下载文档原格式
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。
APIC 201405原料药厂清洁验证指南：7.0 分组法（括号法）和最差情况分级（中英文）2014-07-15julia翻译蒲公英7.0 Bracketing and Worst Case Rating 分组法（括号法）和最差情况分级7.1 Introduction 介绍The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used.原料药工厂中的多产品设备清洁要求进行清洁验证。
清洁工作量会比较大。
为了减少验证的工作量，可以采用最差情形方法进行验证。
By means of a bracketing procedure the substances are grouped.采用分组法时，物质按类进行分组。
A worst case rating procedure is used to select the worst case in each group.然后在每组中采用最差情形分级法选择各组中最差的情况。
Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists.对最差情形进行验证。
《APIC原料药工厂中清洁验证指南》英文版Cleaning Verification Guideline for APIC Raw Material Manufacturing Plants1. Introduction2. Scope3. Cleaning proceduresClear and concise cleaning procedures should be established and followed for all equipment and areas involved in the manufacturing process. These procedures should include step-by-step instructions for disassembling, cleaning, and reassembling the equipment, as well as the use of appropriate cleaning agents and sanitizers.4. Acceptance criteriaAcceptance criteria for cleanliness should be defined for each equipment or manufacturing area based on the potential risk of cross-contamination and product adulteration. These criteria should be established in consultation with the quality unit and should be supported by scientific rationale and documented evidence.5. Sampling methodsSampling methods should be designed to provide representative samples of the equipment or manufacturing areabeing evaluated. These methods should take into account the nature and form of the residues to be removed, as well as the accessibility of the sampling locations. Samples should be collected using appropriate sampling tools and containers, and the sampling locations should be clearly documented.6. Analytical techniques7. Documentation requirements8. Training and continuous improvementAll personnel involved in cleaning verification activities should receive appropriate training on the principles and procedures outlined in this guideline. Regular training sessions should be conducted to ensure that employees are updated on the latest techniques and best practices in cleaning validation. Additionally, periodic reviews of the cleaning validation process should be conducted to identify areas for improvement and implement corrective actions as necessary.9. Conclusion。
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)GUIDANCE ON ASPECTS OF CLEANING VALIDATIONIN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS原料药工厂中清洁验证指南Revision September 2016Table 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 DailyDose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。
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)GUIDANCE ON ASPECTS OF CLEANING VALIDATIONIN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS原料药工厂中清洁验证指南Revision September 2016Table of Contents 目录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.―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。
APIC 202105原料药厂清洁验证指南：4.0可接受标准APIC 202105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。
以下为个人结合以前的经验，对多功能生产线的清洁验证的考虑问题，望大家一起讨论，其中有不正确的地方望大家指出，希望大家都越辩越明：1、决定是否清洁验证的问题，是在结合法规（指南））的最低要求的条件下，由公司决定是否进行相应的验证，清洁验证的目的个人认为是“将质量从最终QC检验前移至过程控制的”质量理念的体现，比如公司完全但是若在后期的执行“被验证方法”过程中出现了偏离，那么就得对相应的问题进行调查了。
至于针对于原料药生产过程是否进行验证的问题，其实在APIC cleaning validation有一定的指导（非强制）（见APIC celfic cleaing validation 2014 第19页的cleaning levels和figure 1：typical product changeover senarios）比如低于level 0的清洁级别，APIC推荐的是仅仅可以目视即可（当然公司根据公司实际情况决定是否除了visual inspection外，还是进行analytical verification或者进一步进行cleaning validation），比如APIC清洁指南中提到的不同产品的中间体A-3到中间体B-3，或者相同产品的相邻连个工序中间体A-2到中间体A-1,或者某些情况下的API粗品到API 精制）其中需要的明确的是analytical verification相当于清洁至合格的概念，由于风险相对较低，所以是被允许的；而cleaning validation则相当于对于清洗过程的管控以及最终的清洁结果的检测双重控制。
2、清洁验证的目的是验证“清洗方法”，而非我们认为的“被清洁设备”以及“被清洗产品”，虽然“被清洁设备”以及“被清洁产品”往往和清洁方法相关（比如“被清洁设备”形状决定了清洗流程的设计（比如清洗连管，以及是否能COP,WIP,CIP等等），“被清洗产品”决定了清洗溶剂的选择等等）。
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)GUIDANCE ON ASPECTS OF CLEANING VALIDATIONIN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS原料药工厂中清洁验证指南Revision September 2016Table of Contents 目录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.―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。
APIC 201405原料药厂清洁验证指南：7.0 分组法（括号法）和最差情况分级（中英文）2014-07-15julia翻译蒲公英7.0 Bracketing and Worst Case Rating 分组法（括号法）和最差情况分级7.1 Introduction 介绍The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used.原料药工厂中的多产品设备清洁要求进行清洁验证。
清洁工作量会比较大。
为了减少验证的工作量，可以采用最差情形方法进行验证。
By means of a bracketing procedure the substances are grouped.采用分组法时，物质按类进行分组。
A worst case rating procedure is used to select the worst case in each group.然后在每组中采用最差情形分级法选择各组中最差的情况。
Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists.对最差情形进行验证。
APIC原料药厂清洁验证指南（201405 中英文）ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)GUIDANCE ON ASPECTS OF CLEANING VALIDATIONIN ACTIVE PHARMACEUTICAL INGREDIENT PLANTSAPIC 原料药工厂中清洁验证指南May 2014Table of Contents1.0 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, BelgiumTom Buggy, DSM Sinochem Pharmaceuticals, The NetherlandsPaul Clingan, MacFarlan Smith, UKAnke Grootaert, Janssen Pharmaceutica, BelgiumPeter Mungenast, Merck KGaA, Germany.Luisa Paulo, Hovione FarmaCiencia SA, PortugalFilip Quintiens, Genzyme, BelgiumClaude Vandenbossche, Ajinomoto Omnichem, BelgiumJos van der Ven, Aspen Oss B.V., The NetherlandsStefan 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, BelgiumAnthony 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 Guide1[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 Validation2[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.1[1]ISPE Baseline? Pharmaceutical Engineering Guide, Volume 7 –Risk-Based Manufacture of Pharmaceutical Products, International Society for Pharmaceutical Engineering (ISPE), First Edition, September 2010, . 2[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.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。
