APIC 201405原料药厂清洁验证指南：4.0可接受标准(2)

如果可以获得OEL值，则可以从OEL值计算ADE值。

4.2.2. Acceptance criteria based on Therapeutic Daily Dose 基于日治疗剂量的可接受标准

When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process —A to API Process —B.

如果可以获得有限毒性数据和日治疗剂量（TDD）值，可以采用本计算方式。它可以用在原料药生产工艺A更换到原料药生产工艺B。 Procedure 程序

Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.

根据以下公式建立允许最大残留（MACO）值：

TDD previous × MBMACO = Snext SF × TDDnext

TDD上一产品 × MBS下一产品 MACO = SF × TDD下一产品 MACO Maximum Allowance Carryover: acceptable transferred amount from the previous product into your n允许最大残留：从上一产品中可以接受转入下一产品的数量(mg) ext product (mg) TDDprevious Standard Therapeutic Daily Dose of the investigated product (in the same dosage from as TDDnext) (mg/day) TDDnext Standard Therapeutic Daily Dose for the next product (mg/day) MBSnext Minimum batch size for the next product(s) (where MACO can end up (mg) SF Safety factor (normally 1000 is used in calculations based on TDD).

4.2.3. Acceptance criteria based on LD50 基于半致死量的可接受标准 In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50 data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.

如果没办法获得其它数据（例如，ADE、OEL、TDD等值），只能获得半数致死量数据（例如化学物质、中间体、清洁剂??），MACO可以基于半数致死量数据来计算。 Procedure 程序

安全系数（一般基于TDD值采用1000来计算） 下一产品的最小批量（MACO会携入的产品）(mg) 下一产品的日标准治疗剂量(mg/day) 所讨论的产品的日标准治疗剂量（以下一产品TDD计的同样剂量）(mg/day) Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO (See [3] oe page 53 - for reference).

根据以下公式，计算NOEL值（无可见影响水平），用于建立MACO值（参见第53页的【3】部分，供参考）

LD50× BW NOEL = 2000 From the NOEL number a MACO can be calculated according to: 从NOEL值，用以下公式计算MACO值：

NOELprevious × MBSnext MACO = SFnext × TDD next

NOEL上一产品 × MBS下一产品 MACO = SF下一产品 × TDD 下一产品 MACO Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg) 允许最大残留：从上一产品中可以接受转入下一产品的数量(mg) 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

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