下载文档原格式
欧盟GMP附录15确认和验证欧盟GMP附录15确认和验证ANNEX 15 附件15Qualification and Validation确认和验证Table of Contents 目录1. Qualification and Validation 确认和验证2. Planning for Validation 验证计划3. Documentation 文件4. Qualification 确认5. Process Validation 工艺验证6. Cleaning Validation 清洁验证7. Change Control 变更控制8. Revalidation 再验证9. Glossary 术语表Qualification and Validation 确认和验证Principle 原理1.This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.1.本附件描述了确认和验证的原理，适用于医药产品的生产者。
EU GMP 第1部分第5章生产——增加基因毒性的评估生效时限2015-02-25 11:50:00（粉色字为2015年1月23日新增内容，红字斜体为2014年8月13日修订内容）Ref. Ares(2015)283689 - 23/01/2015 EUROPEAN COMMISSIONHEALTH AND CONSUMERS DIRECTORATE-GENERALPublic Health and Risk AssessmentMedicinal products – quality, safety and efficacyBrussels, 13 August 2014Ares(2014)2674301EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines forGood Manufacturing Practice forMedicinal Products for Human and Veterinary UsePart 1Chapter 5: Production人兽药EU GMP指南第1部分第5章：生产Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.Status of the document: Revision [a]Reasons for changes: Changes have been made to sections 17 to 20 to improve the guidance on prevention of cross-contamination and to refer to toxicological assessment guidance. Changes were also introduced in sections 26 to 28 on the qualification of suppliers in order to reflect the legal obligation of manufacturing authorisation holders to ensure that active substances are produced in accordance with GMP. The changes include supply chain traceability. Section (33) is inserted to clarify and harmonise expectations of manufacturers regarding the testing of starting materials while section (68) introduces guidance on notification of restrictions in supply.变更理由：对17-20条进行变更，以改进指南中防止交叉污染的部分，及引用毒理学评估指南。
ICH Q8（中英文）blueski推荐[2009-12-20]出处：Julia的blog作者：不详INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE人用药物注册技术要求国际协调会议ICH Harmonised Tripartite Guideline ICH三方协调指南Pharmaceutical Development药物开发Q8Recommended for Adoption at Step 4 of the ICH Process on 10 November 2005 by the ICH Steering Committee ICH指导委员会2005年11月10日ICH第四阶段推荐采用This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 本指南根据ICH规程由合适的ICH专家工作组起草并经向法规部门咨询。
在规程的第4步，建议欧洲共同体、日本和美国的药政部门采用其最终的草案。
TABLE OF CONTENTS目录1. INTRODUCTION简介 (1)1.1 Objective of the Guideline指南目的 (1)1.2 Scope范围 (1)2. PHARMACEUTICAL DEVELOPMENT药物开发 (1)2.1 Components of the Drug Product制剂产品的组分 (4)2.1.1 Drug Substance活性成分 (4)2.1.2 Excipients辅料 (4)2.2 Drug Product制剂 (5)2.2.1 Formulation Development配方开发 (5)2.2.2 Overages超量 (6)2.2.3 Physicochemical and Biological Properties物化和生化性质 (7)2.3 Manufacturing Process Development制造工艺开发 (7)2.4 Container Closure System容器系统 (9)2.5 Microbiological Attributes微生物属性 (9)2.6 Compatibility兼容性 (10)3. GLOSSARY术语 (11)1. INTRODUCTION 简介1.1 Objective of Guideline 指南目的This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical Development) section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format. 本指南就 CTD 格式申请文件中第3.2.P.2 章：药物开发需要叙述的内容给出了建议。
European regulatory guidelines for biosimilarsAndrzej Wiecek 1and Ashraf Mikhail 21Department of Nephrology,Endocrinology and Metabolic Diseases,Medical University of Silesia,Katowice,Poland and 2Department of Renal Medicine,Morriston Hospital,Swansea,UKAbstractThe impending arrival en masse of biosimilars on Western markets is placing drug regulatory agencies under pressure to realign their policies.Biosimilars require more rigorous assessments than traditional chemical generics.This is because of the molecular complexity of recombinant proteins,and the complex-ity of biological manufacturing processes.Small differences can arise in a recombinant protein product which are hard or impossible to detect with even state-of-the-art analytical techniques.Yet,these differences can have significant impact on the safety and efficacy of the drug.The European Medicines Agency (EMEA)has taken the lead in issuing guidelines,most of which are still under review.The guidelines advocate pre-clinical and clinical testing of biosimilars prior to market authorization,complemented by tailored pharmacovigilance plans.These guidelines provide a valuable base from which to develop in this evolving regulatory environment.Keywords:biopharmaceuticals;biosimilars;EMEA;regulatory guidelinesIntroductionA generation of biotechnology-derived therapeutic agents are reaching the end of their patent lives,heralding the market entry of biosimilars.However,recombinant proteins are associated with a number of issues which distinguish them from traditional chemical drugs and their generics.Recombinant proteins are highly complex at the molecular level,and biological manufacturing processes are highly elaborate:they involve cloning,selection of a suitable cell line,fermentation,purification and formulation.In addition,the therapeutic properties of recombinantproteins are highly dependent on each step of the manufacturing process.The result is that different manufacturing processes yield a unique product,which may have a distinctive safety and efficacy profile (hence the name ‘biosimilar’instead of ‘biogeneric’,which implies identity).A biosimilar may differ significantly from a reference brand product.Furthermore,such differences may not be detectable with even state-of-the-art analytical techniques.The only certain way to assess the safety and efficacy of a biosimilar is to conduct pre-clinical and clinical tests.Are current regulations adequate?Current European Union (EU)legislation is embodied in three documents,dating from 2001onwards.The first covers items such as blood-derived products and vaccines [1],without referring specifically to biotechnology-derived drugs.Article 10contains a paragraph which remains the object of contention:‘The applicant shall not be required to provide the results of toxicological and pharmacological tests or the results of clinical trials if he can demonstrate:(i)either that the medicinal product is essentially similar to a medicinal product authorised in the Member State ...(ii)or that the constituent or constituents of the medicinal product have a well established medicinal use,with recognised efficacy and an acceptable level of safety,by means of a detailed scientific bibliography’.The first point importantly lacks a precise definition of ‘essentially similar’,while the second ignores the significant differences that can occur between manufac-turing processes.An amendment in 2003[2]describes recombinant proteins as a ‘new class of biological medicinal product’,but provides no further guidance.The last update,in 2004[3],begins to broach the topic of biosimilars,stating ‘Biological medicinal products similar to a reference medicinal product do not usually meet all the conditions to be considered as a generic medicinal product mainly due to manufacturing process characteristics.When a biological medicinal product does not meet all the conditions to be considered as aCorrespondence and offprint requests to : A.Wiecek,Department of Nephrology,Endocrinology and Metabolic Disease,Medical University of Silesia,Francuscka St 20-40,40-027Katowice,Poland.Email:awiecek@spskm.katowice.plNephrol Dial Transplant (2006)21[Suppl 5]:v17–v20doi:10.1093/ndt/gfl477ßThe Author [2006].Published by Oxford University Press on behalf of ERA-EDTA.All rights reserved.For Permissions,please email:journals.permissions@by guest on October 18, 2013/Downloaded from 谭阳2013.10.18generic medicinal product,the results of appropriate tests should be provided in order to fulfil the require-ments related to safety(pre-clinical tests)or to efficacy (clinical tests)or to both’.Although this amendment recognizes the difference between biosimilars and classical generics,the document does not delve any deeper into the matter.The European Medicines Agency(EMEA),a decen-tralized body of the EU,has taken the lead in bridging the gap.The EMEA’s Committee for Proprietary Medicinal Products(CPMP),and its descendant,the Committee for Medicinal Products for Human Use (CHMP),have issued a number of guidance documents. The overarching document,CHMP/437[4],sets the scene by recognizing that the generic approach no longer suffices where biosimilars are concerned.The other documents can be categorized according to their focus on quality or clinical issues,or their focus on changes to an existing manufacturing process or an entirely new process.An important distinction to be made in this regard is between‘comparability’,which assesses products preceding and following a change in manufacturing process,and‘similarity’,which assesses products from entirely different manufacturing pro-cesses,with a focus on safety and efficacy.The guidelines pertaining to changes in a manufacturingprocess have already been approved[4–6],although the document on quality issues will be superseded by the QE5document from the ICH(International Conference on Harmonisation).The ICH seeks to harmonize regulatory processes across the US,Europe and Japan.EMEA guidelines relevant to new manu-facturing processes for biosimilars are still under review [7,8].They are supplemented by a number of Concept Papers,which provide the basis for a case-by-case approach.EMEA structureEuropean guidelines are being generated through consultation both within the EMEA and externally (Figure1).Internally,the CHMP collaborates with a number of Working Parties(WP)through scientific advice and peer review.An important WP is the Biological WP(BWP)which operates closely with the Safety WP and Quality WP.The BWP’s remit includes developing guidelines on quality and clinical requirements for biologics,and participation in the shaping of ICH guidelines.Externally,the EMEA/CHMP operates within a network including Scientific Advisory Groups(SAGs),the National Competent Authorities(NCAs)of EU Member States,patient groups,universities and academic societies.Finally,the EMEA welcomes and encourages input from practicing physicians.Together,these groups aim to reach a consensus on medicinal products containing biotechnology-derived active substances.EMEA guidelinesGuidelines for changes in a manufacturing process The guidelines for quality[6]and clinical[7]studies required after a change in a manufacturing process advocate a case-by-case approach.The quality checks depend on the nature of the recombinant protein and the nature of the manufacturing change.Whether pre-clinical or clinical studies are required depends chiefly on the results from the quality assessment,and particularly on the ability of analytical techniques to characterize the biological product.All variations must be tracked within the pharamacovigilance database for the product.Guidelines for novel manufacturingprocesses(Biosimilars)The relevant guidelines,yet to be approved,were published in2005[7,8].They reaffirm the principles which are applicable to innovator companies, e.g. the applicants should demonstrate the consistency and robustness of their manufacturing process. Studies for biosimilars always have to be carried out in comparison with the original reference product. They involve batteries of in vitro assays,impurity profiling,and clinical pharmacokinetic(PK)and pharmacodynamic(PD)studies.Generally,clinical efficacy trials will be warranted,complemented by immunogenicity tests using validated assays.As ever, a post-approval continued benefit-risk assessment (pharmacovigilance plan)isnecessary.Fig.1.Diagram illustrating the interactions within the European Medicines Agency(EMEA)and between the EMEA and external groups.Ongoing peer review and scientific advice is given between the EMEA’s Committee for Medicinal Products for Human Use (CHMP)and various Working Parties(WPs).Discussion and input is encouraged from practicing physicians(including nephrologists), National Control Authorities(NCAs),Clinical Trials Authorities (CTAs),Working Parties(WPs),Scientific Advisory Groups(SGAs) and academics.v18 A.Wiecek and A.MikhailBiosimilar-specific guidelinesThe Concept Papers and their annexes provide guidance specific for certain biological products,and have been published for recombinant human insulin [9,10],growth hormone(GH)[11,12],granulocyte colony-stimulating factor(GCSF)[13,14]and epoetin (EPO)[15,16].They provide specific details on the various studies which need to be carried out for biosimilars,both pre-clinical and clinical.Further, such Concept Papers will progressively appear accord-ing to demand.The annexe to the insulin Concept Paper[9]places special emphasis on the comparative nature(relative to an innovator brand)of the studies.The PK properties of the biosimilar and the reference product should be assessed in a single-dose crossover study using subcutaneous administration.Provided that equiva-lence can be concluded from PK and PD data,there is no anticipated need for clinical efficacy studies. However,immunogenicity issues can only be settled by a clinical study with a comparative phase of at least 6months,followed by pharmacovigilance procedures. The annexe to the growth hormone Concept Paper [11]resembles the insulin annex,with a few noteworthy differences.Besides references to specific bioassays and PD markers,the main difference is that equivalent therapeutic efficacy between the biosimilar and the reference product should be demonstrated in at least one adequately powered,randomized,parallel group,confirmatory clinical trial.Treatment-naıve children with growth hormone deficiency are recommended as the target population,as they provide the most sensitive model.The annexe to the EPO Concept Paper[15]outlines somewhat more stringent requirements,reflecting the greater molecular complexity of EPO compared with insulin or GH.At least two adequately powered, randomized,parallel group clinical trials are necessary. Safety data over at least12months from at least300patients treated with the biosimilar in the efficacy trials is considered sufficient to provide an adequate pre-marketing safety database,and to exclude excessive immunogenicity.Treatment-naıve patients(or patients who have not received EPO treatment for at least3months)with renal anaemia are recommended as the target population,as they provide the most sensitive model.As ever,a rigorous pharmacovigilance plan is required,and special attention should be paid to the possibility of antibody-induced pure red cell aplasia(PRCA). DiscussionThe market for biotechnology-derived medicinal products is evolving rapidly with the imminent entry of biosimilars.Recombinant proteins are associated with a host of complex quality,safety and efficacy issues,and biosimilars are associated with a number of uncertainties.Nevertheless,the EMEA has forged ahead in providing guidance for national regulatory bodies in Europe.The EMEA guidelines are,however, a work in progress,and readers should consult the EMEA web site(www.emea.eu.int)for the latest updates.Some sections of the guidelines are still controver-sial.For instance,it is stated that comparative clinical trials can be foregone if the biosimilar can be characterized in detail by physicochemical and in vitro techniques,or alternatively that comparative PK/PD studies can replace clinical trials.The annex to the insulin Concept Paper echoes this:efficacy data need not be provided if equivalence can be concluded from PK and PD data.In contrast,the other three Concept Papers regard comparative clinical studies as a necessity.However,non-clinical studies cannot guarantee similarity,and therefore should not be allowed to replace clinical studies where biosimilars are concerned.The emphasis on adequate screening for immuno-genicity events is well-warranted,given the incidence of PRCA.Post-marketing monitoring is an essential component in tracking rare but serious adverse events like these.The guidelines state that immuno-genicity analyses should be performed especially in cases where repeated administration is proposed.A useful addition to the guidelines would be to require branding of biosimilars,to allow optimal and accurate pharmacovigilance.Currently,no legal framework exists in the US for the approval of biosimilars,and the FDA have released no guidance documents.The EMEA has provided a valuable base for EU legislation to evolve from.However,if we wish to ensure patient safety with the arrival en masse of biosimilars to the market, it is imperative that their unique characteristics be recognized.Accrued experience will then allow regulatory authorities to optimally match guidelines to the genuine risks and benefits associated with biosimilars.Conflict of interest statements.A.W.has participated in meetings sponsored by Roche.A.M.has participated in meetings sponsored by Roche,Janssen-Cilag and Amgen.References1.The European Parliament and the Council of the EuropeanUnion.Directive2001/83/EC of the European Parliament and of the Council of6November2001on the Community code relating to medicinal products for human use.Official Journal of the European Union2001;67–1282.The Commission of the European missionDirective2003/63/EC of25June2003amending Directive2001/ 83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use.Official Journal of the European Union2003;46–943.The European Parliament and the Council of the EuropeanUnion.Directives2004/27/EC of the European Parliament and of the Council of31March2004amending Directive2001/83/EC on the Community code relating to medicinal products for human use.Official Journal of the European Union2004;34–57European regulatory guidelines for biosimilars v19mittee for Medicinal Products for Human Use.Guidelineon similar biological medicinal products.CHMP/437/042005 mittee for Proprietary Medicinal Products.Guideline oncomparability of medicinal products containing biotechnology-derived proteins as active substance.Non-clinical and clinical issues.EMEA/CPMP/3097/02/Final2003mittee for Proprietary Medicinal Products.Guideline oncomparability of medicinal products containing biotechnology-derived proteins as active substance:quality issues.EMEA/ CPMP/BWP/3207/00/Rev12003mittee for Medicinal Products for Human Use.Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance:quality issues.European Medicines Agency.EMEA/CHMP/BWP/ 49348/2005,23November2005mittee for Medicinal Products for Human Use.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical issues.EMEA/CHMP/42832/2005mittee for Medicinal Products for Human Use.Annexguideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical issues.Guidance on similar medicinal products containing recombinant human insulin.EMEA/CHMP/32775/ 2005mittee for Medicinal Products for Human Use.ConceptPaper,similar biological medicinal products containing recom-binant human insulin.Annex to the guideline for the develop-ment of similar biological medicinal products containing biotechnology derived proteins as active substance:(Non) clinical issues.CHMP/Comparability Working Party/146710/ 2004mittee for Medicinal Products for Human Use.Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical issues.Guidance on similar medicinal products containing somatropin.EMEA/CHMP/ 94528/2005mittee for Medicinal Products for Human Use.ConceptPaper,similar biological medicinal products containing recom-binant human growth hormone.Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance:(Non) clinical issues.CHMP/Comparability Working Party/146489/ 2004corr.2004mittee for Medicinal Products for Human Use.Annexguideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical issues.Guidance on biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor.EMEA/CHMP/31329/2005mittee for Medicinal Products for Human Use.ConceptPaper,similar biological medicinal products containing recom-binant human granulocyte-colony stimulating factor.Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance:(Non)clinical issues.CHMP/Comparability Working Party/146701/2004mittee for Medicinal Products for Human Use.Annexguideline on similar biological medicinal products containing biotechnology-Derived proteins as active substance:non-clinical and clinical issues:guidance on biosimilar medicinal products containing recombinant erythropoietins.European Medicines Agency.EMEA/CHMP/94526/2005mittee for Medicinal Products for Human Use.ConceptPaper,similar biological medicinal products containing recombi-nant human erythropoietin.Annex to the guideline for the develop-ment of similar biological medicinal products containing biotechnology derived proteins as active substance:(Non)clinical issues.CHMP/Comparability Working Party/146664/2004v20 A.Wiecek and A.Mikhail。
欧盟专卖医药产品委员会（简称CPMP）制剂开发指导说明开发制剂指导原则75/318/EEC附件的关于申请的第二部分A.4部的内容经修订，产品授权上市必需这些数据。
1. 引言制剂开发研究需要常规开展并建立剂型的选择，并且所建议的剂型适合于申请中指定目的。
目的在于确定对批次重复性很关键的配方和工艺过程，因此需要常规监测。
由于活性成分和剂型种类繁多，本指导原则仅仅是对信息类型的说明，而这些信息在建立影响成品质量的要素时是非常有用的。
在本文所阐述的一般原则之后，个别指导原则已经在特定类型产品中予以阐述。
本文所阐述的原则主要适用于含化学活性物质产品，可能不适用于其他产品。
对于生物制品，例如疫苗、血液制品，另外的方法可能是合适的。
2. 产品的组成2.1 活性物质2.1.1 相容性应该在合适处提供活性物质与辅料相容性研究结果。
在产品组合固定情况下，应该提供活性成分之间的相容性研究结果。
如果能够的话，应该提供初步稳定性研究结果，作为支持数据。
2.1.2 物理化学特性活性成分的处方测试可以提供有用的信息。
在选择有关建议剂型和给药途径时，有必要考虑到活性成分的物理化学特性。
当物理参数可变、并且是影响产品质量的关键时，需要以可接受的标准制定合适的方法或者以其他合适的方法，控制活性成分的规格。
这可能导致：相对于较简单的剂型（例如溶液剂），用于特定剂型（例如固体制剂）的活性物质，需要进行额外的物理特性测试或药典专论项下的测试。
需要检测的物理特性可能包括溶解性能、含水量、粒径和晶型等。
i) 溶解性能可以影响剂型的选择和分析方法的选择。
ii) 含水量能影响其他参数，例如晶型、粒径，从而影响稳定性。
iii) 粒径可能影响生物利用度、含量均匀性、悬浮性、溶解性能和稳定性。
iv) 晶型和多态性可能影响溶解度、生物利用度或稳定性。
显然，这些参数相互作用，需要结合起来考虑。
影响生物利用度的关键参数的合适限度，来自于在体内有可接受表现的产品批次。
译者：高杨校译：许真玉按语：2003年10月欧盟药品评价管理局（EMEA）起草了直接接触塑料包装材料指导原则（GUIDELINE ON PLASTIC IMMEDIATE PACKAGING MATERIALS），并与2005年12月1日发布。
该指导原则根据风险级别，对于直接接触原料药或制剂的塑料包材应进行哪些研究，如何在申报资料中呈现，提供了指导意见。
这一指导原则对于我国直接接触药品的塑料包材研究具有很高的借鉴意义。
因此笔者进行了翻译，特此供业界参考研究。
以下为指导原则正文。
目录1 介绍1.1 目标1.2 概述1.3 一般原则2 在申请上市文件中的位置3 应提交的数据3.1 总体信息3.2 质量标准4 提取研究5 相互作用研究5.1 迁移（浸出）研究5.2 吸附研究6 毒理学资料/文献7 术语解释附件1 申报资料决策树附件2 塑料包装材料申报资料决策树附件3 提交信息对照表1 介绍1.1 目标制定本指导原则旨在替代《医药产品管理办法》3AQ10a的“直接接触塑料包装材料指导原则”，同时进一步强调在原料药和制剂申请上市时，应针对其直接接触药品的塑料包装材料提供相关信息。
本指导原则涉及人用药品和兽药所用的直接接触药品的塑料包装材料的申请。
对于人用药品，本指导原则涉及欧盟法规2003/63/EC（法规2001/83/EC的修正版）附录I第一部分第3单元的章节3.2.1.6、3.2.2.2和3.2.2.7；对于兽药，则涉及欧盟法规2001/82/EC的附录I第二部分的章节A、C和G。
1.2 概述本指导原则囊括了对直接接触药品塑料包装材料的具体要求。
对于其他包装材料或容器密封系统的特性，如包材性能，本指导原则不会考虑为它们制定一个合适的总体要求。
本指导原则范围仅限于直接接触药品塑料包装材料，也就是与原料药或制剂发生直接接触的包装材料，它们可能只是容器密封系统中的容器、封盖或其他部件的某一部分。
弹性体、天然和人工橡胶不在本指导原则范围之内。
European Union欧阳光明（2021.03.07）药品生产质量管理规范GUIDE TO GOOD MANUFACTURING PRACTICE FORMEDICINAL PRODUCTS目录第一章质量管理CHAPTER 1: QUALITYMANAGEMENT原则................................................................................................................. (5)Principle...................................................................................................... .. (5)质量保证................................................................................................................. .. (5)Quality Assurance.................................................................................................... (5)药品生产质量管理规范(GMP) (7)Good Manufacturing Practice for Medicinal Products (7)质量控制(QC)............................................................................................................. . (9)Quality Control......................................................................................................... (9)产品质量回顾................................................................................................................. .. (10)第二章人员CHAPTER 2:PERSONNEL.............................................................................................. 11 ......................................................................................................................... . (11)Principle...................................................................................................... . (11)......................................................................................................................... . (12)General........................................................................................................ (12)关键人员................................................................................................................. (12)Key Personnel..................................................................................................... .. (12)培训................................................................................................................. .. (12)Training....................................................................................................... (15)人员卫生................................................................................................................. . (16)Personnel Hygiene....................................................................................................... . (16)第三章厂房和设备CHAPTER 3: PREMISES AND EQUIPMENT (18)原则................................................................................................................. .. (18)Principle...................................................................................................... (18)厂房................................................................................................................. (18)Premises......................................................................................................通则................................................................................................................. (18)General........................................................................................................ (18)生产区................................................................................................................. . (19)Production Area............................................................................................................. ...........19贮存区................................................................................................................. . (21)Storage Area............................................................................................................. . (21)质量控制区................................................................................................................. (22)Quality Control Area (22)附助区................................................................................................................. . (22)Ancillary Areas........................................................................................................... .. (22)设备................................................................................................................. (23)Equipment................................................................................................... (23)第四章文件CHAPTER 4: DOCUMENTATION.................................................................................. (24)原则.................................................................................................................Principle...................................................................................................... (24)通则................................................................................................................. (25)General........................................................................................................ (25)文件要求................................................................................................................. (27)Documents Required...................................................................................................... .. (27)Specifications.............................................................................................. . (27)Specifications for starting and packaging materials (27)Specifications for Intermediate and Bulk Products (27)Specifications for Finished Products (28)Manufacturing Formulae and Processing Instructions (28)Packaging Instructions.................................................................................................. . (30)Batch Processing Records (31)Batch Packaging Records (32)Procedures and Records........................................................................................................ .33 Receipt......................................................................................................... . (34)Sampling..................................................................................................... .. (34) (35)Other............................................................................................................ . (35)第五章生产CHAPTER 5: PRODUCTION........................................................................................... (36)原则................................................................................................................. (36)Principle...................................................................................................... .. (36)通则........................................ ........................................................................ . (36)General........................................................................................................ .. (36)生产过程中对交叉污染的预防 (39)Prevention of Cross-contamination in Production (39)验证................................................................................................................. (40)Validation.................................................................................................... (40)原料................................................................................................................. (41)Starting Materials...................................................................................................... . (41)生产操作：中间产品和待包装产品 (42)Processing Operations: Intermediate and Bulk Products (42)包装材料................................................................................................................. (43)Packaging (43)包装操作................................................................................................................. (44)Packaging Operations................................................................................................... . (44)成品................................................................................................................. (46)Finished Products....................................................................................................... (46)不合格、回收料和退货物料 (46)Rejected, Recovered and Returned Materials (46)第六章质量控制CHAPTER 6: QUALITY CONTROL (48)原则................................................................................................................. (48)Principle...................................................................................................... (48)通则................................................................................................................. (48)General........................................................................................................ (48)质量控制实验室规范 (49)Good Quality Control Laboratory Practice (49)Documentation............................................................................................ . (49)Sampling..................................................................................................... (50)Testing......................................................................................................... .. (52)销售产品的稳定性考察 (54)第七章委托生产与委托检验CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS (55)原则................................................................................................................. (55)Principle...................................................................................................... (55)通则................................................................................................................. (56)General........................................................................................................ (56)委托方................................................................................................................. .. (56)The Contract Giver............................................................................................................ . (56)受托方................................................................................................................. . (57)The Contract Acceptor...................................................................................................... .. (57)合同................................................................................................................. (58)The Contract....................................................................................................... . (58)第八章投诉与召回CHAPTER 8: COMPLAINTS AND PRODUCT RECALL (59)原则................................................................................................................. (59) (59)投诉................................................................................................................. (59)Complaints.................................................................................................. . (59)召回................................................................................................................. .. (60)Recalls......................................................................................................... .. (60)第九章自查CHAPTER 9: SELF INSPECTION (61)原则................................................................................................................. . (61)Principle...................................................................................................... . (61)附件8 原辅料和包装材料的取样ANNEX8 SAMPLING OF STARTING AND PACKAGING MATERIALS (63)原则................................................................................................................. . (63)Principle...................................................................................................... . (63)人员................................................................................................................. . (63)Personnel..................................................................................................... . (63)原辅料................................................................................................................. (63)Starting materials...................................................................................................... (64)包装材 (65)Packaging material........................................................................................................ .. (65)第一章质量管理CHAPTER 1 QUALITY MANAGEMENTPrinciple原则生产许可证持有厂家只能生产医药产品，以确保药品符合其预期的使用目的，符合销售许可证的要求，并不因药品安全性、质量或药效方面的问题而给患者带来风险。
European Union药品生产质量管理规范GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS目录第一章质量管理CHAPTER 1: QUALITY MANAGEMENT原则.。
.。
.。
......。
....。
..。
..。
.。
..。
...。
.。
.。
.。
.。
..。
...。
..。
.。
......。
.。
.。
...。
.。
.。
.。
....。
.。
..。
......。
.。
..。
.。
.。
.。
....。
.。
.。
.。
..。
.。
.5 Principle..。
..。
.。
.。
.。
.。
.。
.。
.。
...。
.。
..。
....。
....。
.。
.。
.。
.。
...。
.......。
.。
...。
.。
.。
.。
.。
..。
...。
.。
..。
.......。
..。
..。
....。
.。
...。
.5质量保证。
.。
.....。
.。
..。
...。
..。
.。
.。
.。
.....。
.。
..。
.。
.。
...。
.。
... .。
..。
.。
...。
..。
.。
.。
.。
.。
.。
.。
.。
..。
....。
..。
...。
..。
.。
5Quality Assurance....。
...。
.。
.。
..。
.。
..。
.。
.。
..。
...。
......。
.。
.。
.。
.。
.。
.....。
...。
..。
.。
.。
.。
....。
..。
..。
.。
.。
.。
.。
.。
...。
.。
.。
..。
...。
5药品生产质量管理规范（GMP）。
.。
...。
.。
..。
.。
..。
.。
..。
.。
..。
.。
.。
....。
..。
..。
.。
.。
.。
..。
........。
.....。
.。
.。
.。
.。
(7)Good Manufacturing Practice for Medicinal Products。
...。
.。
.。
.。
..。
..。
..。
.。
.....。
..。
..。
.。
.。
..。
.。
..。
..。
...。
..。
7质量控制(QC）。
.。
.。
.。
.......。
欧盟GMＰ中英文比较————————————————————————————————作者: ————————————————————————————————日期:EuropｅanUnion药品生产质量管理规范GUIDETOGＯOD MANUFACTＵRＩNGPRＡCＴICEFＯRMEDＩCINAL ＰＲOＤUＣTS目录第一章质量管理CＨAＰＴER1:QUALITYMANＡＧEMENＴ原则.．.．....．...．...．...．.............. .....．.......．..．.．..．.．.．.....．..．．.．....................．....．...．．.．．．........．．....．.．..．．.．..．.....．.....．.．.5rｉncipｌｅ.......．..................．....．...．．．...．....．．........．.．.....．．..．...．.．．.．.．.....．.......．.．.．...．.．.．............．...．.......... ....．.．....．. (5)质量保证...........．...．..．．..．...．．．．.．............．.....．....．....．．...．．..．..．．....．.．.．...........．．.................．．.．..．......．......．．. (5)ＱｕａliｔyＡssurancｅ........．.....．.．...．．.．....．...．....．．............．.．.........．. .......．......．...．....．...．..．..．．.．.．...．......．.．......．．．..．....５药品生产质量管理规范(GMP）........．.．．....．...．.......．.．...．．....．...．....．．．．.．.．．．．.．．7...．.．GｏoｄＭanｕfaｃturingPracticｅfｏrＭedicinalPrｏdｕcts．....．．.....．．...．....．...．．......．.......．.....．..........．．....．．．．..．..． (7)质量控制(QC).... ..．.．......．...．.......．...．...．.................．....．．.....．......．...．...．........．.．....．....．.．.．．...．．....．..．.．....．. (9)Qｕality Control．.............．...．.．.．........．..．.........．...．......．............．....．.．.......．...．..．.．..．．..．.．.．..．....．．.......．..........．......9产质量量回顾．.．....．．...．.．...．..．...．.．...．..．.....．....．．...．．...．...．．.．.．.......．．......．．...．.....．．......．．....．．．......．..．.．．.......．．10第二章人员CHAPTＥR2：PＥRSOＮNEL．..．..．．．．.．．．.．．．.．.．．．.．．.．．．..．....．.．.．.11原则.．.．．．．．．．．．..．．．．.．........．.．．..．..．11Priｎcipｌe..．.．.．...．.......．...．.....．．....．....．.........．.....．.．........．．.．.．........................．........．............．........．..11通则.............．.....．....．........．.．..．.......．..．....．..．．....．..．．．...．．.......．..．．．....．.....．....．.........．.....． (12)Geｎeral.．.．．．..．.．.........．...．....．.．......．...．．.....．．..．．..．............．．．...．....．.．．.．....．．.．...．．.．.....．．...．...........．..．．.．12关键人员....．........．..．．.．...........．.．.．．．.．..．．．．...........．.．....．.....．.......．.．...．..．...．....．..．．．．.....．．．.．..．.......．....．．......．.．．．..１２eyPｅｒｓonnel......．．.．.................．...．...．．...........．....．....．.．...．..．....．.．........．................．．......．．...．.．.......．..．............1２培训....．．．．.......................．．...．．...．......．....．..．.....．．．...．．..．..．..．．．...．．．.........．..............．..．.．...．.........．.........．...．..．．．....１2Trａｉning..．．．.．......．........．...．．.......．．....．.．．....．..．..．...．....．....．...．.....．．．.......．..........．....．．..．...．......．..．．．....１5人员卫生．.......．.．．．..．.．．..．...．...．........16．.．..．.....．.．...．...........．.．..．.．....．．........．........．...．....．..．....................．..．．．.....．．Peｒsonnel Hygiｅn ｅ.．.......．......．............．........．....．.........．..．..．......．．．..．......．．...．......．．.........．．.......．．....．.．.......．....１6第三章厂房和设备CＨAPTEＲ3:PＲEＭISEＳANDEＱUIＰMENT.．..．........．．.............．....．........．．．．..．.....．.．．..．.．....．．...．.．...1８原则.．....．........．.．．.....．....．..．.．..．..．．..．..．..．...．．.....．．..．．．.........．．....．．．.．．.．.......．．..．..．..........．．..．.......．..．． (18)Pｒｉｎcipｌｅ...........．....．.．..．.．．..．...........．．.....．...．．.．.....．.．．..........．．．...．...．.．....．..．．........．...．．..．..．．．．.....．.．..．.．.1８厂房.......．..．..．.．．．..．.........．.．.....．..．.．............．．..．...．．....．．．．.．...........．..．....．.．．.....．...．..．..．...．．............．.．．.18Premｉses... .．.........．...．.．．.．．.........．.........．..........．.．...．..．．..．....．..．..．.....．..．...．.．...．..．.．...．..．..．....．..........．．.1８通则.....．........．........．......．．.．.......．..．..............．......．..．．．.......．...．...．.....．.．..．..．..................．. (18)Gｅnera ｌ.．.．..．....．.........．...．.．．.....．．....．.．..．........．．........．...．..．..．....．......... ...．．...．..．．.．．..．......．.........．．........１8生产区.．．...．...．.．..．....．...．．..．.........．......．．....．......．．.．........．.．....．．．.．．..．............．...．．.．....．..．..．.．.．．.....．. (19)PｒｏｄuctionArｅa...．..........．...．.....．.......．....．.．..．....．．..．．..．．.........．.......．．．..．......．.............．．．....．．.． (1)９储存区.....．.．．...．..．.....．...........．....．.．........．.．．..．...........．.....．.．．．....．..．.. .．...．．．...．．..．.．.......．..．..．.．..．．.．.．..２1SｔorageArea.．．...............．.....．.．..........．．....．.．.........．..．....．．........．..．......．.......．.．.．.．......．.．.....．.．．..． (21)质量控制区．...........．．.........．．.....．．.．.．........．．...．．............．．..．．.......．.......．．．．........．．....．..............．．22QualｉtyControlＡrea..．．.．...．........．..．....．．．....．．．..．.....．......．...．.．..．.．....．.．.．..．.....．.....．.．........．．......． (22)附助区....．．..．.....．.．...．..．.．．．.......．..．．.．.．．.．..．.......．...．...．．....．．... ...．．.．.．...．..．．.．....．.．..．....．．.．．．..．.．．.....．．.2２AｎcｉllaryArｅa ｓ..........．．．．...．.........．....．..．.........．.．..．.．.．.....．.．...．..．........．...............．.．...．．...．..．．......．．22设备..．.．.．.．．...........．．........．．．..．.....．..．......．.......．.............．.........．．．..．．..．......．....．..．.......．.．．.．.....．.．.．..2３Equipmｅｎｔ．...．....．．.．.．．.．.........．.．..．．．..．.．.．.......．.．．.．．．..．.......．．..... .．．.．．.．.．．...．.．...．．..．.......．...．......．.. (23)第四章文件CHAPTER４:ＤOCUMEＮＴATIO Ｎ..．...．．..．.．．...．．.......．.．.....．..........．.．....．.．..．.....．....．.．.........．..．．24原则..．..．.．...．.．...．.......．.．.．．....．..．..．．．．..．．．．............．．．........．........．...．．...．....．．.．.．．.．..．...．．.....．.....．..．..．..24Principｌｅ．........．.....．.....．...........................．.．..．.．．......．．......．．．．....．.．....．．.．．．．........．．........．．.．......．．...．．24通则．．..．．．...．......．..．．.........．.．...．..........．．...．.．．...．...．...．..．......．..．.........．.．........．.．．....．.．........．.........．.．２5General.．．..．................．..．．.....．.........．．.....．..........．．.．．....．..．.．．..．.．.......．.............．...．....．.........．.．....．．.25文件要求．.....．.............．.．．...．...．..............．....．........．.．...．...．....．.．.．......．..．..．..．.....．..........．.....．.....．２7DocumeｎtｓReqｕired...．．....．.．.......．..．...............．...........．.．....．......．...．..．．..．.．......．....．..........．.．...．...２7Specificatioｎｓ．..．.．...．........．.............．...．.．..．．....．.......．．...．．．.．.．．．．...．...........．．.．.．．.....．..．．......．．.．......．.．.27Sｐecificatｉonsｆorstarｔiｎｇanｄpackagingｍaterials.．.．....．............．...．．．......．．......．..．..．..．.......．.．.2７SpecｉficaｔionsｆorＩｎtermｅdiａｔｅaｎdBuｌkProduｃts...．．......．．.....．．．．.．..............．.....．....．.....．.．.. (2)Speciｆications for FiｎishedPrｏducts......．...．...．..．.．..．........．.．....．...．....．.．.．..．..．..．.......．.．..．．....．...．.．28 ManufａｃtｕrｉnｇFoｒmulａe andPｒocesｓingInstructｉoｎs...．．...．．.........．..．.．．............．..................．.2８PaｃkaginｇInstructionｓ．......．.．.．．...．.......．....．..．...．．.．.．..．...．......．．.....．．...．...................．．.........．..．..．.．.３0BatchPrｏｃｅｓsingＲｅcｏrds..．.．．..．.........．..........．．.．......．.．.．．．......．．....．.....．．．.....．............．.....．.．．....．．．.3１BaｔcｈPａｃkaｇｉngRｅcoｒｄs.．..．．.．..．．.．.．....．．．......．..．.．.....．．.．...．..．．．..．..．.．.．.......．..．.................．...．．.． (3)ProｃeduresaｎdＲecｏrds．........ .．．．....．．...．..........．................．..．．．.......．.．....．...．.．..．.．.．......．........．...．.3３Receipt... .．..．．............．...．...．..．.．.．......．..．..．..．....．..．.........．....．．..．...３４．.．．．．．．．....．．.．．．．.．．........．...．.....Sａmpliｎg.............．．．.....．.．.．........．.......．．．.....．.．.．．.．....．...．..．．．．．．..．．.................．．.．........．．...．．.........．.．．..34Ｔeｓtinｇ.．．.............．．..........．．．.......．.．.．...．..．....．..．．......．.....．...．.．..．.．...．..．..．...．．.．..．............．．．．...．..........３5Otｈer...．．.．．.....．．.．...．．．...．....．.......．．.．...．...．．............．.....．．...．.．．.．.....．.....．．．.........．..．....．....．．.．.．....．．...．...３5第五章生产CHAPTEＲ5:ＰRODＵCTＩO Ｎ．．．.．.．.．.．.．.．．．..．．..．．..．．.．.．..．．．．.．．．．．..3６原则．..．.．．．．．．.．.．．．．．．．．．．..．．．..．．．．．..．．．．.．．.．．.．．３6Ｐrincipｌe..．.．．．．.．．．．..．．．．．．．．．．..．.．．.. .．．.．.．．．．．．36通则．．．．..．..．.．.．．.．．．．..．.．．．..．．．．.．.．．..．..．．.．．．36Gｅｎｅraｌ．．.．.．．．．．．．..．．．．．．．.．.．.．．．.．．..．.．..．．．．．．..36生产过程中对交叉污染的预防．.．．.．..．.．．.．．..．．．.．.．．..．．．39PrevenｔionoｆＣroｓｓ－ｃｏｎｔamination inＰrｏducｔion.．.......．..........．.．..．.......．...．．.....．．.．.........．........3９验证.．．....．...．.．.．.．..．....．......．.....．....．....．.．....．．．...．........．...．.．．．....．．..．........．．........．......．..............．.．...4０Valiｄａtion．．．.．........．．.．．．.....．.........．.．.....．．..．..．.．.．.．.．.......．．..．...................．....．..．．．．．.......．...．．．．..．40原料.．.........．...．..．.．....．.．....．.．.．．....．.......．.．.．..．........．.．......．．．....．...．...．．．．．．．．.．.．．......．．.. (4)StartingＭatｅrｉals..．．.．..．.．．.........．．．.........．．.．...．...．．.．........．．..．．....．．．.........．...．...．..．..．．..．..．....．...．．．.．..４１生产操作：中间产品和待包装产品．....．...．．．．.........．.．..........．..．..．.．.．......．...．..．.....．. (4)PｒoｃessingOpｅrａtionｓ：Iｎtｅrmediate anｄBuｌk Proｄｕcｔs.．．．..........．.．....．..．．.............．．.．......． (42)包装材料.....．.．．．.．.....．.．...........．.....．.．．.．.．........．...．...．............．.............．．...．.．........．...．....．.．...．．.．.．43PaｃkagiｎgMatｅriaｌs.．...．．．...．.．.........．．..．．...．..．．．．.........．．．..．...．....．........．...．..．．.．.．．....．...．．．...．..．....．．．.43包装操作.....．．．.....．...．..．.....．.....．..．．......．..．..．.．..．...．．．.．...．......．..．．..．.........．.....．．..．......．．...．．......．.．..44PacｋagingＯpeｒａｔioｎs.......．．．.．...．.......．．.．...．.．．.．.....．.．..．.......．.．.．..........．...．．.....．．...．.......．．.........．. (44)成品．..........．..．....．..．．....．....．..．....．....．.......．．.....．...．...．．....．．.．........．...．........ .....．．.．. (46)FinishedProduｃts．.．..．.．..．...．.......．..．．．..............．...．...．．.....．.....．．..．．.....．.........．.......．.....．．.............．.46不合格、回收料和退货物料...．..．..........．.．.．.．.．．．....．．.........．..........．．.．.．..．....．.．...．...．．....．....４6Rejected,ＲecoveredandRetｕrnedMaｔeｒiａls.．................．．．．．.．.．.．．.．..．．．.......．..．．．.....．.....．....．..．..46第六章质量控制CHAPＴＥＲ６:QUALＩTYCONTROL．......．....．.............．.....．．.．．..．.....．．．.......．...............．．. (48)原则.....．.．..．．......．．．...........．.．.．..．.．..．....．.．...．．.．．.．.．...．..．..．...．．.．．.．．．.......．..．..．．．..........．.....．．.．...．........４８Ｐrinciｐle．．．...．.....．．...．.........．......．...．..．.．...．．．.．...．．..．...........．........．.．．...........．....．.....．..．．.．..．．.．....．.． (48)通则..．.....．.．．...．．..．.．........．．...．.．．..．...........．....．.．..．.....．.．..．..．....．......．...．..．.．．....．...．．．．..．.．.....．．.．．.....．.4８Geneｒal.......．....．..．...........．.....．.....．...．.........．.．.．..．...．．.．..．.．.......．...........．.....．...．.．..........．..........． (4)质量控制实验室规4范.....．.....．....．.．．.．.....．.........．......．.．.....．.．......．....．．．.．．．．.．．．９GoｏdQuａｌityControlLabｏratoryＰractice.．.．..............．....．.．．..．...．．．...．..．.....．..．..．．...．......．.．......．.４9 Dｏｃumenｔaｔiｏn.．....．.．．.............．..．......．..．.．..............．...．.．.....．....．.．．.....．．．....．..．..........．.．．.．．....．....．..．49Samplｉng....．.......．.．............．.....．....................．.．.．..．.．．．..．..．．....．．.．...．.．...．...．.．.......．..．．..．.....．..．.....．.50Ｔｅｓtiｎg.．.....．...........．.....．．.....．．.．...........．.....．..．......．......．.....．..．.......．..．............．....．.....．．．..．．..．....．..52销售产品的稳固性考察．．.．.．．．...．.......．..．．..．...．..．.．.．．.....．.．....．．..．．..............．.．......．...．.．..........５４第七章拜托生产与拜托查验CＨAＰTＥR7:CONTRACTＭAＮＵFACTUREANＤＡＮALYＳIS．..．.........．...．...．．..．......．．. (55)原则．.....．..．．..．.....．..．．...．...．.．.．.....．..．.....．...．......．......．．．..．．.．.．.．．..............．..．.....．.......．.．.．.......．..．..．．.55Priｎcｉpｌe..．.．．．．.．.．.．..．．...．．..．.....．..........．.......．...........．..．......．．．...．..... .．．．．...．......．...．.．.．..．......．.． (55)通则.．..．..．..．.．．．........．..........．.．.．.．..．..．...．．．．.....．．...．...．...．.．．.....．....．．．．..．.....．..．......．...．．.．.．.........．...．..56Ｇeneral.．．..．．...．.....．．...．........．．........．.．..................．．......．.........．........．.. ....．.．.．.......．．.．........．．.．.．..．．．.56拜托方．．.．.....．..．.．......．....．..．..．．.．.．．．..．....．．....．.......．..．．.........．. ..．.．．．．...．．．.．.．.．..．．...．..．．．...．.．...．．.．．....．.5６TｈeConｔraｃtGive ｒ..．.．．．.............．...．.....．........．．..．....．．.......．..．.....．.．...............．.．．.．．.........．...．．...．..５6受托方...．..．...........．...．．....．..．......．...．...．........．.．......．...．.．............．．．...．．....．........．......．.．....．.....．.．.．５7TheCoｎｔractＡcceptor....... .．..．.....．..．．．.．.．..．.．.....．....．.......．.．.．.....．.....．.．.......．．.．..．..．．..．..．...．..．..．. (57)合同..．．.....．．.......．..．.．．....．..．..．.．.....．...................．．..．.....．．..．.....．．．．..．........．．.........．.．.．．....．.......．..．．.．5８TheＣｏntｒact..．．...．.．．．．..．.......．.．．．............．....．．......．.....．．．.．.．....．........．......．．.．．．.．．......．..．..．...．．.....．.．.5８第八章投诉与召回CＨAPTＥR8：ＣOＭＰLAIＮTSANDPRＯDUCTRECALL.....．..．...．..．..．.........．.．.........．......．..5９原则．.．...．．.．．.．.．..．...．......．.........．..．........．．...．.....．．.．．.．.．..．........．........．...．......．..．．．.．.....．．..．......．....．．．.5９Princｉｐle．.．............．．...．..．.........．..．.．.．...．．...............．．..．..．．．．.............．..．．.．...．..．....．......．．．.．．.....．.．．.．．．．59投诉.......．.．...．...．.．．．...．...．...．．....．.......．....．......．........．..．.．．．.....．.......．.．....．.．．.．．....．...．...．.．...........．．.．.59Compｌaints........．．....．.．...．....．．．．．．.........．...．.．..．．......．....．....．..．..．.............．．.... .．.........．．．.．......．.....． (5)召回.．.....．..．．.........．．．........．......．....．...........．..．．.．..．..．...．......．....．．.．.．...．......．.．...．．.．.........．...．....．.．..．..60Recall ｓ．....．.......．．..．.．．..........．.．..．.......．..．．....．..．．....．....．.．...．.......．..．.．.．....．．..．.．．.．.....．....．.．....．. (60)第九章自查CHAPTER9：SEＬFＩNSPECTION．.．.．..．.．.．.......．．..．............．...．.．...．....．．.....．..．..．..．.....．.....．.．..． (61)原则...．．.....．...．.．.．．．....．...．....．....．．..．..．..．..．.．...........．..．.．...．.........．....................．.....．．..．..．．.．...．.．.．...．61Priｎcipl ｅ.......．..．.．.．.．．.．.．.．．...．...........．.....．..........．......．..．.....．．....．．....．．..．...........．.．....．.......．. (61)Ａ附件8?原辅料和包装资料的取样ＡNNEＸ８SAMPLIＮGOFSTARTINGANＤＰACKＡＧINGMATERIALS．．.....．.．......． (63)原则.．...．.............．.........．.．.........．...．..．．．...．...．.．.．.....．.．..．．.．...．...．.．....．.．.．．...．....．.....．.．..．.......．........．.6３Prｉncｉple．.．．..．......．..．．....．...．...．．...．...．...．..．.．...．..．．．..．..．..．....．....．...．．....．.....．．．.．．.．.....．....．...．...．．．......．..63人员...．.．．...........．....．.....．.．.．．......．．．........．.........．...．..．........．.....．......．....．.......．．.......．..........．.......．．.6３Personne ｌ.......．．.．.．.．..．...．.．.....．.．........．..．．...．..．．．.．.....．．.....．.．．.．... .．.．....．．..．..．．....．.．.．.．.．．.....．...．.....．...．．63原辅料........．.......．.．...........．.．....．．...．．..．．.．...．．....．..．．...．．.．..．.．．.. .．...............．.....．.........．.......．.．..．.. (63)Staｒtｉngｍaterials．... .．..．...．....．....．.．．.....．.......．..．．.....．．．..．．.．.．.．.．．...．.．....．..．.........．....．..．．．.....．..........．.64包装材料..．..．..．......．...．．...．...．．...........．．.．......．........．．.....．............．.．..．..．....．...．.......．..．..．.．....．..．.....6５Paｃｋaｇingｍaｔｅｒial... .．......．.......．.．....．...．..．......．．..．．......．........．.．．．.．．..．......．．....．....．....．．.．.........．.....．.65第一章质量管理CHAPTER1ＱUALITＹMANAGEＭＥNTPriｎcｉple原则生产赞同证拥有厂家只好生产医药产品,以保证药品切合其预期的使用目的，切合销售赞同证的要求,其实不因药品安全性、质量或药效方面的问题而给患者带来风险。
欧盟专卖医药产品委员会（简称CPMP）制剂开发指导说明开发制剂指导原则75/318/EEC附件的关于申请的第二部分A.4部的内容经修订，产品授权上市必需这些数据。
1. 引言制剂开发研究需要常规开展并建立剂型的选择，并且所建议的剂型适合于申请中指定目的。
目的在于确定对批次重复性很关键的配方和工艺过程，因此需要常规监测。
由于活性成分和剂型种类繁多，本指导原则仅仅是对信息类型的说明，而这些信息在建立影响成品质量的要素时是非常有用的。
在本文所阐述的一般原则之后，个别指导原则已经在特定类型产品中予以阐述。
本文所阐述的原则主要适用于含化学活性物质产品，可能不适用于其他产品。
对于生物制品，例如疫苗、血液制品，另外的方法可能是合适的。
2. 产品的组成2.1 活性物质2.1.1 相容性应该在合适处提供活性物质与辅料相容性研究结果。
在产品组合固定情况下，应该提供活性成分之间的相容性研究结果。
如果能够的话，应该提供初步稳定性研究结果，作为支持数据。
2.1.2 物理化学特性活性成分的处方测试可以提供有用的信息。
在选择有关建议剂型和给药途径时，有必要考虑到活性成分的物理化学特性。
当物理参数可变、并且是影响产品质量的关键时，需要以可接受的标准制定合适的方法或者以其他合适的方法，控制活性成分的规格。
这可能导致：相对于较简单的剂型（例如溶液剂），用于特定剂型（例如固体制剂）的活性物质，需要进行额外的物理特性测试或药典专论项下的测试。
需要检测的物理特性可能包括溶解性能、含水量、粒径和晶型等。
i) 溶解性能可以影响剂型的选择和分析方法的选择。
ii) 含水量能影响其他参数，例如晶型、粒径，从而影响稳定性。
iii) 粒径可能影响生物利用度、含量均匀性、悬浮性、溶解性能和稳定性。
iv) 晶型和多态性可能影响溶解度、生物利用度或稳定性。
显然，这些参数相互作用，需要结合起来考虑。
影响生物利用度的关键参数的合适限度，来自于在体内有可接受表现的产品批次。
2.2 辅料和其他非活性成分辅料的选择和辅料的特性应该适合于预期的目的。
2.2.1 应该解释处方内所有成分的作用，以及将其列入的理由在一些案例中，需要实验数据证明列入的理由，例如防腐剂（参见“防腐剂、抗氧剂使用指导原则”）。
根据辅料在处方中的作用，以及建议的制造工艺，选择合适质量的辅料。
在一些案例中，有必要提交如何确定某些辅料在处方中的用量。
2.2.2 辅料之间的相容性例如，在一个双防腐剂体系，应该研究防腐剂的合用问题，以支持稳定性数据。
2.2.3 当新成分用于产品生产时例如，一种新的缓释材料、一种新的抛射剂或渗透促进剂，需要和申请文件一起提供该成分的全部信息以及在产品处方中的作用，以证实其安全性。
当一种新物质被用作产品成分时，与新活性成分一样处理，需要按照辅料指导原则要求提供全部支持数据，除非该物质已被批准用于食品或局部用化妆品。
当一种辅料通过非传统途径给药或者高剂量应用时，仍然需要额外的支持数据。
3. 处方产品设计产品的处方时，需要考虑治疗活性、剂量学、活性物质的给药途径和产品的使用方法。
3.1 过量基于过量的风险，一般不鼓励在医用产品处方中过量投料，尽管是一种实践。
过量主要用于弥补制造过程中活性成分或关键辅料的损失，即生产过程过量投料为延长保质期，也就是为延长稳定性而过量投料。
这在以前的案例中非常明显，由于不可能给病人增加剂量，而为延长稳定性过量投料，将会导致过剂量，因为这些批次产品在生产后不久即流通到病人环节。
任何成分过量投料均应合理。
大量过量（例如超过10%）投料不应该被常规用于掩盖本身不稳定制剂。
最好缩短保质期，而降低病人过量用药的风险。
不应该为掩盖分析测试程序的不精确或不准确，或者不理想的制造工艺，而进行相似的过量投料。
在处方中过量加入某种活性物质，应该基于产品的安全和功效考虑是合理的。
应该记住，过剂量也可能由药物的传递机制引起，例如计量剂量吸入药物在鼻腔内的沉积。
3.2 物理化学参数a) pH值应该提供证据显示，已适当地研究了pH值在一定范围内对处方的影响。
要考虑pH值对活性成分、相关辅料（例如抗微生物的防腐剂）的影响。
在研究口服产品的生物利用度时，活性处方的pH值曲线可能是有用的。
在稳定性研究期间，应该研究pH依赖的任何长期影响。
当必须用缓冲液控制pH值在一定范围时，应该提交pH值的生理学影响。
b) 其他参数根据不同剂型，在制剂开发过程中要考虑到溶出、再分散、粒径分布、聚集性、流变学特性等参数。
对于肠外给药剂型，尚需考虑强度调整、乳剂粒径和形状、晶型的变化、粘度和通针性等。
3.3 液体和半固体剂型3.3.1 处方的组成处方中关键成分的含量应该通过试验结果确定其合适范围。
这些成分可能是：抗菌防腐剂抗氧剂其他，包括表面活性剂、溶剂、螯合剂、渗透促进剂、片剂润滑剂、释放调节剂等。
3.3.1.1 多剂量剂型应该添加抗菌防腐剂，由于其自身不具有防腐作用（参见“防腐剂指导原则”）；但是，单剂量无菌制剂不得添加防腐剂。
选择合适防腐剂的用量时，要考虑到贮存条件、重组、使用前的稀释以及使用时打开包装的频率等因素。
要按照欧洲药典的测试方法测试防腐系统的效力。
防腐剂的使用要遵守A标准，除非另有试验证实。
应该验证测试方法，包括合适的阴性、阳性对照、合适机体的选择，以证实合适的抗菌和抗真菌活性。
用来发放的大包装药物，需经更严格的测试。
测试方案应该允许包含在用保质期的样品，这些数据将在随后的该产品文件中出现。
测试时间应该尽可能短，尤其拟无菌使用的产品，例如肠外给药制剂眼用制剂。
大包装药物如果要延长有效期，必须要合理，需要额外的模拟使用微生物挑战测试，参见“防腐剂指导原则”。
应该仔细选择包装尺寸，以达到预期目的和适合使用频率。
通过适当的成品规格来控制有效期内产品的防腐剂含量。
3.3.1.2 在产品生产过程或贮存期间，抗氧剂可能已经被降解了。
为了在产品建议有效期内（包含使用期间）维持足够活性，应当有合适的试验数据支持和证实抗氧剂的含量水平。
3.3.2 与其他产品的相容性这对静脉注射给药产品尤其重要。
在给药前，数据表指导重组或稀释；应该提供数据显示，药物与推荐溶剂和给药装置在推荐使用期间或预期使用期间的物理化学相容性。
将一种产品与另外一种产品混合使用前，要提供全部的相容性数据，包括在推荐的使用有效期内、在推荐的贮存温度下以及在可能的极端浓度条件下。
3.4 固体剂型显然，固体制剂的化学不相容性或不稳定性，没有液体制剂或半固体制剂那样明显。
然而，SmPC推荐的稀释或混合使用（例如与酒），在给药前要进行合适的相容性研究。
活性物质和辅料不同的理化性质，可能导致分布不均和药物传递靶位的改变。
所以开发研究要提交散装或单位固体剂型的均匀性和性能特性。
3.4.1 均匀性混和过程通常需要确保活性物质均匀分布。
表面性质、晶型、粒径等不同，可能导致干混粉末隔离。
在开发阶段就应该提交混合工艺均匀性数据，并经验证研究确认，该部分数据放在卷宗PartⅡB。
开发阶段进行的研究，为大规模混合工艺的验证提供了有用的预测。
4. 包装材料包装材料的最初选择应该合理，要适当考虑使用时医务人员和病人的安全性。
要适当研究容器的完整性和防儿童包装的闭合。
要考虑到产品和包装之间可能的相互作用（参见塑料基本包装材料指导原则）。
也适用于给药前药品的混合和稀释（例如加到大体积输液内的药品）。
包装材料的最初选择也应该考虑到建议的生产方法。
尤其是无菌产品，所选择的容器要能允许成品的最佳灭菌（见以下第5部分）。
4.1 容器的吸附应该提供数据显示，如果与安全性和稳定性相关的话，已经考虑液体或半固体制剂内活性成分和添加剂吸附的可能性。
已知胶塞、玻璃瓶、塑料容器和给药装置均可能发生吸附。
在一些极端案例中，吸附可能导致渗透通过容器壁。
应该进行模拟使用条件的研究，例如测试配有给药装置的输液瓶远端的产品。
4.2 浸出应该提供数据显示，任何包装组分均未明显浸出到液体制剂和精细分割的固体制剂中。
这样的浸出可能引起安全问题。
4.3 剂量可重复性如果使用给药装置，例如滴管、笔注射装置，应该提供证据证明给药剂量在相应的测试条件下的重复性和准确性，测试条件尽可能与病人使用产品相关。
特别注意，根据使用指导手册，lyophilisate的正确重组和混悬剂重新悬浮时的均匀性。
特别注意，根据病人使用手册，lyophilisate的在两腔室的正确重组和混悬剂重新悬浮时的均匀性。
5. 生产工艺在开发制剂时，要解释生产工艺选择的合理性。
必须说明运用合适质量的起始物料制备制剂所选择的方法是合适的。
工艺应该采用适当规格的定义，以保证成品的质量。
如此，工艺开发研究为工艺优化和验证要求制订了基础。
应该提交微生物学研究和理化参数研究的资料，需要确定关于产品质量的合适的微生物控制。
生产工艺的开发对于生物制品具有重大意义。
对于拟无菌使用产品（例如肠外制剂、眼用制剂和无菌局部用制剂），应该合理选择适当的灭菌方法。
应该记着，所有这些产品应该尽可能在最终的容器内终端灭菌，采用经过充分验证的方法灭菌，例如欧洲药典所收载的蒸汽、干热、电离辐射等。
如果不可能终端灭菌，可以考虑通过截留细菌的滤器过滤除菌、无菌处理等，如果该方法经过科学验证是合理的。
如果未采用欧洲药典收载的终端灭菌方法，要在卷宗内提供正确的科学的解释和理由。
理由可能是：一个给定的产品是热不稳定的，就是说处方的活性成分或关键成分在所用的灭菌条件下显著降解。
然而，包装材料本身的热不稳定性，对热稳定产品来说，应该不是不采用终端灭菌的充分理由。
在决定使用非终端灭菌工艺前，要充分研究可替代包装材料的使用。
6．结论开发研究形成一个重要的背景，以确保医疗产品质量适于预期的使用。
一个正确设计的配方，按照GMP原则生产，使用适当的验证过程和测试程序，应该一贯遵守所需的成品规格。
然而开发研究通常不接受GMP检查，不过也应该遵守合适的原则。
正确进行的开发研究能够确保应用有关放行和保质期规范，以便在放行时和整个有效期内使产品符合所需的特性（参见“成品规格和控制测试”指导原则）。
