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；