APIC颁布原料药工厂清洁验证指南

APIC颁布原料药工厂清洁验证指南An APIC multinational working group has compiled a new guidance on cleaning validation with the title "APIC Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredients Plants". Publication date is May 2014 and the document can be downloaded from the APIC website. The following is a summary description of the document. The document contains 55 pages and is subdivided into 13 chapters. APIC多国工作组汇编了新的清洁验证指南，题为“APIC原料药工厂清洁验证指南面面观”。

颁布日期为2014年5月，文件可以从APIC官网下载。

以下是该文件的摘要。

文件包括55页，分为13章。

Foreword 前言Objective 目的Scope 范围Acceptance Criteria 可接受标准Levels of Cleaning 清洁水平Control of Cleaning Process 清洁工艺控制Bracketing and Worst Case Rating 括号法和最差情况分类法Determination of the Amount of Residue 残留量的检测Cleaning Validation Protocol 清洁验证方案Validation Questions 验证问题References 参考文献Glossary 术语Copyright and Disclaimer 版权和声明The topic cleaning validation gained new importance in the EU with the publication of the EMA Guideline "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" and with the chapter Cleaning Validation in the draft of the revision of Annex 15. The foreword refers to the integration of cleaning validation within a quality system supported by quality risk management processes in order to protect the patients. According to the authors the document is aligned with ISPE Risk-MaPPand it recommends the revised PDA Technical Report 29 as a valuable guidance document. The document is supposed to assist companies in cleaning validation and to serve as a starting point for internal discussions. It should in no way be considered as a technical standard. The document addresses six topics:清洁验证主题在欧盟EMA指南前言指出了清洁验证应与质量体系结合，由质量风险管理过程支持，以保护患者利益。

根据文件作者们所言，该文件与ISPE的药品风险管理是一致的，并推荐将修订后的PDA第29号技术报告作为参考文件。

该文件意在清洁验证方面给公司提供帮助，作为内部讨论的基础，而不应作为一个技术标准。

文件阐述了以下6个主题：Acceptance criteria 可接受标准Levels of cleaning 清洁水平Control of the cleaning process 清洁工艺的控制Bracketing and worst case rating 括号法和最差情况分类法Determination of the amount of residue 残留量的检测Cleaning validation protocol 清洁验证方案Acceptance Criteria (Chapter 4) 可接受标准（第4章）The acceptance criteria preferably should be based on the acceptable daily exposure (ADE) calculations whenever this data is available. Alternatively, occupational exposure limits (OEL) are recommended as acceptance criteria. The document then presents examples for the calculation of acceptance criteria. Based upon the ADE the maximum allowable carryover (MACO) is calculated by way of example.如果可以得到可接受日暴露（ADE）值，则可接受标准应优先采用ADE进行计算。

另外，也推荐采用职业暴露限度（OEL）值作为可接受标准。

文件举出了可接受标准的计算实例，例中采了ADE计算允许最大残留（MACO）值。

As (further) examples for acceptance criteria and their calculation the document lists:文件中给出了可接受标准及其计算样例：Acceptance criteria using health-based data (ADE, MACO)采用健康的数据（ADE、MACO）计算可接受标准Acceptance criteria based on the therapeutic daily dose (TDD)采用日治疗剂量（TDD）计算可接受标准Acceptance criteria based on LD50采用半数致死量计算可接受标准Acceptance criteria based on a general limit (ppm value)采用通用限度（ppm值）计算可接受标准The same chapter addresses the calculation of acceptance criteria by means of swab and rinse tests. The chapter closes with a rationale for the use of different limits in pharmaceutical and chemical production of active pharmaceutical ingredients. A competent chemist should accompany the finding of a rationale. It is mentioned expressly that in the production of active pharmaceutical ingredients the risk of carry-over of contaminants because of manufacturing processes (such as extraction or filtration ...) can be much lower than in the manufacture of medicinal products. Based on this consideration limits could be set higher. Naturally, these considerations do not apply to physical manufacturing processes (drying, milling). In this case, the methods applied should be those normally used in pharmaceutical production. Annex 1 contains five examples of MACO calculations according to the acceptance criteria mentioned above.在同一章中，还说明了采用擦拭和淋洗取样方式如何计算可接受标准。

该章结尾阐述了在原料药生产中，采用与药品生产所不同的限度的合理性。

需要有一名具备资质的化学家审核限度的合理性。

文件中提到，在原料药生产中，由于生产工艺的特点（例如萃取或过滤），污染物被带入下一产品的风险比起制剂生产过程来，要低的多。

基于该考虑，可以将限度设定在较高数值。

当然，这些考虑并不适用于物理生产过程（干燥、磨粉），这些步骤中应使用制剂生产中的常规方法。

附录1包括了5个根据上述可接受标准计算MACO的实例。

Levels of Cleaning (chapter 5) 清洁水平（第5章）Depending on the step of manufacture and/or the use of multi-purpose equipment the cleaning intensity varies. The document recommends that at least three levels of cleaning (level 0-2) are implemented according to the difficulty of cleaning. Depending on the level different activities are required as concerns visualinspection, analytical verification and cleaning validation. An example presents different product changeover scenarios. In that case the number of cleaning validation activities is defined with at least three consecutive runs. In cases in which it takes some time to finalize the cleaning validation cleaning verification has to be performed in the meantime. In the course of cleaning validation the dirty hold time should also be determined.根据生产步骤和/或设备是否为多用途情况，清洁的程度会有很大差异。