ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)
GUIDANCE ON ASPECTS OF CLEANING VALIDATION
IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS
原料药工厂中清洁验证指南
Revision September 2016
Table of Contents 目录
1.0 FOREWORD 前言
2.0 OBJECTIVE 目的
3.0 SCOPE 范围
4.0 ACCEPTANCE CRITERIA 可接受标准
4.1 Introduction 介绍
4.2 Methods of Calculating Acceptance Criteria 可接受标准的计算方法
4.2.1. Acceptance criteria using health-based data 使用基于健康数据的可接受标准
4.2.2 Acceptance criteria based on Therapeutic Daily
Dose
基于日剂量的可接受标准
4.2.3. Acceptance criteria based on LD50 基于半数致死量的可接受标准
4.2.4 General Limit as acceptance criteria 作为可接受标准的通用限度
4.2.5 Swab Limits 擦拭限度
4.2.6 Rinse Limits 淋洗限度
4.2.7 Rationale for the use of different limits in pharmaceutical and chemical production 在药品和化学生产中使用不同限度的合理性
5.0 LEVELS OF CLEANING 清洁级别
5.1 Introduction 介绍
5.2 Cleaning Levels 清洁级别
5.3 Cleaning Verification/Validation 清洁验收/验证
6.0 CONTROL OF CLEANING PROCESS 清洁过程的控制
7.0 BRACKETING AND WORST CASE RATING 分类法和最差情况分级法
7.1 Introduction 介绍
7.2 Bracketing Procedure 分类法程序
7.3 Cleaning Procedures 清洁程序
7.4 Worst Case Rating 最差情况分级
8.0 DETERMINATION OF THE AMOUNT OF RESIDUE 残留量检测
8.1 Introduction 介绍
8.2 Validation Requirements 验证要求
8.3 Sampling Methods 取样方法
8.4 Analytical Methods 分析方法
9.0 CLEANING VALIDATION PROTOCOL 清洁验证方案
9.1 Background 背景
9.2 Purpose 目的
9.3 Scope 范围
9.4 Responsibility 职责
9.5 Sampling Procedure 取样程序
9.6 Testing procedure 分析方法
9.7 Acceptance criteria 可接受标准
9.8 Deviations 偏差
9.9 Revalidation 再验证
10.0 VALIDATION QUESTIONS 验证问题
11.0 REFERENCES 参考文献
12.0 GLOSSARY 词汇
13.0 COPYRIGHT AND DISCLAIMER 版本及声明
1.0 FOREWORD 前言
This guidance document was updated in 2014 by the APIC Cleaning Validation Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC) of CEFIC.
本指南文件于2014年由APIC清洁验证工作组代表CEFIC的APIC委员会进行了更新。
The Task Force members are:- 以下是工作组的成员
―Annick Bonneure, APIC, Belgium
―Tom Buggy, DSM Sinochem Pharmaceuticals, The Netherlands
―Paul Clingan, MacFarlan Smith, UK
―Anke Grootaert, Janssen Pharmaceutica, Belgium
―Peter Mungenast, Merck KGaA, Germany.
validation verification―Luisa Paulo, Hovione FarmaCiencia SA, Portugal
―Filip Quintiens, Genzyme, Belgium
―Claude Vandenbossche, Ajinomoto Omnichem, Belgium
―Jos van der Ven, Aspen Oss B.V., The Netherlands
―Stefan Wienken, BASF, Germany.
With support and review from:- 以下为提供支持和进行审核的人员
―Pieter van der Hoeven, APIC, Belgium
―Anthony Storey, Pfizer, U.K.
―Rainer Fendt, BASF, Germany.
A further revision of the guidance document has now been done in 2016 to bring it in line with the European Medicines Agency Guidance on use of Health Based data to set acceptance criteria for cleaning. The main changes were introduced in Chapter 4, Acceptance Criteria.
本指南文件进一步修订已于2016年完成，使其与EMA使用基于健康数据设定清洁可接受标准的指南保持
一致。主要变化在是第4章“可接受标准”中。
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to
receive a large amount of attention from regulators, companies and customers alike.
原料药生产工厂的清洁验证一直是法规人员、公司和客户等关注的问题。
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk
Management Processes should give assurance that API Manufacturing Operations are performed in such a way
that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
原料药生产企业应将清洁验证与有效的质量体系相结合，由质量风险管理来支持，了解与清洁验证相关的
患者风险，评估其影响，并在必要时降低风险。
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
重要的是，不能将对制剂生产企业的要求直接用于原料药生产商，而不考虑在此阶段所用生产工艺的差异。
For example, higher limits may be acceptable in chemical production compared to pharmaceutical production because the carry-over risk is much lower for technical and chemical manufacturing reason
s
例如，与制剂生产相比，化学生产可以接受较高的残留限度，因为技术原因，化学生产所带入后续产品的
残留风险会低很多。
The document reflects the outcome of discussions between APIC member companies on how cleaning validation requirements could be fulfilled and implemented as part of routine operations.
本文件反映了APIC成员公司之间关于如何满足清洁验证的要求及作为日常操作来实施的讨论结果。
In addition, APIC is aligning this guidance with the ISPE Risk MaPP Guide1that follows the Quality Risk Management Processes as described in the ICH Q9 Guidance on Quality Risk Management.
另外，APIC将本指南与“ISPE基于风险的药品生产指南”保持一致，遵守“ICH Q9质量风险管理”中的“质量风险管理流程”。
A further revision of the Guidance has now been done to include the general principles of the EMA Guideline2on setting health based exposure limits for determining safe threshold values for the cleaning of API’s in shared facilities.
对指南的进一步修订现已完成，其中包括了EMA设定基于健康的暴露限以决定共用设施中原料药清洁安
全阈值指南中的通用原则。
The criteria of Acceptable Daily Exposure (ADE)or Permitted Daily Exposure (PDE) are now recommended to be used by companies to decide if Dedicated Facilities are required or not and to define the Maximum
-Purpose Equipment.
Acceptable Carry Over (MACO) of API’s in particular, in Multi
目前推荐公司使用“可接受日暴露水平（ADE）”标准或允许日暴露量（PDE）来决定是否专用设施需要
界定原料药“最大可接受残留MACO”，特别是针对多用途设备。
Chapter 6 defines factors that should be considered in Controls of the Cleaning Process to manage the Risks related to potential chemical or microbiological contamination.
第6章对“清洁工艺的控制”中要考虑的因素进行了定义，以管理与潜在化学和微生物污染有关的风险。
The PDA Technical Report No. 29 – Points to Consider for Cleaning Validation3is also recommended as a valuable guidance document from industry.
也推荐企业将“PDA第29号技术报告----清洁验证中应考虑的问题”作为有用的指南文件进行参考。
1ISPE Baseline? Pharmaceutical Engineering Guide, Volume 7 – Risk-Based Manufacture of Pharmaceutical Products, International Society for Pharmaceutical Engineering (ISPE), First Edition, September 2010,
2European Medicines Agency, EMA/CHMP/CVMP/SWP/169430/2012, Guideline on setting health based exposure limits for use
in risk identification in the manufacture of different medicinal products in shared facilities.
3Parenteral Drug Association (PDA) Guidance for Industry.Technical Report No. 29 (Revised 2012) Points to Consider for
Cleaning Validation, Destin A. LeBlanc, Gretchen Allison, Jennifer L. Carlson, Koshy George, Igor Gorsky, Irwin S. Hirsh, Jamie Osborne, Greg Randall, Pierre-Michel Riss, George Verghese, Jenn Walsh, Vivienne Yankah.