<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 prent 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 tho given below, tests for residual solvents are not generally mentioned in specific monographs, becau 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 u 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 purpos, residual solvents in pharmaceuticals are defined as organic volatile chemicals that are ud 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 lection 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 ud 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。
Becau 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-bad requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Solvents that are known to cau unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their u can be strongly justified in a risk-benefit asssment. Solvents associated with less vere toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adver effects. Ideally, less toxic solvents (Class 3, Table 3) should be ud where practical. The complete list of solvents included in this general chapter is given in Appendix 1. The tables and the list are not exhaustive. For the purpos of this Pharmacopeia, when a manufacturer has received approval from a competent regulatory authority for the u 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 process are known to result in the prence of such residual solvents. It is only necessary to test for residual solvents that are ud 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 choo to test the drug product, a cumulative procedure may be ud to calculate the residual solvent levels in the drug product from the levels in the ingredients ud 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 ud 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 purpos 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 ud by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals, and the term acceptable daily intake (ADI) is ud 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 assd 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 class 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
