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
sub-chronic-to-chronic extrapolation, LOEL-to-NOEL extrapolation, database completeness. MF Modifying Factor: a factor to address uncertainties not covered by the other factors PK TDDnext MBSnext Pharmacokinetic Adjustments Standard Therapeutic Daily Dose for the next product (mg/day) Minimum batch size for the next product(s) (where MACO can end up) (mg) 偿因素的综合系数 修正因子：用于表达未被其它因子覆盖的不确定因素 药动学调整 下一产品的标准治疗日服用剂量 下一产品的最小批量（MACO全部带入其中） The draft EMA/CHMP/CVMP/SWP/19430/2012 makes reference to the Permitted Daily Exposure (PDE). The PDE uses the no observed effect level (NOEL) instead of the no observed adverse effect level (NOAEL) used in the ADE calculation. The PDE may also be used as alternative to the ADE to calculate the MACO.
EMA/CHMP/CVMP/SWP/19430/2012草案中引用了允许日暴露（PDE）值。PDE采用了无可见影响水平（NOEL）代替无可见不良反应水平（NOAEL）用于ADE的计算。PDE值也可以用于代替ADE值来计算MACO值。
Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest ADE) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio).
可以选择最差情况方案来替代对每个可能的产品更换情况下的残留计算。这时，可以选择活性最强的原料药（ADE最低）作为上一产品，选择批量TDD比值（MBS/TDD比值）最小的原料药作为后续产品。
If OEL data is available, the ADE can be derived from the OEL.
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)