情况下，药品需要首先制成精细粉末以便可能存在的残留溶剂能够释放。该操作应尽快以防止在操作过程造成挥发溶剂损失。

Note—The organic-free water specified in the following procedures produces no significantly interfering peaks when chromatographed.

【注-以下程序指明的去有机水在色谱中对峰没有明显干扰。】

Class 1 and Class 2 Residual Solvents

The following procedures are useful to identify and quantify residual solvents when the information regarding which solvents are likely to be present in the material is not available. When the information about the presence of specific residual solvents is available, only Procedure C is needed to quantify the amount of residual solvents present. A flow diagram for the application of the residual solvent limit tests is shown in Figure 1.

一类和二类残留溶剂

以下程序在溶剂可能存在于物料中不适用时对残留溶剂的鉴别和量化是有帮助的。当明确的特定残留溶剂的存在是适用的，只有方法C能用于确定残留溶剂存在的数量。下图1为残留溶剂限量检测方法流程图。

Procedure— [Note—It is recommended to increase the temperature of the transfer line between runs to eliminate any potential condensation of solvents. ] Separately inject (following one of the headspace operating parameter sets described in Table 5) equal volumes of headspace (about 1.0 mL) of the Class 1 Standard Solution, Class 2 Mixture A Standard Solution, Class 2 Mixture B Standard Solution, and Test Solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. If a peak response of any peak, other than a peak for 1,1,1-trichloroethane, in the Test Solution is greater than or equal to a corresponding peak in either the Class 1 Standard Solution or either of the two Class 2 Mixture Standard Solutions, or a peak response of 1,1,1-trichloroethane is greater than or equal to 150 times the peak response corresponding to 1,1,1-trichloroethane in the Class 1 Standard Solution, proceed to Procedure B to verify the identity of the peak; otherwise the article meets the requirements of this test.

操作过程 【注-建议增加传输线路间的温度，以消除任何潜在冷凝溶剂】根据下表5的一项设定顶空操作参数，将相同体积的（约1.0mL）一级标准溶液，二级混匀液A标准溶液，二级混匀液B标准溶液和待测液分别顶空进样，记录色谱并测量主峰的响应值。若待测液任何一个峰的响应值大于或等于一级标准溶液或者两个二级混匀液（A和B）标准溶液相对应的峰响应值，或1,1,1-三氯乙烷峰响应值大于一级标准溶液中1,1,1-三氯乙烷峰响应的150倍，根据操作B继续操作以鉴别峰；否则待测物符合检测标准。

表5. 顶空操作参数Table 5. Headspace Operating Parameters 顶空操作参数设臵 1 2 3 平衡温度（℃） 80 105 80 平衡时间（分钟） 60 45 45 传输管温度（℃）（如果合适）85 110 105 注射温度（℃）（如果合适） 80-90 105-115 80-90 载气：适当压力的氮气或者氦气 加压时间 （秒）（如果合适）≥60 ≥60 ≥60 进样量（mL） 1 1 1 *或参照生产厂家建议，尽可能满足方法要求，在达到灵敏度要求前提下进进样量尽可能少。 Procedure B—

Class 1 Standard Stock Solution, Class 1 Standard Solution, Class 2 Standard Stock Solutions, Class 2 Mixture A Standard Solution, Class 2 Mixture B Standard Solution, Test Stock Solution, Test Solution, and Class 1 System Suitability Solution— Prepare as directed for Procedure A. 操作B

一级标准储备液，一级标准溶液，二级标准储备液，二级混匀液A标准溶液，二级混匀液B标准溶液，待测储备液，待测液和一级系统适应性溶液――配制方法如操作A。

Chromatographic System (see Chromatography 621)— The gas chromatograph is equipped with a flame-ionization detector and a 0.32-mm × 30-m fused-silica column coated with a 0.25-μm layer of phase G16 or a 0.53-mm × 30-m wide-bore column coated with a 0.25-μm layer of phase G16. The carrier gas is nitrogen or helium with a linear velocity of about 35 cm per second and a split ratio of 1:5. [Note—The split ratio can be modified in order to optimize sensitivity. ] The column temperature is maintained at 50 for 20 minutes, then raised at a rate of 6 per minute to 165, and maintained at 165 for 20 minutes. The injection port and detector temperatures are maintained at 140 and 250, respectively. Chromatograph the Class 1 Standard Solution and the Class 1 System Suitability Solution, and record the peak responses as directed for Procedure: the signal-to-noise ratio of benzene in the Class 1 Standard Solution is not less than 5; the signal-to-noise ratio of each peak in the Class 1 System Suitability Solution is not less than 3; and the resolution,

R, between acetonitrile and cis-dichloroethene in the Class 2 Mixture A Standard Solution is not less than 1.0.

色谱系统（参见色谱法<621>）――气相色谱由氢火焰离子检测器，0.32mm×30m，装填有厚度为0.25μm厚的G16固定相的熔融石英柱组成。石英柱也可由装填有0.25μm厚的G16固定相，0.53mm×30m大内径开管柱。载气为线速35cm/秒，分流比为1：5的氮气或者氦气。【注：为了优化灵敏度可对分流比进行调整】柱温在50℃维持20分钟，然后以6℃/分钟的速率升至165℃，然后在165℃维持20分钟。进样口和检测器温度分别维持在140℃和250℃。记录一级标准溶液，一级系统适应性溶液和二级系统适应性溶液 的色谱，按下列操作记录峰响应值：一级标准溶液中苯的信噪比不得小于5；一级系统适应性溶液中的每个峰的信噪比不得小于3；在二级系统适应性溶液中，乙腈和三氯乙烯的分离度R不得小于1.0。

Procedure— [Note—It is recommended to increase the temperature of the transfer line between runs to eliminate any potential condensation of solvents. ] Separately inject (following one of the headspace operating parameter sets described in Table 5) equal volumes of headspace (about 1.0 mL) of the Class 1 Standard Solution, the Class 2 Mixture A Standard Solution, the Class 2 Mixture B Standard Solution, and the Test Solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. If the peak response(s) in the Test Solution of the peak(s) identified in Procedure A is/are greater than or equal to a corresponding peak(s) in either the Class 1 Standard Solution or either of the two Class 2 Mixture Standard Solutions, proceed to Procedure C to quantify the peak(s); otherwise the article meets the requirements of this test.

操作过程―【注-建议增加传输线路间的温度，以消除任何潜在冷凝溶剂】根据表5的一项设定顶空操作参数，将相同体积的（约1.0mL）一级标准溶液，二级混匀液A标准溶液，二级混匀液B标准溶液和待测液分别顶空进样，记录色谱并测量主峰的响应值。若待测

液中任何一个峰（在操作A中区别出）的响应值大于或等于一级标准溶液 或者两个二级标准液（A和B）标准溶液 相对应的峰响应值，根据操作C继续操作以定量峰值；否则待测物符合检测标准。

Procedure C—

Class 1 Standard Stock Solution, Class 1 Standard Solution, Class 2 Standard Stock Solution A, Class 2 Mixture A Standard Solution, Test Stock Solution, Test Solution, and Class 1 System Suitability Solution— Prepare as directed for Procedure A. 操作C

一级标准储备液，一级标准溶液，二级标准储备A，二级混匀液A标准溶液，待测储备液，待测液 和一级系统适应性溶液――配制方法如操作A。

Standard Stock Solution— [note—Prepare a separate Standard Stock Solution for each peak identified and verified by Procedures A and B. For the Class 1 solvents other than 1,1,1-trichloroethane, prepare the first dilution as directed for the first dilution under Class 1 Standard Stock Solution in Procedure A. ] Transfer an accurately measured volume of each individual USP Reference Standard corresponding to each residual solvent peak identified and verified by Procedures A and B to a suitable container, and dilute quantitatively, and stepwise if necessary, with water to obtain a solution having a final concentration of 1/20 of the value stated in Table 1 or 2 (under Concentration Limit).

标准储备液――【注意－根据操作A和操作B区别和确认的峰，

配制每一个峰相对应溶剂的标准溶液】根据操作A和操作B 测定的结果精确量取一定量的USP标准品，移至适当的容器，加水稀释至定量，如有必要可逐步稀释，最终得到浓度为表1或者表2值（在浓度限下）1/20的溶液。

Standard Solution— Transfer 1.0 mL of this solution to an appropriate headspace vial, add 5.0 mL of water, apply the stopper, cap, and mix.

标准溶液--取1.0mL此溶液至顶空瓶中，加入5.0mL水，加塞、轧盖、混匀。

Spiked Test Solution— [Note—Prepare a separate Spiked Test Solution for each peak identified and verified by Procedures A and B. ] Transfer 5.0 mL of Test Stock Solution to an appropriate headspace vial, add 1.0 mL of the Standard Stock Solution, apply the stopper, cap, and mix.

示踪溶液（掺料溶液）――【注意－根据操作A和操作B区别和确认的峰，配制每一个峰相对应溶剂的示踪溶液】取5.0mL待测储备液至顶空瓶中，加入1.0mL标准溶液 ，加塞、轧盖、混匀。

Chromatographic System (see Chromatography 621)— [Note—If the results of the chromatography from Procedure A are found to be inferior to those found with Procedure B, the Chromatographic System from Procedure B may be substituted. ] The gas chromatograph is equipped with a flame-ionization detector and a 0.32-mm × 30-m fused-silica column coated with a 1.8-μm layer of phase G43 or a 0.53-mm × 30-m wide-bore column coated with a 3.0-μm layer of phase G43. The carrier

gas is nitrogen or helium with a linear velocity of about 35 cm per second, and a split ratio of 1:5. [Note—The split ratio can be modified in order to optimize sensitivity. ] The column temperature is maintained at 40 for 20 minutes, then raised at a rate of 10 per minute to 240, and maintained at 240 for 20 minutes. The injection port and detector temperatures are maintained at 140 and 250, respectively. Chromatograph the Class 1 Standard Solution, the Class 1 System Suitability Solution, and the Class 2 Mixture A Standard Solution, and record the peak responses as directed for Procedure: the signal-to-noise ratio of 1,1,1-trichloroethane in the Class 1 Standard Solution is not less than 5; the signal-to-noise ratio of each peak in the Class 1 System Suitability Solution is not less than 3; and the resolution, R, between acetonitrile and methylene chloride in the Class 2 Mixture A Standard Solution is not less than 1.0.

色谱系统（参见色谱法<621>）――【注意－若操作A得到的色谱结果低于操作B得到的色谱结果，操作B的色谱系统可以被替代】气相色谱由氢火焰离子检测器，0.32mm×30m，装填有厚度为1.8μm厚的G43固定相的熔融石英柱组成。石英柱也可由装填有3.0μm厚的G43固定相，0.53mm×30m大内径开管柱。载气为线速35cm/秒，分流比为1：5的氮气或者氦气。分流比可根据条件修改调整。柱温在40℃维持20分钟，然后以10℃/分钟的速率升至240℃，然后在240℃维持20分钟。进样口和检测器温度分别维持在140℃和250℃。记录一级标准溶液，一级系统适应性溶液 和二级混匀液A标准溶液的色谱，按下列操作记录峰响应值：1，1，1－三氯乙烷在一级标准溶液中的信噪比不得小于5；一级系统适应性溶液 的每个峰的信噪比不得小于3；在二级混匀液A标准溶液中，乙腈和二氯甲

烷的分离度R不得小于1.0。

Procedure— [Note—It is recommended to increase the temperature of the transfer line between runs to eliminate any potential condensation of solvents. ] Separately inject (following one of the headspace operating parameters described in Table 5) equal volumes of headspace (about 1.0 mL) of the Standard Solution, the Test Solution, and the Spiked Test Solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the amount, in ppm, of each residual solvent found in the article under test by the formula: 5(C/W)[rU /(rST-rU)]

操作过程――【注-建议增加传输线路间的温度，以消除任何潜在冷凝溶剂】根据表5的一项设定顶空操作参数，将相同体积的（约1.0mL）标准溶液，待测液 和示踪溶液顶空进样，记录色谱并测量主峰的响应值。根据下面的公式计算被检测药品中每个残留溶剂的量，单位为ppm：

5（C/W）[ru/（rst-ru）]

in which C is the concentration, in μg per mL, of the appropriate USP Reference Standard in the Standard Stock Solution; W is the weight, in g, of the article under test taken to prepare the Test Stock Solution; and rU and rST are the peak responses of each residual solvent obtained from the Test Solution and the Spiked Test Solution, respectively.

C为USP标准品在标准溶液中的浓度（μg/ml）；W为用于配制待测储备液 的样品的重量（g）；ru 和rst分别为待测液 和示踪溶液 中每一个残留溶剂的峰值响应。

水不溶物water-insoluble articles

Procedure A— [Note—Dimethyl sulfoxide may be substituted as an alternative solvent to dimethylformamide. ] 操作A (注：二甲基甲酰胺可替代二甲亚砜)

Class 1 Standard Stock Solution— Transfer 1.0 mL of USP Class 1 Residual Solvents Mixture RS to a 100-mL volumetric flask previously filled with about 80 mL of dimethylformamide, dilute with dimethylformamide to volume, and mix. Transfer 1.0 mL of this solution to a 100-mL volumetric flask, previously filled with about 80 mL of dimethylformamide, dilute with dimethylformamide to volume, and mix (reserve a portion of this solution for the Class 1 System Suitability Solution). Transfer 1.0 mL of this solution to a 10-mL volumetric flask, dilute with dimethylformamide to volume, and mix.

一级标准储备液：吸1.0mlUSP一级残留溶剂混匀对照，于事先已加入80ml二甲基甲酰胺的100ml量瓶中，用二甲基甲酰胺稀至刻度，混匀，吸上述溶液1.0ml，于预先加入80ml的二甲基甲酰胺的100ml量瓶中，用二甲基甲酰胺稀至刻度，混匀(作为一级系统适用性溶液)。再吸取1.0ml上述溶液于10ml量瓶中，用二甲基甲酰胺稀至刻度，混匀。

Class 1 Standard Solution— Transfer 1.0 mL of Class 1 Standard Stock Solution to an appropriate headspace vial, containing 5.0 mL of water, apply the stopper, cap, and mix.

一级标准溶液：吸取1.0ml一级标准储备液至已加入5.0ml水的顶

空瓶中，加塞，轧盖，混匀。

Class 2 Standard Stock Solutions— Transfer 1.0 mL of USP Residual Solvents Class 2—Mixture A RS to a 100-mL volumetric flask, previously filled with about 80 mL of dimethylformamide, dilute with dimethylformamide to volume, and mix. This is Class 2 Standard Stock Solution A. Transfer 0.5 mL of USP Residual Solvents Class 2—Mixture B RS to a 10-mL volumetric flask, dilute with dimethylformamide to volume, and mix. This is Class 2 Standard Stock Solution B.

二级标准储备液：吸取1.0ml二级混匀物A对照，至预先加入80ml二甲基甲酰胺的100ml量瓶中，用二甲基甲酰胺稀至刻度，混匀，作为二级混匀A标准储备液。吸取0.5ml二级USP混匀B对照，至10 ml量瓶中，用二甲基甲酰胺稀至刻度，混匀，作为二级混匀物B标准储备液。

Class 2 Mixture A Standard Solution— Transfer 1.0 mL of Class 2 Standard Stock Solution A to an appropriate headspace vial containing 5.0 mL of water, apply the stopper, cap, and mix.

二级混匀A标准溶液：吸取二级混匀A标准储备液1.0ml至顶空瓶中，加水5.0ml，加塞，轧盖，混匀。

Class 2 Mixture B Standard Solution— Transfer 1.0 mL of Class 2 Standard Stock Solution B to an appropriate headspace vial containing 5.0 mL of water, apply the stopper, cap, and mix.

二级混匀B标准溶液：吸取二级混匀B标准储备液1.0ml至顶空瓶中，加水5.0ml，加塞，轧盖，混匀。

Test Stock Solution— Transfer about 500 mg of the article under test, accurately weighed, to a 10-mL volumetric flask, dissolve in and dilute with dimethylformamide to volume, and mix.

测试储备液：准确称取专论下规定约500mg的样品于10ml量瓶中，用二甲基甲酰胺溶解并稀至刻度，混匀。

Test Solution— Transfer 1.0 mL of Test Stock Solution to an appropriate headspace vial, containing 5.0 mL of water, apply the stopper, cap, and mix.

测试溶液：吸取1.0ml测试储备液至顶空瓶中，加水5.0ml，加塞，轧盖，混匀。

Class 1 System Suitability Solution— Mix 5 mL of Test Stock Solution with 0.5 mL of the intermediate dilution reserved from Class 1 Standard Stock Solution. Transfer 1.0 mL of this solution to an appropriate headspace vial, containing 5.0 mL of water, apply the stopper, cap, and mix.

一级系统适用性溶液：吸取5ml测试储备液与0.5ml一级标准储备溶液的中间稀释浓度溶液。吸取上述溶液1.0ml至顶空瓶中，加5.0ml水，加塞，轧盖并混匀。

Chromatographic System (see Chromatography 621— The gas chromatograph is equipped with a flame-ionization detector and a 0.53-mm × 30-m wide-bore column coated with a 3.0-μm layer of phase G43. The carrier gas is helium with a linear velocity of about 35 cm per

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