发布时间 : 星期二 文章APIC 201405原料药厂清洁验证指南：4.0可接受标准更新完毕开始阅读
NOELprevious LD50 No Observed Effect Level (mg/day) 无可见影响水平(mg/day) Lethal Dose 50 in mg/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important (mg/kg) 50%的动物致死量，单位mg/kg。动物种类（大鼠、小鼠等）和摄入途径（注射、口服等）也很重要(mg/kg) 成年人平均体重（例如70kg）(kg) 经验常数 下一产品的日标准治疗剂量(mg/day) 下一产品的最小批量（MACO会携入的产品）(mg) BW Is the weight of an average adult (e.g. 70 kg) (kg) 2000 TDDnext 2000 is an empirical constant Standard Therapeutic Daily Dose for the next product (mg/day) MBSnext Minimum batch size for the next product (s) (where MACO can end up) SFnext
Safety factor 安全系数 The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.
安全系数（SF）根据摄入途径不同而不同（见下）。一般系数200用于口服剂型原料药生产。 Safety factors: 安全系数 Topicals 10 – 100 局部给药 Oral products 100 – 1000 口服给药 Parenterals 1000 – 10 000 注射给药
4.2.4 General Limit as acceptance criteria 可接受标准的一般限度
If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. Companies may choose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.
如果MACO计算结果太高，不能接受，或者与带入数字不相关，或中间体毒性数据未知，则适用通用限度方法。公司可以选择例如一个最高限度作为原则。通用限度一般设定为一种污染物质在后续批次中最大浓度上限（MAXCONC）。 Procedure 程序
Establish MACOppm, based on a general limit, using the following equations. 利用以下公式，基于一个通用限度建立MACO限度，ppm为单位。 MACOppm = MAXCONC x MBS MACOppm Maximum Allowable Carryover: acceptable transferred amount from 允许最大残留：所讨论的产品（上一产品）被带入the investigated product (“previ下一产品的可接受值，一ous”). Calculated from general p般表达为ppm限度 pm limit. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm) o允许上一产品在下一产品中的最大浓度通用限度（kf “previous” substance in the ng/kg或ppm） ext batch. MBS Minimum batch size for the next product(s) (where MACO can end up) 下一产品的最小批量 E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).
例如，对于通用限度为100ppm：MACO = 最小批量（MBS）的0.01%，对于通用限度为10ppm：MACO = 最小批量（MBS）的0.001%。
Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested.
注：ICH杂质文件（Q3）指出，在被测试的产品中，单个未知杂质可以达0.1%，总未知杂质可以达到0.5%。
A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-500 ppm (100 ppm in APIs is very frequent) of the previous product into the next product depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity …).
根据各公司所生产产品的属性不同（例如，毒性、药物活性等），从上一产品带入下一产品中的污染物质最大浓度通用上限通常设定为5-500ppm（原料药中100ppm是很常见的）。
The Threshold of Toxicological Concern (TTC) concept could be applied to intermediates or API’s with no clinical (e.g. early development) or toxicological data. This concept includes three categories of products with limited or no data: 毒性关注阈值（TTC）概念可以应用于没有临床（例如早期研发阶段）或毒性数据的中间体或原料药。这个概念将数据有限或没有数据的产品分为3个类别
??Products that are likely to be carcinogenic; ??可能致癌的产品
??Products that are likely to be potent or highly toxic;
??可能具有效价或高毒性的产品
??Products that are not likely to be carcinogenic, potent or highly toxic. ??可能致癌、具有效价或高毒性的产品
The corresponding ADE’s recommended for these three categories are 1, 10, 100 μg/day, respectively.
对应此三类所推荐的ADE值分别为1、10和100μg/天。
Another possibility to calculate your ADE for intermediates or API’s, with no clinical or toxicological data (e.g. early development), is based upon the exposure duration of your next product. The values of the CHMP guideline on the Limits of Genotoxic Impurities (ref. EMEA/CHMP/SWP/431994/2007) can be used for your ADE. 在没有临床或毒性数据（例如研发早期）时，计算中间体或API的ADE还有另一个办法，就是基于下一产品的暴露时长。可以将CHMP指南“基因毒性杂质”（参见EMEA/CHMP/SWP/431994/2007）限度值可以用于ADE计算。 Note - If you decide to employ the concept of levels of cleaning (ref. section 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable.
注：如果你决定采用清洁水平概念（参见第5部分），则对于不同水平可以采用不同的安全系数（ppm限度）。特别是如果被清洁的产品是在同一条合成链中，且其限度包括在原料药的质量标准中，则残留水平较高（确认过的）时也是可以接受的。
4.2.5 Swab Limits 擦拭限度
If homogeneous distribution is assumed on all surfaces, a recommended value can be set for the content in a swab. The maximum allowable carry over from one batch to another can be established based on e.g. ADE, NOEL or TDD (see above). If the total direct contact surface is known, the target value for contamination per square meter