【技术交流】APIC 201405原料药厂清洁验证指南：1.0前言 2.0目的 3.0范围（中英文）

ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)

[1] ISPE Baseline? Pharmaceutical Engineering Guide, Volume 7 – Risk-Based Manufacture of Pharmaceutical Products,International Society for Pharmaceutical Engineering (ISPE), First Edition, September 2010, www.ispe.org.

[2] Parenteral 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.

GUIDANCE ON ASPECTS OF CLEANING VALIDATION

IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS

原料药工厂中清洁验证指南

May 2014

Table of Contents

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	基于日治疗剂量的可接受标准
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

The original version of this guidance document has now been updated by the APIC Cleaning Validation Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC) of CEFIC.

本指南文件的原版本现已由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.

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.

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 reasons

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 Guide[1] that 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”。

The criteria of Acceptable Daily Exposure (ADE) is now recommended to be used by companies to decide if Dedicated Facilities are required or not and to define the Maximum Acceptable Carry Over (MACO) of API’s in particular, in Multi-Purpose Equipment.

目前推荐公司使用“可接受日暴露水平”标准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。

A new chapter is introduced to define factors that should be considered in Controls of The Cleaning Process to manage the Risks related to potential chemical or microbiological contamination.

放入了一个新章节，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 Validation[2] is 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。

The following topics are discussed in the PDA document: Cleaning process (CIP/COP): design and qualification

以下问题在PDA文件中进行了讨论：清洁工艺（CIP/COP）：设计和确认

—       Types of residues, setting acceptance criteria, sampling and analytical methods

—       残留类型、设定可接受标准、取样和分析方法

—       Maintenance of the validated state: critical parameters measurements, process alarms, change control, trending & monitoring, training and periodic review

—       维护验证状态：关键参数测量、工艺警示、变更控制、趋势&监控、培训和周期性评审

—       Documentation

—       文件记录

2.0 Objective 目的

This document has been prepared to assist companies in the formulation of cleaning validation programmes and should not be considered as a technical standard but a starting point for internal discussions. The document includes examples on how member companies have dealt with specific areas and issues that arise when performing cleaning validation.

本文件的目的是帮助公司制订清洁验证程序，不能作为是一个技术标准，只应该作为内部讨论的出发点。本文包括了成员公司如何处理其特殊领域的例子，以及在实施清洁验证时提出的问题点。

3.0 Scope 范围

Six specific areas are addressed in this Guidance document:

本指南文件包括6个方面

l         Acceptance Criteria

l         可接受标准

l         Levels of Cleaning

l         清洁水平

l         Control of the cleaning process

l         清洁工艺的控制

l         Bracketing and Worst Case Rating

l         分类法和最差情况分级

l         Determination of the amount of residue

l         残留量的检测

l         Cleaning Validation Protocol

l         清洁验证方案

Finally, the most frequently asked questions are answered to give further guidance on specific points related to cleaning validation.

最后是一些常见问题及回答，对一些与清洁验证有关的特殊情况给予指导。