发布时间 : 星期五 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
APIC 201405原料药厂清洁验证指南：4.0可接受标准（上）（中英文）
注：本文件是由 CEFIC 的 APIC 内的清洗验证工作组制定。
CEFIC: 欧洲化学工业委员会(cefic,europeanchemicalindustrycouncil)
4.0 Acceptance Criteria 可接受标准 4.1. Introduction 概述
Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational. 公司在验证时要证明各设备日常所用的清洁程序能将带入下一产品的潜在残留限制在一个可以接受的水平。所建立的限度必须进行科学合理的计算。 This section provides practical guidance as to how those acceptance criteria can be calculated. It is important that companies evaluate all cases individually. There may be specific instances where the product mix in the equipment requires further consideration.
本部分提供实用的指南，指导如何计算这些可接受标准。公司对各案进行各案评估是非常重要的。有时还需要考虑产品从哪步开始混入设备中。
The acceptance criteria preferably should be based on the Acceptable Daily Exposure (ADE) calculations whenever this data is available. The Acceptable Daily Exposure defines a limit at which a patient may be exposed every day for a lifetime with acceptable risks related to adverse health effects. Calculations of Acceptable Daily Exposures of API’s and intermediates are usually done with involvement of industrial hygienists and toxicologists, who review all available toxicology and clinical data to set the limits. The justification of the calculation should be documented.
如果可以获得可接受日暴露（ADE）值，最好依据其计算可接受标准。可接受日暴露限度定义的是患者终身每天暴露于该浓度，但对健康的不良影响仍处于可接受风险水平。原料药和中间体的ADE一般由企业的卫生学家和毒理学家来制订，他们会审核各种可以获得的毒性和临床数据来设定限度。计算的合理性要进行记录。
In many cases Occupational Exposure Limits (OEL) will be defined for API’s, Intermediates and Industrial Chemicals by Industrial Hygienists and toxicologists and the OEL data is then used to define containment measures such that operators are adequately protected while working with the chemicals.
在很多情况下，会由行业卫生学家和毒理学家对原料药、中间体和工业级化学品的职业暴露限度（OEL）值进行界定，这时应使用OEL数据来制订限制措施，例如，操作人员在操作化学物质时需要受到充分保护。
The OEL data can also be used to calculate the ADE for cleaning of equipment. OEL数据也可以用于计算设备清洁的ADE值。
In certain cases where availability of pharmacological or toxicological data is limited, for example for chemicals, raw materials, intermediates or API’s in early phase clinical trials, cleaning limits based on fraction of clinical doses, LD50 or general cleaning limits may be calculated. In these cases, carcinogenic, genotoxic and potency effect of these structures should be evaluated by toxicologists.
在特定情况下，如果药性或毒性数据有限，例如，化学物质、原料、中间体或处于早期临床试验的原料药，其清洁限度可以基于临床剂量、半数致死量或一般清洁限度来计算。在这种情形下，需要有毒理学家对其结构的致癌性、基因毒性和效价影响进行评估。
The acceptance criteria for equipment cleaning should be based on visually clean in dry conditions and an analytical limit.
设备清洁的可接受标准应依据干燥状态下目视清洁及分析限度。
Unlike in pharmaceutical production, where residues on the surface of equipment may be 100 % carried over to the next product, in API production the carry-over risk is much lower for technical and chemical manufacturing reasons. Therefore all the following examples for calculating the limits can be adapted to the suitable situation by using different factors. A competent chemist with detailed knowledge about the equipment and the chemical processes and the properties of the chemicals involved such as solubility should justify this factor by evaluating the specific situation. 在制剂生产中，设备表面残留会100%被带入下一产品，而在原料药生产中，由于技术和化学生产原因，带入风险要低很多。因此，以下限度计算举例可以采用不同安全因子后用于适当的情形。应有一名具备设备和化学工艺知识，知晓所涉及化学品特性，如溶解度的化学家对特定情形下应使用的安全系统进行评估。 4.2. Methods of Calculating Acceptance Criteria 计算可接受标准的方法 4.2.1 Acceptance criteria using health-based data 采用健康基础数据的可接受标准
The Maximum Allowable Carryover (MACO) should be based upon the Acceptable Daily Exposure (ADE) when this data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the ADE, into your next product.
在可以获得可接受日暴露水平（ADE）值时，最大允许残留（MACO）应基于ADE计算。MACO计算的原则是基于ADE值，计算你允许从你的上一个产品带入下一个产品中的残留量。 Procedure 程序
Calculate the ADE (Acceptable Daily Exposure) according to the following equation and use the result for the calculation of the MACO.
根据以下公式计算ADE值，将结果用于MACO值的计算： MACO = NOAEL × BW UFc × MF × PK
From the ADE number, a MACO can be calculated according to: 根据以下公式从ADE值计算MACO值：
ADE previous MACO = × MBSnext TDDnext
ADE上一产品 × MBS下一产品 MACO = TDD下一产品 MACO Maximum Allowable Carryover: acceptable transferred amount from the previous product into your next product (mg) ADE Acceptable Daily Exposure (mg/day) NOAEL No Observed Adverse Effect Level (mg/kg/day) BW Is the weight of an average adult (e.g. 70 kg) UFc Composite Uncertainty Factor: combination of factors which reflects the inter- individual variability, interspecies differences,组分不确定因子：反映单个变量之间、不同品种差异、亚急性折算为急性外推、LOEL折算为NOEL外推、数据完整性等补平均成人体重 未观察到副反应的水平 可接受日暴露水平 允许最大残留：从上一产品带入下一产品的最大可接受量