中英对照-APIC 原料药厂清洁验证指南：7.0 分组法(括号法)
ICH-Q7a(中英文对照)
Q7a（中英文对照）FDA原料药GMP指南Table of Contents 目录1. INTRODUCTION 1. 简介1.1 Objective 1.1目的1.2 Regulatory Applicability 1.2法规的适用性1.3 Scope 1.3范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1总则2.2 Responsibilities of the Quality Unit(s) 2.2质量部门的责任2.3 Responsibility for Production Activities 2.3生产作业的职责2.4 Internal Audits (Self Inspection) 2.4内部审计（自检）2.5 Product Quality Review 2.5产品质量审核3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.人员的资质3.2 Personnel Hygiene 3.2 人员卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和结构4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 排污和垃圾4.7 Sanitation and Maintenance 4.7 卫生和保养5. PROCESS EQUIPMENT 5. 工艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁5.3 Calibration 5.3 校验5.4 Computerized Systems5.4 计算机控制系统6. DOCUMENTATION AND RECORDS6. 文件和记录 6.1 Documentation System andSpecifications6.1 文件系统和质量标准 6.2 Equipment cleaning and Use Record6.2 设备的清洁和使用记录 6.3 Records of Raw Materials,Intermediates, API Labeling and Packaging Materials6.3 原料、中间体、原料药的标签和包装材料的记录 6.4 Master Production Instructions (Master Production and Control Records)6.4 生产工艺规程（主生产和控制记录） 6.5 Batch Production Records (Batch Production and Control Records)6.5 批生产记录（批生产和控制记录） 6.6 Laboratory Control Records6.6 实验室控制记录 6.7 Batch Production Record Review6.7批生产记录审核7. MATERIALS MANAGEMENT7. 物料管理 7.1 General Controls7.1 控制通则 7.2 Receipt and Quarantine7.2接收和待验 7.3 Sampling and Testing of Incoming Production Materials7.3 进厂物料的取样与测试 7.4 Storage7.4储存 7.5 Re-evaluation7.5复验8. PRODUCTION AND IN-PROCESS CONTROLS8. 生产和过程控制 8.1 Production Operations8.1 生产操作 8.2 Time Limits8.2 时限 8.3 In-process Sampling and Controls8.3 工序取样和控制 8.4 Blending Batches of Intermediates or APIs8.4 中间体或原料药的混批 8.5 Contamination Control8.5 污染控制9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES9. 原料药和中间体的包装和贴签 9.1 General9.1 总则 9.2 Packaging Materials9.2 包装材料 9.3 Label Issuance and Control9.3 标签发放与控制 9.4 Packaging and Labeling Operations9.4 包装和贴签操作10. STORAGE AND DISTRIBUTION10.储存和分发 10.1 Warehousing Procedures10.1 入库程序 10.2 Distribution Procedures10.2 分发程序11. LABORATORY CONTROLS11.实验室控制 11.1 General Controls11.1 控制通则 11.2 Testing of Intermediates and APIs11.2 中间体和原料药的测试 11.3 Validation of Analytical Procedures11.3 分析方法的验证 11.4 Certificates of Analysis11.4 分析报告单 11.5 Stability Monitoring of APIs11.5 原料药的稳定性监测 11.6 Expiry and Retest Dating11.6 有效期和复验期 11.7 Reserve/Retention Samples11.7 留样12. V ALIDATION12.验证 12.1 Validation Policy12.1 验证方针 12.2 Validation Documentation12.2 验证文件 12.3 Qualification12.3 确认 12.4 Approaches to Process Validation12.4 工艺验证的方法 12.5 Process Validation Program12.5 工艺验证的程序 12.6 Periodic Review of Validated Systems12.6验证系统的定期审核 12.7 Cleaning Validation12.7 清洗验证 12.8 Validation of Analytical Methods12.8 分析方法的验证13. CHANGE CONTROL13.变更的控制14. REJECTION AND RE-USE OFMATERIALS14.拒收和物料的再利用 14.1 Rejection14.1 拒收 14.2 Reprocessing14.2 返工 14.3 Reworking14.3 重新加工 14.4 Recovery of Materials and Solvents14.4 物料与溶剂的回收 14.5 Returns14.5 退货15. COMPLAINTS AND RECALLS15.投诉与召回16. CONTRACT MANUFACTURERS(INCLUDING LABORATORIES)16.协议生产商（包括实验室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, ANDRELABELLERS17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者 17.1 Applicability17.1适用性 17.2 Traceability of Distributed APIs and Intermediates17.2已分发的原料药和中间体的可追溯性 17.3 Quality Management17.3质量管理 17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability17.5稳定性 17.6 Transfer of Information17.6 信息的传达 17.7 Handling of Complaints and Recalls17.7 投诉和召回的处理 17.8 Handling of Returns17.8 退货的处理18. Specific Guidance for APIsManufactured by Cell Culture/Fermentation 18. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General18.1 总则 18.2 Cell Bank Maintenance and Record Keeping18.2细胞库的维护和记录的保存 18.3 Cell Culture/Fermentation18.3细胞繁殖/发酵 18.4 Harvesting, Isolation and Purification18.4收取、分离和精制 18.5 Viral Removal/Inactivation steps18.5 病毒的去除/灭活步骤19. APIs for Use in Clinical Trials19. 用于临床研究的原料药 19.1 General19.1 总则 19.2 Quality19.2 质量 19.3 Equipment and Facilities19.3 设备和设施 19.4 Control of Raw Materials19.4 原料的控制 19.5 Production19.5 生产 19.6 Validation19.6 验证 19.7 Changes19.7 变更 19.8 Laboratory Controls19.8 实验室控制 19.9 Documentation19.9 文件20. Glossary20. 术语Q7a GMP Guidance for APIsQ7a 原料药的GMP 指南1. INTRODUCTION1. 简介 1.1 Objective1.1目的 This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. 本文件旨在为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP ）提供指南。
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。
中英对照-APIC原料药厂清洁验证指南：7.0分组法(括号法)
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
《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。
FDA清洁验证检查指南(中英文对照)
FDA清洁验证检查指南（中英文对照）清洗过程验证检查指南GUIDE TOINSPECTIONS VALIDATION OF CLEANINGPROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。
本指南不受FDA约束，并没有赋予任何人任何权利、特权、收益或豁免权。
I．介绍I. INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。
这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。
本指南是为了通过讨论实际操作是可接受的(或不可接受的)，来建立检查要求的一致性和统一性。
同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。
最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。
本指南只适用于化学残留物的设备清洗。
II．背景对于FDA来说，要求设备在使用前进行清洗并不新奇。
1963GMP 法规(部分133.4)中指出“设备***应该按照清洁和有序的方式进行维护***。
”在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。
当然，清洁设备的主要理由是防止药品被污染或掺假。
在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。
而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。
有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。
导致FDA对由于不满足要求的过程导致交叉污染的可能性的进一步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。
用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。
本案例中的交叉污染被认为是由于回收溶剂的重新使用。
回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。
APIC_清洁验证指南_201609 中英文
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。
植物原料药清洁验证指南
16
16 16
6.0
6.1 6.2 6.3 6.4 6.5
BRACKETING AND WORST CASE RATING
Introduction Bracketing Procedure Cleaning Procedures Investigations and Worst Case Rating (WCR) Worst Case Rating
MACO =
= 2 000 (mg)
Result:
MACO is 2 g (2000 mg)
Example 2: Now product B in example 1 will be cleaned out. The following product is product A in example 1. Calculate the MACO for B in A! 250 (mg) x 200 000 000 (mg) ---------------------------------------1000 x 10 (mg)
40
41 41 41 42 42 43 44 46
9.0
VALIDATION QUESTIONS
47 53 54 55
10.0 REFERENCES 11.0 GLOSSARY 12.0 COPYRIGHT AND DISCLAIMER
2
Cleaning Validation Guidance
1.0
3.0 Scope
Five specific areas are addressed in this Guidance document, namely:
• • • • •
《APIC 原料药工厂中清洁验证指南(2016版)》中英文(APIC Cleaning Validation Guide 2016)
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。
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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。
至关重要的是，选择最差情形的科学合理性要进行记录。
This chapter gives an overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other solutions than those given in this example.本章介绍了所需要进行的工作、可接受标准和数据评估方法。
需要强调的是，这只是一个指导性的例子，而实际情况下，设备、生产的物质和清洁程序可能有所不同，则可能需要采用与例中不同的解决方案。
The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances and other chemicals within the bracket, including those not individually tested.最差情形分级优先性是用来支持清洁方法对组内所有原料药和化学物均有效的结论的，包括那些并没有进行单独检测的物质。
7.2 Bracketing Procedure 分组法The objective of a bracketing project, is for the company to demonstrate that it has a scientific rationale for its worst case rating of the substances in the cleaning validation program. The first thing to do is to make groups and sub groups - which we will term “bracketing”, from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning validation. A multipurpose facility, Clean Company, is presented as an example we will follow.分组法的目的是让公司可以证明清洁验证方案中，对原料药进行最差情形分级具有科学合理性。
首先要做的是进行分组和分小组----我们称为“分组法（括号法）”，在一个组中，再根据分级结果选择一个最差情形。
分组流程应包括在公司方针中，或在SOP或相当清洁验证文件中。
以下的例子中我们假定有一个多功能工厂、一个清洁公司。
a) Equipment Train The Clean Company is a multipurpose site for synthesis and isolation of organic substances (see figure 1). It is divided into six equipment trains separated from each other and intended for different use (earlier API steps, final API purification, drying etc.). In TrainA 9 substances can be produced, in TrainB 9 substances can be produced, in TrainC 8 substances can be produced, in TrainD 8 substances can be produced, in TrainE 10 substances can be produced, and in TrainF11 substances can be produced. With no bracketing and worst case rating, cleaning validation studies would be required for each of the 55 substances.设备链：清洁公司是一个多功能场所，生产有机物质合成和分离步骤（参见图1）。
其设备被分为6条生产设备链，相互独立，用于不同用途（较早的原料药步骤、最终原料药精制、干燥等）。
在A链中，可以生产9种物质，在B链中，可以生产9种物质，在C链中可以生产8种物质，在D链中，可以生产8种物质，在E链中可以生产10种物质，在F链中可以生产11种物质。
如果不采用分组法和最差情形法的话，则需要对55种物质分别进行清洁验证。
The first grouping criteria is that the substances in a group are produced in identical equipment trains and cleaned out following the same cleaning procedure/SOP. The ideal with regard to cleaning validation (as will be discussed in 7.3) each train could be considered as a group. Then 6 worst cases would ideally be identified. In reality, the number of worst cases identified will often be something between these two extremes (more than 6, but less than 55).进行分组的第一个标准是组内的物质是在同一条设备链中生产，并采用同一个清洁程序/SOP进行清洁。
理想状态是每条链可以作为一个组来进行清洁验证（如7.3中讨论的一样）。
这样，理想状态下需要识别出6种最差情形。
现实中，最差情形的识别可能会是两个极端情况（多于6个，但少于55个）。
CleanCompany 清洁公司Figure 1 Clean Company’s ideal example (1 train considered as 1 group) gives 6 worst cases.In this example the main classes in this bracketing are based on the different Trains. The following equipment classes are maintained:图1：清洁公司的理想案例（设备链1被作为第一组）给出了6个最差情形。
在此例中，组内主要级别是基于不同生产链的。
以下设备分级不变：? TrainA? TrainB? TrainC? TrainD? TrainE? TrainFb) Substances 物质If the company has two or more trains used for the same purpose (such as earlier API steps, final API purification, drying etc.) a choice of which products to be produced in each of the trains used for the same purpose is done. The combination of substances (starting materials, intermediates or APIs) in a train can be chosen based on one or more of the following strategies, or combinations of them:如果公司有2个或更多设备链用于同一个生产目的（例如，更早的原料药生产步骤、最终原料药精制、干燥等），已选好了在每个设备链中生产哪个产品。