21世纪的清洁验证：原料药世纪的清洁验证-原料药清洁接受标准

21世纪的清洁验证：原料药的清洁接受标准

本文讨论了如何从临床和毒理学研究建立真正的以科学为基础的限度，以风险分析为基础的方法来评估清

洁验证数据，从此数据为基础数据设置统计过程控制限额。

Introduction

Part I of this article1 discussed the history of Cleaning Validation Acceptance Limits for Active

Pharmaceutical Ingredients and where the currently used industry limits came from, analyzed the current

approaches to setting acceptance limits, and discussed some of the problems and weaknesses of these

approaches. Part II will discuss how to establish true science-based limits using data from clinical and

toxicological studies, a risk-based approach to evaluating cleaning validation data, and guidance on

setting statistical process control limits from that data.

介绍

本文的第一部分讨论了原料药的清洁验证验收标准的历史和现行的行业限度出处，分析了目前设置验收标

准的做法，并讨论了这些方法的问题和不足。第二部分将讨论如何从临床和毒理学研究建立真正的以科学

为基础的限度，以风险为基础的方法来评估清洁验证数据，从数据统计过程控制限度的指导数据。

Establishing Science-Based Limits

As discussed at the end of Part I, setting cleaning validation limits based on all available safety data is much

preferred over an approach that considers only one factor (therapeutic dose). ISPE’s recently published Risk-MaPP

Baseline Guide2 goes into great detail in describing how to set health-based limits using all the toxicological and

clinical data available. Although Risk-MaPP is new and is structured to align with the principles described in the

recent ICH Q9 document, much of its contents are based on long-existing principles and long-used procedures in

toxicology. The following discussion will summarize some of the guidance on determining health-based limits

provided in the Risk-MaPP Guide.

建立以科学为基础的限度

在第一部分最后的讨论中，设置清洁限度时基于所有可用的安全数据比只应用一个因子（治疗剂量）要好

得多。ISPE的最近公布的基线指南2风险MaPP到非常详细的描述如何使用所有可用的毒理和临床数据设置

基于健康基础的限制。虽然风险MAPP是ICH Q9在新的最近的文件中结构调整后所述的原则，但是其内容

多是在毒理学上基于长期存在的原则和长期使用的程序。下面的讨论中会总结一些指导，确定风险MAPP

指南提供的基于健康的限度。

Before attempting to set limits of any kind, it is important to understand what hazard an API may actually present

to a patient. Risk-MaPP states that a…

在试图建立任何形式的限度之前，重要的是要了解的API实际上可能带给病人什么危害。风险MAPP指出...

“„hazard describes the inherent property of a compound to produce adverse effects, e.g., in patients that may

be exposed to the compound as a trace contaminant in another pharmaceutical product.” and “Each compound

has its own inherent ability to cause adverse effects (i.e., toxicity) – effects that may be well documented in the

case of the API…..”

“......危害描述化合物的固有属性产生的不利影响，例如，患者可能暴露在其他医药产品的微量污染物中。”

和“每种化合物都有其自身固有的能力造成不利影响（比如，毒性）。API存在的情况下，它的影响可被记

录 “

Once the hazard is identified, the hazard should be characterized by examining its dose-response relationship and

the consequences of exposure. The consequence is then considered in the establishment of an Acceptable Daily

Exposure (ADE). In Risk-MaPP, the ADE is defined as:

一旦发现危害，危害的特点应当通过检查其剂量-反应关系和暴露其后果。然后考察其后果并确定一个日可接受剂量（ADE）。在风险-MAPP中，ADE被定义为：

“The daily dose of a substance below which no adverse events are anticipated, by any route, even if exposure

occurs for a lifetime.”

“无论任何方式摄入该物质，即使终身摄入，只要每日剂量低于此限度则无预期的不良事件发生。”

Although it should be obvious, I will point out here that, from Risk-MaPP’s definition, the ADE is a very

conservative value.

虽然应该是显而易见的，我这里还是要指出，从风险-MAPP的定义来说，ADE是一个非常保守的值。

During the identification of the hazard, a formal review of all available data for the compound is performed. For an

API, the data used in this analysis would be the data submitted in the company’s regulatory filing. By definition,

this includes all of the preclinical and clinical data required for approval of the drug. Through review of these data

the “critical effect” can be identified. The critical effect is the first significant adverse effect that is observed as the

dose increases. For every hazard there is a dose below which no effects are expected and this can be the basis for

determining an ADE. Exposures below this ADE will not lead to any other adverse effects.

在危害识别过程中，会对一种化合物的所有可用的数据进行正式审查。在这种分析中所使用的API的数据，

将提交该公司进行文件监管。根据定义，这些数据包括所有的药物审批所需的临床前和临床数据。通过对

这些数据的彻底审查可以识别API的“关键作用”。关键作用随着剂量的增加产生第一种显著不利影响。对

于每一种危险都有一个剂量影响下限，在此剂量下面预期是没有影响的，这可能是确定ADE剂量的根据。

低于这个ADE的接触不会导致任何其他不利影响。

The next step is to define the no-observed-adverse-effect level (NOAEL) for the critical effect to be used for

derivation of the ADE. The dose at which a significant adverse effect is first observed is the

lowest-observed-adverse-effect level (LOAEL). The application of uncertainty factors and other adjustment factors

results in ADEs that are unlikely to produce any undesirable compound-related effects.

下一步是定义观测不到的不利影响剂量水平(NOAEL)关键性而引出ADE。 一个首先发现的明显的剂量的不利

影响是最低负面影响剂量水平(LOAEL)。 应用不确定性因素和其他调整性因素的结果是不会产生任何与化合

物相关的不良反应与效果。

The ADE is derived by dividing the NOAEL for the critical effect adjusted for body weight (e.g., 60 kg) by various