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1、Conferences & Trainingson GMP and Regulatory Affairs讲座&培训GMP及药政The Organisation CONCEPT HEIDELBERGThe Organisation CONCEPT HEIDELBERG Founded on 1 April 1978Europes leading institute of further education for the pharmaceutical industry - in the field of production, QA and regulatory affairs 240 GMP/
2、FDA Compliance Courses per yearExclusive co-operation with the European Compliance AcademyOffice in HeidelbergCONCEPT HEIDELBERGCONCEPT HEIDELBERG 成立于1978年4月1日欧洲的领导学院针对医药 工业（产品，QA和药政领域） 的进修 每年240 GMP/FDA 课程与European Compliance Academy独家合作位于 Heidelberg的办公室. was founded in January 1999. is an independ
3、ent educational organisation chaired by a scientific advisory board. more than 2,800 members from 45 different countries GMP search engine: www.gmp-compliance.org. 成立于 1999年1月. 是一个由科学顾问委员会主持的独立教育组织. 超过45个不同国家的2,800个成员GMP 搜索引擎: www.gmp-compliance.orgwww.gmp-compliance.orgwww.gmp-compliance.orgThe CON
4、CEPT HEIDELBERG Speakers Team The CONCEPT HEIDELBERG Speakers Team Quality ControlQuality ControlDr Gnter BrendelbergerDr Gnter BrendelbergerProduction / IT SystemsProduction / IT SystemsDr Andreas MangelDr Andreas MangelAPIs / Regulatory AffairsAPIs / Regulatory AffairsDr Barbara JentgesDr Barbara
5、JentgesPharmaceutical EngineeringPharmaceutical EngineeringHarald MartinHarald MartinValidationValidationSven PommeranzSven PommeranzGMP, ISO 9000 QM SystemsGMP, ISO 9000 QM SystemsOliver SchmidtOliver SchmidtBiotechnology / MicrobiologyBiotechnology / MicrobiologyDr Ulrich HerberDr Ulrich HerberAna
6、lytics / Pharmaceutical LawAnalytics / Pharmaceutical LawDr Gerhard BeckerDr Gerhard BeckerHygiene / MicrobiologyHygiene / MicrobiologyDr Karl-Friedrich NiethDr Karl-Friedrich NiethMedical Devices / Quality ManagementMedical Devices / Quality ManagementDr Heinrich PrinzDr Heinrich PrinzIT Management
7、IT ManagementPeter DollenbacherPeter DollenbacherGMP ComplianceGMP ComplianceDr Berthold StemmleDr Berthold StemmleCONCEPT HEIDELBERG CONCEPT HEIDELBERG 的演讲队伍的演讲队伍 质量控制质量控制Gnter Brendelberger Gnter Brendelberger 博士博士生产生产 / / IT IT 系统系统Andreas Mangel Andreas Mangel 博士博士原料药原料药 / / 药政药政Barbara Jentges
8、Barbara Jentges 博士博士制药工程制药工程Harald MartinHarald Martin验证验证Sven PommeranzSven PommeranzGMP, ISO 9000 QMGMP, ISO 9000 QM系统系统Oliver SchmidtOliver Schmidt生物工程生物工程 / / 微生物微生物Ulrich Herber Ulrich Herber 博士博士分析方法分析方法/ /药物法律药物法律Gerhard Becker Gerhard Becker 博士博士卫生卫生 / / 微生物微生物Karl-Friedrich Nieth Karl-Fried
9、rich Nieth 博士博士医疗器械医疗器械 / / 质量管理质量管理( (QM)QM)Heinrich Prinz Heinrich Prinz 博士博士IT IT 管理管理Peter DollenbacherPeter DollenbacherGMP GMP 遵守遵守Berthold Stemmle Berthold Stemmle 博士博士Europes most important API Conference with Europes most important API Conference with EU Commission and FDA SpeakersEU Commis
10、sion and FDA Speakers欧洲最重要的原料药会议欧洲最重要的原料药会议 与欧盟委员会和与欧盟委员会和FDAFDA讲演人一起讲演人一起GMP (ICH Q7A) Compliance and Inspection for COS/CEPGMP for Active Pharmaceutical Ingredients (APIs)ICH Q7A, Annex 18 to EU Guide to GMPDr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergGMP (ICH Q7A)
11、 遵守遵守COS/CEP检查检查原料药的GMP (APIs)ICH Q7A, 欧盟GMP指南附件18 Dr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergGeneralThe guideline was published by the EMEA (European Agency for Evaluation of Medicinal Products).Pharmaceutical manufacturers should only use APIs manufactured accord
12、ing to GMP in the manufacture of medicinal products.Not mandatory in the EU but when there are causes for concern, or when required by certain Member States, GMP inspections of API manufacturers will be carried out.An application for a centralised authorisation will trigger an inspection by inspecto
13、rs of the competent authorities in the EU. Requirements laid down in the guideline should be fulfilled.总则该指南由EMEA (European Agency for Evaluation of Medicinal Products)出版发行药物制造商应当在医药产品的制造中仅使用那些按照GMP生产的原料药欧盟没有命令要求，但当某个成员国表示关注或有要求时，将会对原料药的工厂开展GMP检查一项关于集中授权的申请将会引发由欧盟内由资质的专家构成的检查员的检查。在下面指南中规定的要求应当履行Tabl
14、e of ContentsIntroductionQuality ManagementPersonnelBuildings and FacilitiesProcess EquipmentDocumentation and RecordsMaterials ManagementProduction and In-Process ControlsPackaging and Identification Labelling of APIs and IntermediatesStorage and DistributionLaboratory ControlsValidationChange Cont
15、rolRejection and Reuse of Materials目录介绍质量管理人员建筑和设施工艺设备文件和记录物料管理生产和过程控制包装和原料药以及中间体的标签识别仓储和分销实验室控制验证变更控制不合格和物料的再使用Table of ContentsComplaints and RecallsContract Manufacturers (including Laboratories)Agents, Brokers, Traders, Distributers, Repackers, and RelabellersSpecific Guidance for APIs manufactu
16、red by Cell Culture/FermentationAPIs for Use in Clinical TrialsGlossary目录投诉和召回合同制造商代理商，经纪人，贸易商，分销商，重新包装人，和重新贴签人由细胞培养/发酵制造的原料药的专门指南用于临床试验的原料药词汇表1. Introduction 1.1 Objective Provide GMP guidance for APIs under an appropriate system for managing quality.Help to ensure APIs quality and purity.Manufactu
17、ring“ includes all operations of receipt of materials, Production, packaging, repackaging, relabelling, quality control, release, storage and distribution of APIs and the related controls.Should“ indicates recommendations that are expected to apply unless shown to be inapplicable.Does not cover safe
18、ty aspects or environmental aspects.Does not define registration/filing requirements or modify pharmacopeial requirements1. 介绍 1.1 目的目的为原料药在适当的系统下进行质量管理，提供GMP指导帮助保证原料药的质量和纯度制造包括接受物料，生产，包装，重新包装，重新贴签，质量控制，放行，仓储和原料药的分销以及相关的控制等所有的操作“应当”指希望被应用的推荐措施，除非该措施证明是不适用的不涉及安全方面或环保方面不定义注册/文件要求或修正药典的要求1. Introductio
19、n1.2 Regulatory ApplicabilityWhen a material is classified in a region or country as API, manufactured there or used in a drug product, GMP requirements according to the guide have to be followed .1.3 ScopeThe guide applies to the manufacture of APIs for use in human drug products.APIs manufactured
20、by chemical sysnthesis, extraction, cell culture/fermentation, recovery from natural sources.API Starting Material“ is a raw material, intermediate, or an API that is incorporated as a significant structural fragment into the structure of the API manufactured; defined chemical properties and structu
21、re!1. 介绍1.2 药政适应性当一种物料被一个地区或国家列为原料药，在该地区制造或在某种药物产品中使用，必须根据本指南遵循GMP要求。1.3 范围本指南应用于由化学合成，提取，细胞培养/发酵，自然原料提取的原料药制造。原料药起始物料是原料，中间体，或一种原料药，它具有所要生产的原料药的有效结构部分；明确的化学属性和结构Application of the Guide to API ManufacturingChemical synthesis: production of API starting material- introduction of API starting materia
22、l into process production of intermediate(s) isolation and purification- physical processing and packagingDerived from animal sources: collection of organ, fluid, or tissue cutting, mixing, initial processing introduction of the API starting material into process isolation.Extracted from plant sourc
23、es: collection of plants cutting and initial extraction further extraction physical processingAPI consisting of comminuted or powdered herbs: collection cutting/comminuting physical processing and packagingBiotechnology-Fermentation/cell culture: establishment of master and working cell bank mainten
24、ance of working cell bank cell culture/fermentation isolation and purification physical processing and packagingClassical“ fermentation to produce an API: Establishment and maintenance of the cell bank introduction of the cells into fermentation,. 本指南在原料药制造的运用化学合成：原料药起始物料的生产在工艺中加入原料药起始物料中间体生产分离和提纯物理
25、加工和包装源于动物原料的：采集器官，液体，或组织切割，混和，初步加工在工艺中加入原料药起始物料分离从植物原料中提取的：采集植物切割和初步提取进一步提取物理加工原料药由粉末或粉末状草药组成：采集切割/粉末化物理加工和包装生物技术发酵/细胞培养：建立主细胞库和工作细胞库工作细胞库的维护细胞培养/发酵分离和提纯物理加工和包装生产一个原料药标准的发酵：细胞库的建立和维护在发酵中加入细胞 1.3 ScopeThe company should designate and document the rationale for the point at which proiduction of the AP
26、I begins. (available?, inspectors aide memoire!(AM)From this point on ,appropriate GMP as defined in the Guide should be applied to these intermediate and/or API manufacturing steps.This includes validation of critical process steps determined to impact the quality of the API.(AM critical steps iden
27、tified?)The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification and packaging.Physical processing such as granulating, coating, blending with excipients/subbatches, milling require full GMP!1.3 范围工厂应确定并把原料药是从哪个点开始的制成文件（可能？检
28、查官帮助备忘录！（AM)从这个确定的点起：本指南中相应的GMP规则应该被应用于这些中间体和/或原料药的制造步骤这包括对决定原料药质量的关键工艺步骤的验证（AM关键步骤的确认？）随着工艺从最初的原料药步骤到最终步骤，纯化和随着工艺从最初的原料药步骤到最终步骤，纯化和包装，原料药制造的包装，原料药制造的GMP规则逐步严格。规则逐步严格。物理过程，例如造粒，包衣，和赋形剂物理过程，例如造粒，包衣，和赋形剂/零头的混和，零头的混和，粉碎，满足粉碎，满足GMP的要求的要求API Starting Materials (API-SM)Responsibility of companies to propo
29、se the API Starting Material(s); technical, quality, regulatory groups have to define the significant structural fragment! With Starting Material GMP has to be applied!If only one or two synthetic steps exist between an API-SM and the API or if the SM is an API itself regulatory authorities will req
30、uire further information on API-SM! (manufacturer audited, quality management system established, documentation, change control, etc.)In general, the source of the API-SM is not a major factor.EP certification submissions require a statement the product is manufactured according to GMP“ (not the API
31、-SM!)Commercially available substances (late stage API-SM) like 6-APA for semi-synthetic penicillins accepted by FDA as API-SM! Authorities may require further details!原料药起始物料(API-SM)工厂提出起始物料的责任：技术，质量，药政部门必须确定其重要的结构特征！必须应用起始物料的GMP规则。在原料药起始物料与原料药之间只存在一或两个合成步骤，或者如果这种起始物料本身便是一种原料药，药政官方部门将要求原料药的起始物料有更详细
32、的资料！（受审计的制造商，已建立的质量管理系统，文件，变更控制，等）总之，原料药的起始物料的来源不是一个重要因素。EP证书的递交需要一个申明，说明产品是符合GMP的（不是原料药的起始物料）适用于商业的物质（原料药起始物料的后阶段），如用于半合适用于商业的物质（原料药起始物料的后阶段），如用于半合成青霉素的成青霉素的6-APA是被是被FDA所接受的原料药起始物料。官方部所接受的原料药起始物料。官方部门可能要求更详细的材料！门可能要求更详细的材料！API-SMWhere the proposed API-SM is close to the API ensure that details on t
33、he synthetic process and analytical controls used are available in case these would be required by the regulatory authorities! Include in the commercial contract that a confidential part has to be provided directly to authorities if requested!Define also Change Control Requirements in the contract f
34、or supply of API-SM! Any change in synthetic route, analytical controls or specification,needs notification to and acceptance by the API manufacturer Manufacturers of Intermediates, API-SMs, APIs should have a system for evaluating the suppliers of critical materialsAPI-SM那些与原料药很接近的起始物料若能确定其详细的合成工艺并
35、且有检验控制，这样做也是可以满足官方药监部门要求的！包括商业合同，如果需要，其中的保密部分必须直接提供给官方部门。对于起始物料的合同也要明确变更控制的要求任何在合成路线，检验控制或规格中的变更，都需要告知并得到原料药制造商的接受中间体，起始物料，原料药制造商应该对关键物料供应商进行评估。API-SMSynthetic or semi-synthetic APIs API-SM is analytically fully controlled in terms of identity, assay and impurities!API produced by direct fermentatio
36、n Describe micro-organism and media components plus their specifications. No specific starting material to be defined, unless one component is structurally closely related to the API.API extracted from natural sources or manufactured from mined ore Describe the purification process and/or define API
37、-SM based on a scientific rationale which may include risk assessment.原料药起始物料合成或半合成原料药起始物料按照鉴别，含量，杂质等全检控制由直接发酵产生的原料药 在规格里加入微生物和培养基的描述如果一个要素的结构与原料药非常接近，则无须确定起始物料原料药从自然原料中提取或由矿石制造描述精制工艺并且/或根据科学原理，其中可能包括风险评估，来确定原料药的起始物料2. Quality Management Principles Responsibilities of QU(s) Responsibilities of Produ
38、ction Internal Audits Product Quality Review2. 质量管理 原则原则 质量部门职责质量部门职责 生产部门职责生产部门职责 内部审计内部审计 产品质量审核产品质量审核2. Quality Management - GlossaryQuality Assurance (QA), Quality Management (QM) The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality requir
39、ed for their intended use and that quality systems are maintained.Quality Unit(s) An organizational unit independent of production which fulfills both QA and Quality Control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the
40、 size and structure of the organization.Quality Control (QC) Checking or testing that the specifications are met.Quality Attribute: Any product characteristic which may reflectquality, or may affect safety or purity of the product during its expected shelf life.Quality: Totality of features and char
41、acteristics of a product or serviceand its ability to satisfy stated or implied needs. This is, meeting agreed requirements in a cost effective manner. 2. 质量管理词汇表质量保证 (QA), 质量管理 (QM) 以确保所有原料药达到其应用所要求的质量，并以维持质量体系为目的的全部组织安排的总和。质量部门（QU） 独立于生产部门的履行质量保证和质量控制职责的组织机构。按照组织机构的大小和结构，可以是单独的QA 和QC部门,或个人,或小组。质量控
42、制 (QC) 是否符合质量规格的检查或测试。质量属性: 在预期的架上时间内任何可能影响产品质量，安全或纯度的产品特性。质量: 产品或服务，满足规定或潜有需要的特征和特性的总和。即，采取有效的措施符合要求Coordinated activities to direct and control an organization throughout all areas and processes with regard to quality.Glossary: Quality ManagementQuality Management System - QMSSystem needed to impl
43、ement Quality Management efficiently.指导和控制一个组织的协调活动指导和控制一个组织的协调活动贯穿所有与质量有关的区域和工艺贯穿所有与质量有关的区域和工艺词汇表：质量管理质量管理系统QMS需要有效的实施质量管理的系统需要有效的实施质量管理的系统.The Quality Assurance System - QMSystem .recognizes and describes interfaces, responsibilities,Quality ControlTechnicalServicesProductioncompetences,Interactio
44、ns.ensures clearInputs for tasks质量保证系统QM系统 职责的识别和描述质量控制量控制l技技术服服务生生产管辖相互作用确定明确的职责分配InterfacesInterfacesMilestonesMilestonesInformation flow/InteractionsInformation flow/InteractionsTasksTasksCompetencesCompetencesResponsibilitiesResponsibilitiesQMS is the arrangement ofQMS is the arrangement of管辖管辖分
45、界分界信息流动信息流动/ /相互作用相互作用任务任务权限权限职责职责质量管理系统质量管理系统QMSDocumentation SystemGMPDescribes system related qualityDescribes product related qualityQMS文件系统文件系统GMP描述与质量相关的系统描述与质量相关的系统描述与质量相关的产品描述与质量相关的产品GMP + Processes = QMSGMPProduct related QualityDocumented evidenceProcessA set of interrelated or interacting
46、 activities which transforms inputs into outputs. QMSIncluding time-axisIncluding interconnectionsGMP +工艺工艺 = QMSGMP与质量相关的产品与质量相关的产品文件化的证据文件化的证据工艺 一系列相关的或相互作用的，把输入转一系列相关的或相互作用的，把输入转化为产出的活动化为产出的活动QMS包括时间轴包括时间轴包括相互联络包括相互联络General ConsiderationsPIC GMP Chapter 1: Quality Management “. To achieve the qu
47、ality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored.” QMS概论概论PIC GMP 第第 1章章: 质量管理质量管理 “要达到质量目标必须有广泛设计的
48、和正确实施的要达到质量目标必须有广泛设计的和正确实施的质质量保证系统，量保证系统， 加之以加之以GMP规范并如此规范并如此质量控制。质量控制。应该完全文件化应该完全文件化并有效监督并有效监督。” QMSGeneral ConsiderationsIntroduction ISO 9001: “It is emphasized that the quality system requirements specified in this International Standard are complementary - not alternative - to the technical (pr
49、oduct) specified requirements.”GMP概论ISO 9001 介绍介绍: “它被强调, 质量系统要求被指定在这国际标准是补全的- 不能选择- 对技术(产品) 规格的要求。”GMPComparison QMS / GMPGMPGMPhighlowDegree of DetailValidity within the companyQMSQMSGLPGLPGCPGCP比较比较 QMS / GMPGMPGMP高高低低程度详述程度详述公司内部的有效性公司内部的有效性QMSQMSGLPGLPGCPGCPCEFIC ActivitiesDocument combining IS
50、O and GMP RequirementsCEFICWorking Party on GMP and Quality AssuranceQualityManagementSystemfor Active PharmaceuticalIngredients Manufacturersintegrating GMP into ISO 9001December 1997CEFIC 活动 ISO 和和 GMP 要求的文件要求的文件 的组合的组合CEFICWorking Party on GMP and Quality AssuranceQualityManagementSystemfor Activ
51、e PharmaceuticalIngredients Manufacturersintegrating GMP into ISO 9001December 19972.1 PrinciplesQuality should be the responsibility of all involved in manuf.Each manufacturer should establish, document, and implement an effective QMSystem reflecting the Quality Policy supported by upper management
52、.QMS should cover organisational structure, procedures, processes and resources, activities to ensure fulfillment of specifications of APIs.There should be a quality unit (QU) independent of production that fulfills QA and QC responsibilities.Persons authorised to release intermediates and APIs shou
53、ld be specified. All quality related activities to be recorded at the time they are performed.2.1 原则质量，应当成为所有涉及制造过程的职责每个生产商应当建立，成文，执行有效的QMS，来体现对上级管理层的质量方针QMS 应该覆盖组织结构、流程、工艺和资源, 活动来保证APIs 的规格的履行应该有独立的质量部门来履行QA和QC的职责应该指定人员批准中间体和原料药的放行所有与质量相关的活动要在他们实施时及时记录2.1 PrinciplesAny deviation from established pr
54、ocedures should be documented and explained, critical deviations should be investigated, and the investigation and its conclusions should be documented.Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects
55、 and related actions (complaints, recalls, regulatory actions, etc.)No materials should be released or used before completion of evaluation by QU, but exeptions possible under quarantine“ (SOP!).Official inspectors will check these issues according to AM!2.1 原则任何与已建立程序的偏差应当形成文档，作出解释，关键的偏差应当被调查，形成调查和
56、结论的文档应该存在这样的规程，能及时地通知负责的管理层来规范：检查、严重的GMP 不足、产品缺陷和相关行动(投诉、招回、规范行动, 等。)在质量部门的评估没有完成前，不得对物料放行和使用，但可能的留验例外(SOP!).官方的检查员将依据AM检查这些签发文件!Quality Management System, Elements acc. to DIN ISO 9001Responsibility of Senior Management Quality Management System Controlling of Contracts Steering of Design Steering
57、of Documents and Data Materials Management Steering of Products supplied by a Customer Identification and Traceability of Products Steering of Processes Testing Control of Testing Agents Status of Testing Steering of deficient Products Correction and Prevention Measures Handling, Storage, Packaging,
58、 Preservation and Distribution Steering of Quality Records and Documents Internal Quality Audits (Self Inspection) Training Maintenance Statistical Methods质量管理系统质量管理系统, 根据根据DIN ISO 9001的原理的原理高级管理层的责任高级管理层的责任 质量管理系统质量管理系统 合同控制合同控制 设计操控设计操控 文件和数据的控制文件和数据的控制 物料管理物料管理 对客户提供产品的操控对客户提供产品的操控 产品的识别和追踪产品的识别和
59、追踪 工艺操控工艺操控 检测检测 委托检测的控制委托检测的控制 检测状态检测状态 缺陷产品的操控缺陷产品的操控 纠正与预防措施纠正与预防措施 操作，储存，包装，保存和分发操作，储存，包装，保存和分发 质量记录和文件的操控质量记录和文件的操控 内部质量审计（自检）内部质量审计（自检） 培训培训 维护维护 统计方法统计方法Requirements according to DIN EN ISO 90019001 / 4.10 Testing Final Testing according to QM protocol or written testing procedure previous ch
60、ecks with results within acceptance criteria performed no distribution before having conducted all defined tests and approval of data and documentsTesting RecordsEvidence that quality testing according to defined acceptance criteria existsSign/signature Released“ of responsible person/unit依据 DIN EN
61、ISO 9001的要求9001 / 4.10 检测检测 最终检测 根据质量管理方案或书面的程序 用符合标准的结果预先检查 在进行全部规定的检测，数据获批准并记录前，不可销售产品检测记录根据规定的接受标准进行质量检测的证据负责人员/部门签名放行EC GMP Guideline Quality Management System PrincipleThe holder of a manufacturing authorization must ensure that medicinal products -fit for their intended use (effectiveness, saf
62、ety, purity)-comply with the requirements of the marketing authorization-are no risk for patients due to inadequate safety, quality or efficacy.The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by-staff in different depa
63、rtments at all levels-the companys suppliers-the distributorsTo achieve the quality objective reliably there must be acomprehensively designed and correctly implemented system ofQuality Assurance incorporating GMP and thus Quality Control.QA should be -fully documented and its effectiveness monitore
64、d- adequately resourced with competent personnel, sufficient premises, equipment and facilities.EC GMP 指南 QMS原理原理制造许可证的持有人必须保证医药产品-符合既定的使用 (效用，安全，纯度)-遵守市场许可证的要求-对病人没有风险，由于不充分的安全，质量或效用质量宗旨的达到是高级管理层的责任质量宗旨的达到是高级管理层的责任并要求以下的参与和承诺：-不同部门，不同层次的职员-公司的供应商-分销商为了可靠的达到质量宗旨，必须要有一个混和了GMP和质量控制的广泛设计和正确实施的质量保证系统。QA
65、 应当-有充分的文件和有效的监督-有足够的可以胜任的人员，办公室，设备和设施Quality Management SystemCost Accountingnach British Standard质量管理系统费费用用单单nach British StandardEC GMP Guideline Documentation PrincipleGood documentation constitutes an essential part of the QA System.Clearly written documentation prevents errors from spoken comm
66、unication-permits tracing of batch history-facilitates the search for any mistakes in case of complaints-hands over experience-facilitates training of newly recruited employees and deputies of employees-verifies the knowledge of employees-ensures that compliance with marketing authorization dossier
67、can be controlled easily-ensures unchanged constant quality.Specifications, Manufacturing Formulae and Instructions, Procedures,and Records must be free from errors and available in writing.The legibility of documents is of paramount importance.EC GMP 指南文件 原理原理好的文件构成了好的文件构成了QA系统的一个要点部分系统的一个要点部分.清晰的书
68、面文件预防了口头交流的错误-可以进行批历史的追踪-帮助在投诉事件中查找错误-移交经验-帮助培训新员工和新代表-检验员工知识-确保遵照市场许可证的卷宗能容易的控制-确保一成不变的质量规格，制造的规则和指令，程序和记录必须允许错误并书面提供规格，制造的规则和指令，程序和记录必须允许错误并书面提供.文件的易识别是最重要的2.2 Responsibilities of the QU(s)QU should be involved in all quality-related mattersQU should review and approve all quality-rel. DocumentsTh
69、e main responsibilities of the QU should not be delegated. These responsibilities should be described in writing.Responsible To be done by the Q-Unit2.2 质量部门（QU）的责任QU应当包括所有与质量相关的因素QU应当审核，批准所有与质量相关的文件 QU的职责不应当是委任的，应当有书面描述职责职责 由由QU完成完成2.22 Main Responsibilities of QUReleasing or rejecting APIs, interm
70、ediates.Establishing a system to release or reject raw materials.Reviewing batch production, lab control records,. validation protocols and reportsMaking sure that critical deviations/OOS are investigated, internal audits are performed, complaints are investigated and resolved, effective systems are
71、 used for maintaining and calibrating critical equipment, stability data to support retest, expiry dates, storage conditions are available.Approving specifications, master production instructions, procedures impacting quality of intermediates/APIs, contract manufacturer/labs, changes with impact to
72、quality.Performing product quality reviews.2.22 QU的主要职责放行或退回放行或退回原料药，中间体.建立建立 放行或退回原料制度.审核审核 批产品, 实验室控制记录,. 验证方案和报告确认确认 关键偏差/OOS的调查，内审的实施，投诉的调查和解决，有效的用于设备维护和校验的系统，提供支持复测，有效期，贮存条件的稳定性数据批准批准 规格，主生产指令，影响中间体/原料药的程序，合同生产商/实验室，影响质量的变化实施产品质量回顾实施产品质量回顾2.3 Responsibility for Production ActivitiesPreparing, r
73、eviewing, approving and distributing manufacturing instructions (according to SOP).Producing intermediates/APIs acc. to preapproved instructions.Reviewing all batch records; complete, signed?Making sure that production deviations are reported, evaluated, critical investigated, conclusions recorded!
74、.production facilities are clean, calibrations are performed and records kept, validation protocols and reports are reviewed and approved, .new/modified facilities and equipment are qualified.Oversee change control procedure!2.3 生产活动的职责（根据SOP）准备，检查，批准和分发制造指令根据预先批准的指令生产中间体/原料药检查所有的批记录；完全了，签字了？确认产品的偏差
75、被报告，被评价，关键点被调查，结论被记录! .生产设施清洁，校验实施并留存记录，验证方案和报告被审核批准 .新的/更改的设施和设备被确认监督变化控制程序!2.4 Internal Audits (Self Inspection) Compliance with the principles of GMP for APIs Regular internal audits to be performed (schedule!) Findings and corrective actions listed, recorded, followed-up Documentation Attention
76、of management Agreed actions completed timely (responsibility + time schedule) Inspectors will check according to Aide Memoire!2.4 内审 (自检) 按照GMP对原料药的原则 实施定期内审 (计划表!) 发现和纠正表，记录，追查 文件 管理的注意 同意行为及时完成(职责 + 时间表) 检查员将根据备忘录检查检查员将根据备忘录检查!2.5 Annual Product Quality Review .to be conducted to show consisitenc
77、y of the process.Critical in-process control and API test resultsCritical reaction parameters to be evaluated (Dev. Report!)Batches that failed to meet specificationsCritical deviations, investigations, conclusions (impact?)Any changes to the processes, analytical methods, specs, equipment,.Quality
78、related returns, complaints and recallsAdequacy of corrective actions (permanent change?)Results of the review should be evaluated, corrections, changes, revalidation, approvals needed?For inspectors it is very easy to check your QMS andproduct quality!2.5 年度产品质量回顾 .被指导来表明工艺的一贯性被指导来表明工艺的一贯性关键的工序间控制和
79、原料药检测结果评估关键的反应参数 (设计报告!)不合格的批号关键的偏差，调查，结论（影响？）任何变化：工艺，分析方法，规格，设备质量相关的反馈，投诉，召回适当的纠正措施 (一成不变?)回顾的结果应当被评估，校正，更换，再验证，需要批准？回顾的结果应当被评估，校正，更换，再验证，需要批准？检查员们能非常容易地检查你们的检查员们能非常容易地检查你们的QMS（质量管理系统）和质量管理系统）和产品质量产品质量!And what about training?培训是什么?3 Personnel3.1Personnel QualificationThere should be an adequate nu
80、mber of personnel qualified by appropriate education, training and/or experienceto perform and supervise the manufacture of intermediates and APIs.The responsibilities of all personnel engaged in the manufactureof intermediates and APIs should be specified in writing.Training should be regularly con
81、ducted by qualified individualsand should cover at a minimum, the particular operations thatthe employee performs and GMP as it relates to theemployees functions. Records of training should be maintained. Training should be periodically assessed.3 人员人员3.1人员资质应该有足够数量的经过适当教育，培训和/或经验的有资质的人员来实施和监督中间体和原料
82、药的制造所有在中间体和原料药制造中从事活动的人员的职责应当有书面的说明培训应当由有资格的个人来进行定期的指导，应当至少包含员工履行特别的操作，GMP对于员工的相关职能 培训记录应当被保存培训记录应当被保存 培训应当被定期评定培训应当被定期评定3.1 Personnel Qualification TrainingObjectives of GMP Training Define and explain what GMP means How to transfer GMP into daily practice Generate consciousness for GMP Improve qua
83、lification of personnel Motivate personnel Increase safety of APIs/ drug products3.1 人员资质 培训GMP 培训的目标培训的目标 定义和说明GMP意味什么 如何将GMP调入日常作业 产生GMP意识 提高人员资质 人员促动 增加原料药/药物的安全3.1 Personnel QualificationTraining of PersonnelContents and definitions of a training program Wherefore? Define training issues and obj
84、ectives!Who should attend? Name and invite!By whom? Qualified trainer/consultant!How often? Define a program/year and employee!How long and where?What items of GMP/SOPs? Distribute documents!3.1 人员资质人员培训一份培训纲要的规定和内容一份培训纲要的规定和内容 原因? 规定培训的发布和目标!参加者? 姓名和邀请!谁作培训? 有资质的培训人/顾问!多频繁? 规定一个计划/年和雇员!多长时间，哪里?GMP/
85、SOPs的什么项目? 分发文件!3.1 Personnel Qualification - Training of Personnel Training records should include the following: Date of training Area of production, quality control, etc. Objectives Name of teacher(s) Name of participants Signatures of participants Reason for training Initiator/responsible person
86、 for training How to maintaine/archive the training record3.1 人员资质 人员培训 培训记录培训记录应当包括以下内容应当包括以下内容: 培训日期 范围：产品，质量控制，等等 目标 老师的名字 参加人的名字 参加人的签名 培训原因 培训的提倡人/责任人 如何保存/存档培训记录 Training of Personnel Documentation of information given to newly recruited personnel for production:Information given bysupervisor
87、/ superiour aboutWorking hours, break times, How to behave in case of absence Manual for personnelSafety instructionsInformation about hygiene, SOPs, log-books, clothing, hands washing GMP according to a checklistWaste discarding packaging materialsdrug productswaste containers/bagsEnvironmentHow to
88、 handle solvents and cleaning agentsInformation about Companys drug products Special manufacturingHealth condition In case of any change superiour to be informedIntroduction to Head of Production and colleages during demonstration of future working place Head of Production ColleagesSignature of trai
89、ner:Employees signature. . .Date. . .aus: Haffner et al. - Schulung von MitarbeiternPharm.Ind. 56, Nr. 8 (1994) 人员培训 给为生产招进的新员工的资料文件：资料来自于检查员 / 上级工作时间,休息时间, 如何处理缺勤情况人员手册安全指令卫生，SOPs，记录等信息工作簿，衣服，手的清洗 GMP 清单废弃物的抛弃 包装材料药品废弃容器/袋子环境如何处理溶剂，清洗剂关于公司制造的药品的信息健康情况 任何变化需通知上级在未来工作地点的示范期间介绍生产的领导和同事 生产的领导 同事培训人签字:员
90、工签字. . .日期. . .aus: Haffner et al. - Schulung von MitarbeiternPharm.Ind. 56, Nr. 8 (1994)3.1 Training of PersonnelIntroduction to and information about working place;important SOPs to be read, understood and followed:Practical learning by doingWorking place/area: .from: .until: .Documentsreceived:.S
91、OP.Read and understood:SOP.Read and understood:Employees signature .Datenach:Haffner et al. - Schulung von MitarbeiternPharm.Ind. 56, Nr. 8 (1994)3.1 人员培训通知介绍有关工作场所；需要阅读并理解的重要SOPs：动手的手的实际学学习工作场所/区域: .从: .至: .收到的文件:.SOP.阅读并理解:SOP.阅读并理解:员工工签字字 .日期日期nach:Haffner et al. - Schulung von MitarbeiternPharm.
92、Ind. 56, Nr. 8 (1994)3.1 Training of PersonnelHeard is not yet understood;Understood is not yet agreed;Agreed is not yet applied;Applied is not yet permanently followed.(Konrad Lorenz)The best manager doesnt teach his employeeshow to think but that they have to think. (D. Goeudevert)3.1 人员培训听到不等于理解;
93、理解不等于承认;承认不等于实施；实施不等于一成不变.(Konrad Lorenz)最好的经理不是去教员工怎么思考而是让他们必须思考 (D. Goeudevert) 3.2 Personnel Hygiene Personnel should practice good sanitation and health habits. Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be c
94、hanged when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination. Personnel should avoid direct contact with intermediates and APIs. Smoking, eating, drinking, chewing and the stor
95、age of food should be restricted to certain designated areas separate from the manufacturing areas. 3.2 人员卫生 人员应当实践良好的环境卫生和健康习惯 人员应当在他们从事制造活动时穿合适的干净衣服并且衣服应该适时更换。 附加的保护配件，例如：头，脸，手和袖筒如有必要应该穿戴以防止中间体和原料药的污染 人员应当避免与中间体，原料药的直接接触。 吸烟，吃，喝，嚼等行为和存放食物应当限制在指定的区域并与制造区分开3.2 Personnel HygienePersonnel suffering fr
96、om an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs.Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions
97、 should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the persons inclusion would not jeopardize the safety or quality of the APIs.3.3 Consultants .should have suffi
98、cient education, training, experienceRecords should be kept stating name, address, qualifications, and type of service provided.3.2 人员卫生有传染病或在身体的暴露部分有开放伤口的员工不应当从事会对原料药的质量会造成危害的活动任何人在任何时候（无论是医学检查或上级检查）表现出生病或有开放伤口，应当避免会对原料药的质量会造成危害的活动直到情况好转或有资质的医生作出该员工不含有会危害原料药质量和安全的结论3.3 顾问 .应当有足够的教育，培训和经验档案应当有正式姓名，地
99、址，资质和提供服务的类型4 Buildings and Facilities5 Process Equipment4.1.Design and Construction4.2.Utilities4.3.Water4.4.Containment4.5.Lightning4.6.Sewage and Refuse4.7.Sanitation and Maintenance5.1.Design and Construction5.2.Equipment Maintenance andCleaning5.3.Calibration5.4.Computerized Systems4 厂房和设施5 工艺设
100、备4.1.设计和建筑设计和建筑4.2.公共设施公共设施4.3.水水4.4.隔离防护隔离防护4.5.灯光灯光4.6.污水和垃圾污水和垃圾4.7.卫生设施和维护保养卫生设施和维护保养5.1.设计和建筑设计和建筑5.2.设备维护与清洗设备维护与清洗5.3.校验校验5.4.计算机系统计算机系统Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance,
101、and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleani
102、ng, sanitization (where appropriate), and maintenance . 4 Buildings and Facilities5 Process Equipment“在中间体和原料药制造中所使用的厂房和设施应当在被在中间体和原料药制造中所使用的厂房和设施应当在被固定，设计和建造时考虑到设施容易被清洗，维护和易固定，设计和建造时考虑到设施容易被清洗，维护和易于生产操作。设施也应该考虑使潜在的污染最小化于生产操作。设施也应该考虑使潜在的污染最小化“在中间体和原料药制造中使用的设备应该是适当设计和充分在中间体和原料药制造中使用的设备应该是适当设计和充分尺寸，适当
103、的位于它想要使用，清洗，卫生处理（适当的地方）尺寸，适当的位于它想要使用，清洗，卫生处理（适当的地方）和维护和维护4 厂房与设施5 工艺设备GMP starts with the design of facilities ! DQ-IQ-OQ-PQ!There is no room classification for (non sterile) APIs ! Appropriate filtration of incoming air!Closed systems are the preferred option !Dedicated production areas for penicil
104、lins, cephalosporins, certain steroids or cytotoxic anti-cancer agents !No highly toxic non-pharmaceutical materials (herbicides, pesticides) together with an API !Defined areas for receipt, identification, quarantine, sampling, storage, production, packing and labelling, laboratories !Alternative :
105、 Other Control system.Statements - RequirementsPrevent mix-ups or cross contamination!GMP 从设施的设计开始 ! DQ-IQ-OQ-PQ!对（非无菌）原料药没有房间的分级! 适当的进气过滤!密闭系统是首选!专门的生产区域：青霉素，头孢菌素，某些类固醇或细胞毒素的抗肿瘤媒介!高毒性的非药用物料（除草剂，农药）不能与原料药在一起!明确用于接收，鉴别，隔离，取样，贮存，生产，包装和贴标签，实验室的区域!供替代的选择供替代的选择 : 其它的控制系统其它的控制系统.说明说明 要求要求预防混淆或交叉污染预防混淆或交叉污
106、染!Adequate space for equipment !Closed systems can be outdoors !Plant layout to prevent mix-ups and contamination !Adequate (acc. to employees) washing/changing facilities and toilets ! Entering the GMP area via sit-over bench! Adequate lightning in all areas !Separated areas for production and labo
107、ratories !Appropriate measures for recirculated air ! (Recorded controls with signatures or documentation with Facility Management SystemHigher standard (GMP) in areas where API is exposed to environment !Statements - Requirements为设备留足够的空间!密闭系统可以在户外!车间的布局要预防混淆和污染!（参照员工数量）有足够的清洗/更换设施和厕所!通过坐高的长凳进入GMP区
108、域! 在所有区域有足够的照明!生产和实验室区域分开!适当测量再循环空气! (有署名控制的记录或有设施管理系统文件在原料药可扩散到环境的区域有更高的标准 (GMP)!说明说明 要求要求4.2 UtilitiesAll utilities that could impact on product quality should be qualified, monitored, maintained and kept within set limits (SOPs).Steam, gases, compressed air, heating, ventilation (room air pressur
109、e), air conditioning (humidity, temperature), filter systems (microbiological controls), dust extractors.Special attention to control recirculated air!Permanently installed pipework: appropriately identified!Drains should be designed to prevent back-siphonage. (air break or other suitable device)Min
110、imize risks of contamination and cross-contamination4.2 公共设施所有能影响产品质量的公共设施都应当被确认，监控，维护和保持在设定限度内 (SOPs)蒸汽，气体，压缩空气，供暖，通风(房间气压)，空调(湿度，温度)，过滤系统(微生物控制)，集尘器特别注意控制再循环空气!永久性安装的管道：适当标识!排水应当设计成防倒吸的（气隔或其他适用装置）污染和交叉污染的风险最低化 Questiones to ask about the HVAC Which filters are used ? How are they controlled? Is th
111、ere a maintenance and calibration procedure How are the air filters changed (and cleaned)?Where there is no air recirculation : Where is the air intake, the air outlet and the preferred wind direction ?How does the pipework look inside ?How is the pressure difference between rooms ?Where do we need
112、a separate ventilation system ?HVAC = Heating, Ventilation, Air Condition有关有关 HVAC 的问题的问题使用那种过滤器?他们如何受控? 有维护和校验程序？如何更换（和清洗）空气过滤器?哪里没有再循环空气: 在进气口，排气口和首选直流风的地方？怎么看管道的里面 ?不同房间的压力差是多少 ?哪里我们需要有一套独立的通风系统 ?HVAC = Heating（加热）, Ventilation（通风）, Air Condition（空调） Engineering Guidewww.ispe.orgInternationalSoci
113、etyPharmaceuticalEngineering工程指南工程指南www.ispe.orgInternationalSocietyPharmaceuticalEngineeringLevel IIIcontrolledLevel IIprotectedLevel Ino requirementscriticalityproduct handlingopenclosedNon criticalcriticalISPE modelLevel Ino requirements级别级别 III受控受控级别级别 II保护保护级别级别 I不作要求不作要求重要性重要性开开放放密闭密闭非关键非关键关键关
114、键ISPE 模型模型级别级别 I不作要求不作要求产产品品处处理理Critical StepsLast filtration / isolation, purificationFinal drying, milling, sieving, coatingFinal packing of the APICritical steps can be also in earlier stages !Steps after which a process failure or contamination with other substances can not be compensated any mo
115、re !关键步骤关键步骤最后的过滤 / 分离, 提纯最后的干燥, 粉碎, 筛分, 包衣最后的原料药包装关键步骤也会在稍早的阶段!在工艺失败或被其他物质污染后，不能采在工艺失败或被其他物质污染后，不能采取任何补偿的步骤取任何补偿的步骤!Requirements for level I (general)Well maintained chemical plantOrderly and cleanEquipment and pipework identified and labelledLightning to facilitate operations, cleaning and mainten
116、anceWaste containers and pipes clearly labelledNormal working dress级别级别 I 的要求的要求(常规常规)良好维护的化学品厂房整齐干净设备和管道被标识并有标签照明有利于操作，清洁和维护废弃的容器和管子被明显标明正常的工作穿着Area where measures have been taken to prevent contaminationNormally no air recirculationControlled direction of air flowSeparate cubiclesSeparation of uni
117、tsLocal dust extractionRequirements for level II (protected)测量区域采取防止污染的措施正常情况没有空气再循环受控的气流方向分隔的小间部件的隔离局部集尘器级别级别 II 的要求的要求 (保护保护)Area with defined and controlled room standardsStandard must be adequate to prevent any contamination of the productMinimum F9 air filter, better HEPA filterCleaning and mon
118、itoring schedule (SOPs!)Restricted accessSOPs should be in place for the use of rodenticides, insecticides, fungicides, fumigating agents, cleaning and sanitizing agents to prevent contamination of equipment, materials, APIs.Requirements for level III (controlled)确定的并且符合受控的 空间标准的 区域标准必须足以防止任何的产品污染最小
119、F9过滤器,中效过滤器清洗和监测时间表 (SOPs!)进入限制SOPs 应当放在使用灭鼠剂，杀虫剂，防霉剂，熏蒸剂，清洗和消毒剂的地方，以防止设备，物料，原料药的污染。级别级别 III 的要求的要求 (受控受控)Easy to clean:Smooth surface, stainless steel.No cracks, no joints.Minimum equipment in room.Access controlDress codeDocumented cleaning and monitoring program.Requirements for level III (contro
120、lled)易清洗:不锈钢光滑表面没有裂缝，没有接缝房间内最少的设备进入控制服装编码归档清洗和监测程序级别级别 III 的要求的要求 (受控受控)Options for level II (protected) reactor 1reactor 2filtercristallizer centrifugeair intake (filtered)exhaust 级别级别 II 的选择的选择 (保护保护) 反应釜反应釜 1反应釜反应釜 2过滤器过滤器结晶釜结晶釜离心机离心机进风进风 (过滤过滤)排风排风Options for level II and IIIreactorair intake (f
121、iltered)exhaustcharge hole级别级别 II 和和 III的选择的选择反应釜反应釜进风进风 (过滤过滤)排风卸料口卸料口Options for level III (controlled)1.Whole room as clean room (GMP)e.g. final packing of APIeasy to handle, clear standarddifficult to fit in old plantshigh investment and revenue cost2.Part of room as clean roome.g. charging, see
122、ding, sampling, final packingcheap option, but oftern extra ventilation system necessary级别级别 III的选择的选择 (受控受控)1.整个房间作为“洁净室”(GMP)例如最终的原料药包装方便处理，洁净标准很难适合旧厂房高投资和回报2.部分房间作为“洁净室”例如装料，投晶种，取样，最后包装是便宜的选择，但经常需要额外的通风系统Examples for Level III : Open Laminar Air FlowHEPA-FILTERnormal plant areaair intakeclean roo
123、mPRODUCT级别级别 III 的例子的例子: 开放式层流气流开放式层流气流高效高效过滤器过滤器普通厂房区进风进风洁净室产品Examples for Level III : clean room with positive pressurenormal plant areaclean room(packing)dp = 10 - 12 PAdp = 12 - 15 PAHEPA-FILTERair intaketransitcorridorClean corridor principle级别级别 III 的例子的例子: 带正压的带正压的“洁净室洁净室”普通厂房区洁净室洁净室(包装包装)dp
124、= 10 - 12 PAdp = 12 - 15 PA高效过滤器进风进风输送输送走廊走廊洁净走廊的原理4.3 WaterWater used in the manufacture of APIs should be demonstated to be suitable for its intended use.Minimum : Drinking water meeting WHO guidelines.Treated water (DI water, purified water) :Process to be validated, monitored, action limits in p
125、lace.Specification of chemical/physical attributes, microbial counts, objectionable organisms, and endotoxins when required.4.3 水“在原料药制造中使用的水应当被证明适用于它的用途”最小值：饮用水符合WHO的指南治疗用水 (蒸馏水, 纯化水) :工艺验证，监测，现场受限行为化学/物理规格，属性，微生物总数，控制菌，内毒素（有时要求）5.2 Equipment Maintenance and CleaningSchedules and procedures should
126、be in place for the preventative maintenance of equipment, responsibilities defined!Detailed cleaning procedures should be established plus release for use!Cleaning procedures should be validated for GMP steps.Inspection for cleanliness immediately before use. Visually clean criterion!Cleaning valid
127、ation has become an critical issue also for API manufacturers!5.2 设备维护和清洁时间表和程序应当在现场，用于设备的预防性维护，规定职责!应当建立详细的清洗程序，加上使用放行!对GMP步骤，应当验证清洗程序使用前及时清洁检查。目测清洁标准!清洗验证对于原料药制造已经成为一种关键问题!5.3 Calibration - Regulatory AspectsEC - Guide to Good Manufacturing Practice for Medicinal Products:Measuring, weighing, reco
128、rding and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate record of such test should be maintained“ (Chapter 3 Premises and Equipment“, Section 3.41)ISPE-Guide (Vol. 1, Bulk Pharmaceutical Chemicals)The calibration of critical instruments shou
129、ld follow a regular program which provides evidence of consistently acceptable performance. Calibration should follow approved procedures and the results should be documented. All calibration should be traceable to certified standards“ (Chapter 9.4 Calibration)5.3 校验 药政方面EC - GMP医药产品指南：医药产品指南：测量，称重，
130、记录和控制设备应当按照设定的时间间隔用适当的方测量，称重，记录和控制设备应当按照设定的时间间隔用适当的方法检验。应当保存足够的这样的测试记录法检验。应当保存足够的这样的测试记录 “ (第3章 房屋和设备“, 3.41)ISPE-指南指南 (Vol. 1, 化学原料药化学原料药)关键仪器的检验应当遵从正规的程序。该程序提供了可接受的得关键仪器的检验应当遵从正规的程序。该程序提供了可接受的得到一致证据的过程。检验应当遵从批准的程序并将结果记录保存。到一致证据的过程。检验应当遵从批准的程序并将结果记录保存。所有的校验应当能追踪到检定的标准所有的校验应当能追踪到检定的标准 “ (第9.4章 校验)5.
131、3 Calibration - Regulatory AspectsICH - Q7A GMP for APIsControl, weighing measuring, monitoring and test equipment that is critical for assuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule . The current calibration status of c
132、ritical equipment should be known and verifiable .“ 5.3校验 药政方面针对针对 APIs的的 ICH - Q7A GMP 控制，称重，测量，监测和检测仪器对确保中间体或控制，称重，测量，监测和检测仪器对确保中间体或原料药的质量是关键的，应当按照书面程序和时间表进原料药的质量是关键的，应当按照书面程序和时间表进行校验行校验.应当了解并核实关键设备当前的校验状态应当了解并核实关键设备当前的校验状态.“ Calibration - Regulatory AspectsCentral Requirements in GMP-Guidelines:M
133、easuring instruments. . must be calibrated . within suitable intervals . with suitable test equipment . following defined procedures Calibration activities must be documented. . the documentation has to be archived . traceability must be established校验 药政方面GMP 指南中的中心要求指南中的中心要求:测量仪器. . 必须校验 . 在适当间隔内 .
134、 有合适的仪器 . 遵循规定的程序 校验活动必须文件化. . 文件必须被存档 . 必须建立可追溯Calibration BasicsCalibration:Demonstration that a particular measuring device produces results within specified limits by comparison with those, produced by reference standard device over an appropriate range of measurements.Adjusting:Reduction of dev
135、iation to the smallest possible value with support from references that may be applied to optimise accuracy.校验基础校验校验:证明某个特定的测量仪器产生的结果与参考的标准设备在测量的一个适当的测量范围产生的结果对比，结果在指定的范围内调准调准:参考那些应用后可以优化精度的支持性的文献，将偏差减少到最小的可能值Calibration BasicsDo all instruments in the production process have to be calibrated?No, on
136、ly those instruments which are related to the product-/process quality and safety have to be calibrated Critical instrumentsCritical instruments are identified during Risk Analysis and Design Qualification.校验基础校验校验:证明某个特定的测量仪器产生的结果与参考的标准设备在测量的一个适当的测量范围产生的结果对比，结果在指定的范围内调准调准:参考那些应用后可以优化精度的支持性的文献，将偏差减少
137、到最小的可能值Elements of CalibrationMaster-SOPCalibration SOPCalibrationProtocolCal.PlanCalibration-Label LogbookCal.RecordCalibrationWorkTesting EquipmentTrained EmployeesElements of Calibration 校验要素主主-SOP校验校验SOP校验方案校验方案校验计划校验计划校验标签校验标签 日志日志校验记录校验记录校验工作校验工作测试仪器测试仪器受训练的员工受训练的员工校验要素校验要素Elements of Calibrat
138、ionMaster-SOP should contain:Definitions Responsibilities Information concerning the structure of Calibration-SOPsDescription of equipment to be calibrated (List of all)Documentation ProceduresControl over Reference InstrumentsHow to define Calibration IntervalsGuidelines, Standards and References校验
139、要素主主-SOP 应当包括应当包括:定义 职责 关于校验结构的信息-SOPs需校验的仪器的描述 (所有都列出)文件程序控制结束参考仪器如何定义检验间隔指南，标准和文献CalibrationExample of an instrument list :校验校验仪器列表样张 :Elements of CalibrationCalibration-SOP should contain:Detailed description of calibration procedure(s)Reference standard to be used and reference conditionsDetaile
140、d description of instrument/measuring deviceEstimation of uncertainty of measured dataInterval of calibration cycleInstructions for the documentation of calibration(s) -Calibration records (template as enclosure) -Records to be made in the logbook -Calibration Certificates -Calibration labels (templ
141、ate as enclosure)校验要素校验校验SOP应当包括应当包括:校验程序的详细描述使用的参考标准和参考条件仪器/测量装置的详细描述测量数据的不确定的估计校验周期的间隔校验文件 -校验记录 (模板见附件) -日志中的记录 -校验证书 -校验标签 (模板见附件)Elements of CalibrationCalibration records should contain:Identification of the instrument that has been calibrated (ID-No)Who performed the calibration?Date of the c
142、alibrationIdentification of the reference instrument that has been usedActual and specified conditionsNext calibration date (Re-calibration)Calibration label attached to equipment/instrumentElements of Calibration校验记录应当包括校验记录应当包括:已校验仪器的标注 (ID号码)谁来执行校验?校验日期已使用的参考仪器的标注实际的指明的条件下次的检验日期(再校验)校验标签贴在设备/仪器上E
143、lements of CalibrationCalibration LabelsIdentification (calibration date, date of next calibration, signature of test person, ID No. of instrument, .)Calibration status (e.g. calibrated, not under calibration, blocked, .) different label coloursSummary-Labels for complex systemsLabels should be robu
144、st and resistant to product and cleaning- / disinfecting agentsCalibration Date_Performed by_Re-calibration (Date)_ Ident No. _XY Pharma校验要素校验标签校验标签鉴别 (校验日期, 下次校验日期, 试验人员签名, 仪器ID号, .)检验状态 (例如：已校, 未校,被堵, .) 不同标签颜色复杂系统的标签摘要标签应当耐用，能抵抗产品的清洗剂/消毒剂校验校验 日期日期_执行人执行人_再校验再校验 (日期日期)_ ID No. _XY 药业Calibration La
145、bel ?Status is for everybody visibleProduction staff able to verify status of instrument.Durability in chemical plant ?Time consuming.Invitation for inspector !In doubt always refer to the calibration report ! This should be documented in the SOP.校验标签校验标签 ?每个人可见的状态生产的员工能够查证仪器的状态在化学品工厂耐用吗?消耗的时间接受检查接受
146、检查 !总是怀疑的看待校验报告! 标签应当在SOP中记录成文。Elements of CalibrationRecording in the logbookDate/time Observation/ ActivitySignature Action taken(if necessary)Signature / Date Approval(Signature/Date)CalibrationSensor ID 0815Record098/12 _41/2000Adjustment wasnecessary校验要素日志中的记录Date/time Observation/ ActivitySign
147、ature Action taken(if necessary)Signature / Date Approval(Signature/Date)CalibrationSensor ID 0815Record098/12 _41/2000Adjustment wasnecessaryElements of CalibrationCalibration-PlanSchedule of all calibration activities- by type of equipment- by production units/areas- .Print-out of calibration orde
148、rs and instructions Identification and follow-up of calibration activities Activities can be controlled by Commercial Software Calibration Data BaseGMP-compliant maintenance requires a Calibration Plan校验要素校验计划校验计划所有的校验活动时间表- 设备类型- 产品单元/区域- .校验命令和指令的打印输出 校验活动的识别和后续可用商业软件控制活动 校验数据基础GMP的维护保养要求有校验计划的维护保
149、养要求有校验计划Elements of CalibrationTrained employeesEmployees in charge of calibration work should have the training listed down below as a minimum:Staff should have a suitable general education (school/university/skilled worker) background and in addition: Training of all SOPs in context with calibrati
150、on Operating manuals of the instruments Documentation of Calibration/logbook recording General GMP and Change Control Procedures 校验要素受过培训的员工受过培训的员工负责校验工作的员工应当至少有下面所列的训练:员工应当有适当的常规教育（高中，大学，技术工人）背景并加上: 所有与校验关联的SOP的培训 仪器的操作手册 校验/日志记录的文件 常规的GMP和变化控制程序Qualification and CalibrationCalibration work is a pr
151、erequisite to get Qualifacation completedand to ensure GMP compliance!Qualification ProcessRisk Analysis DQIQOQQuestions concerning calibrationPQ- Calibrated according to SOP?- Calibration certificate / label present?- Measurement correctly installed?- Calibration certificate from manufacturer avail
152、able? - Possibility of calibration in the necessary accuracy and in the right range?- Which measuring instruments are quality related?EngineeringCom-missioningInstallationSet the calibrated statusRoutine production验证和校验校验工作是完全达到验证标准和确保符合GMP的前决条件！验证程序检验风险 DQIQOQ有关验证的问题PQ-是否根据SOP校验了？-是否提供校验证书/标签？-衡量是否
153、准确安装？- 是否有可能从制造商处得到证书？- 在必要的准确度和量程中校验的可能性？- 哪些测量的设备是与质量相关的？工程任务安装得到已校验的状态日常生产Calibration - Summary / ConclusionCalibration is a crucial part of the Quality Assurance ProcessCalibration plays an important role in all phases of a production lines life cycle Design Qualification ProductionSetting the a
154、ppropriate calibration focus reduces costs due to avoidance of rejected products caused by out of specification analytical results improves product quality and process reliability!校验-概述/结论校验是质量保证的关键部分校验是质量保证的关键部分在产品的生产周期中校验起着重要的作用设计 验证 生产确定适当的验证重点确定适当的验证重点 减少因不合格产品产生的化验费用 提高产品质量和工艺可靠性！5.4 Computeriz
155、ed SystemsGMP related computerized systems must be qualified and validated.Standard (qualified) software with reduced testing.Access control must be established.Must be covered by change control system.Backup system needed to prevent loss of data.SOP for operation, control, data storage and maintana
156、nce.Retrospektive validation of standard software possible if appropriate documentation is available.Where critical data are inserted manually : double checking needed by person or system.Manuel backup acceptable.5.4 5.4 计算机系统计算机系统相关的计算机系统必须验证相关的计算机系统必须验证 标准的（已验证的）软件标准的（已验证的）软件 必须建立准入控制必须建立准入控制 变更控制
157、系统必须涉及计算机系统变更控制系统必须涉及计算机系统 为防止数据丢失，需要系统备份为防止数据丢失，需要系统备份 建立操作，控制，数据储存和维护的建立操作，控制，数据储存和维护的SOPSOP如果有相关的文件，标准软件的回顾性验证是有必要的如果有相关的文件，标准软件的回顾性验证是有必要的如果关键的数据是人工输入的：另一个人的复核如果关键的数据是人工输入的：另一个人的复核或系统复核是需要的。或系统复核是需要的。PIC/S Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme PI 011-
158、1, 20 August 2003Good Practices for Computerised Systemsin regulated GXP“ EnvironmentsDr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergPIC/S 药物检查惯例药物检查合作 方案 PI 011-1, 2003年8月20日电脑系统的良好操作规范，GXP环境Dr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept Heidelber
159、gTable of ContentsPart One Preamble: Purpose, Scope, IntroductionPart Two Implementation of System-Implementation of computerised systems-The structure and functions of the computer system(s)-Planning and life-cycle management-Management and responsibilities-User Requirement Specifications (URS)-Fun
160、ctional Specifications (FS)-Suppliers, software developerss and quality management-Important QMS and software standarda attributes-Testing-Validation strategies and priorities-GAMP validation approach based on different categories of software products-Retrospective validation目录第一部分-前言：目的，范围，介绍第二部分-系
161、统实施-电脑系统的实施-电脑系统的结构和功能-计划和管理周期-管理和职责- 使用者说明书(URS) -功能说明(FS) -供应商，软件开发商和质量管理-重要的QMS 和软件的标准属性-检测-验证方针和优先次序-根据不同的软件产品的类别进行的GAMP验证方法 -回顾性验证Table of ContentsPart Three System Operation/Inspection/References-Change management-Change control and error report system-System security, including back-up-Data c
162、hanges audit trail/critical data entry-Electronic records and electronic signatures-Personnel-Inspection considerations-Checklists and aide memoires-References for relevant standards and GMP guides/codes-Suggested further reading-Glossary of terms-Abbreviations used in the document目录第三部分第三部分-系统操作系统操
163、作/检查检查/参考参考-变更管理-变更控制和错误报告系统-系统安全，包括备份-数据变更-检查追踪/关键数据输入-电子记录和电子签名-人员-检查考虑-检查清单和备忘录-相关标准的参考和GMP指南/代码-建议-词汇表-文件中的缩写6. Documentation and Records6.1 Documentation System and SpecificationsAll documents related to manufacture should be prepared, reviewed, approved and distributed according to written pro
164、cedures; in paper or electronic form.In case of electronic records for APIs intended for supply of the US, 21 CFR part 11 to be followed.Issuance, revision,superseding and withdrawl of all documents should be controlled with maintenance of revision histories. Detailed SOP with defined responsibiliti
165、es!Procedure for retaining all appropriate documents to be established and retention periods specified for: General production, analytical, control, distribution records; development history, scale-up, technical transfer, process validation reports; training records; equipment IQ,OQ,PQ reports.Reten
166、tion time: shelf life (expiry date) or Life Cycle +1 year; for APIs with retest dates: 3 years after complete distribution 6. 文件和记录6.1 文件系统和规格所有与制造有关的文件都应被准备，审核，批准，并按照规所有与制造有关的文件都应被准备，审核，批准，并按照规定的程序分发；以书面或电子形式。定的程序分发；以书面或电子形式。向美国提供原料药的电子记录，应遵循向美国提供原料药的电子记录，应遵循21 CFR 1121 CFR 11所有文件的分发，改版和撤回应该有维护所有文件
167、的分发，改版和撤回应该有维护修改历史的控制。修改历史的控制。SOPSOP应该详细规定责任！保留所有适当文应该详细规定责任！保留所有适当文件的程序应建立保留期限应明确：件的程序应建立保留期限应明确： 总的产品，分析方法的，控制，分发记录；开发历史，中试，技术转让，工艺验证报告；培训记录；设备IQ，OQ，PQ报告。留样时间：有效期或使用寿命+1年；原料药的复检期：在分销后3年6.1 Documentation System and PecificationsDuring retention period, documents should be readily availablewhere nee
168、ded and used! Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are use
169、d, suitable retrieval equipment and a means to produce a hard copy should be readily available. Could be critical in case of an inspection!6.1 Documentation System and Pecifications6.1 Documentation System and Pecificationsl l在文件的保留期间，文件应该在需要使用的地方方便找到！在文件的保留期间，文件应该在需要使用的地方方便找到！ 规格，指令，程序，和记录需要保留，包括原始
170、的和复制件，规格，指令，程序，和记录需要保留，包括原始的和复制件，例如照像复制本和缩影胶卷，缩微平片，或者其他的原始记录例如照像复制本和缩影胶卷，缩微平片，或者其他的原始记录的准确复制。当缩印技术，如缩影胶卷或电子记录被使用时，的准确复制。当缩印技术，如缩影胶卷或电子记录被使用时，适当的检索设备和能产生硬拷贝的方式应该适当的检索设备和能产生硬拷贝的方式应该便于找到。这个在检查中可能是很重要的！6.1 Documentation System and SpecificationsWhen entries are made in records, these should be made inde
171、libly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still readable.No pencil, no white out, no crossing out6.1 文件系统和规格当登录项是被记录的，这些记录在登录处应当登
172、录项是被记录的，这些记录在登录处应是不可去除的，直接在操作记录后，并且应是不可去除的，直接在操作记录后，并且应识别登录人。更改登录应该标明日期和签名识别登录人。更改登录应该标明日期和签名并且使原始的登录仍然可读。并且使原始的登录仍然可读。不可用铅笔，不可删去，不可划去不可用铅笔，不可删去，不可划去6.1 Documentation System and SpecificationSpecifications should be established and documented for -raw materials, intermediates, APIs, -labelling and p
173、ackaging materials -may be appropriate for materials with possible impact to quality like process aids, gaskets, filters,.For IPCs with the purpose of process monitoring control limits and action limits should be established to avoid OOS-investigations in case of deviating in-process-control results
174、. Description in SOP needed!Electronic signatures on documents should be authenticated and secure (21 CFR part 11 to be followed in case of supplies to the US market)6.1 文件系统和规格对以下项目应该建立规格，并使之文件化对以下项目应该建立规格，并使之文件化 - -原料，中间体，原料药原料，中间体，原料药原料，中间体，原料药原料，中间体，原料药 - -标识和包装材料标识和包装材料标识和包装材料标识和包装材料 - -对于材料可能影
175、响到质量的，如工艺助剂，垫圈，对于材料可能影响到质量的，如工艺助剂，垫圈，对于材料可能影响到质量的，如工艺助剂，垫圈，对于材料可能影响到质量的，如工艺助剂，垫圈，过滤器过滤器过滤器过滤器,.,.l l对于有工艺监测控制限和行动限的对于有工艺监测控制限和行动限的IPCIPC，应建立，应建立OOSOOS调查，以避免中间控制的偏差。调查，以避免中间控制的偏差。SOPSOP中应描述！中应描述！l l文件中的电子签名应鉴定（如向美国市场供应，文件中的电子签名应鉴定（如向美国市场供应， 应应遵循遵循21 CFR part 11 21 CFR part 11 ）6.2 Equipment Cleaning
176、and use RecordRecords of major equipment use, cleaning, sanitizing/sterilization, maintenance should show date, time, product and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance. How was it done? Status label!Inspectors like to see the
177、se activities documented in the log-book!If dedicated equipment is used, individual equipment records are not necessary if batches of the API follow in traceable sequence. Records can be part of batch record.Cleaning Validation has become a major issue also for API manufacturers!6.2 设备清洗和使用记录主要设备的使用
178、，清洗，消毒，维护记录应主要设备的使用，清洗，消毒，维护记录应标明日期，时间，生产产品和批号，使用人，标明日期，时间，生产产品和批号，使用人，清洗人和维护人。如何操作的？状态标签！清洗人和维护人。如何操作的？状态标签！检查官希望这些行为都记录在设备日志里！检查官希望这些行为都记录在设备日志里！如果使用专用的设备，如果原料药的批次是可追溯的，单独的设备记录就不必需。记录可以是批记录的的一部分。清洗验证对原料药制造商也是重要的项目！清洗验证对原料药制造商也是重要的项目！6.3 Records of Raw Materials, Intermediates (IM),API Labelling an
179、d Packaging MaterialsRecords of each delivery should contain: -name of manufacturer/supplier -identity and quantity -supplier control or identification number -number allocated on receipt -date of receipt -results of any tests and conclusions derived from this -trace of use of materials -review of l
180、abels and packaging materials; according to set specifications? -final decision release or reject for all mentioned materials!Approved master labels should be available for comparison!6.3 6.3 原料的记录，中间体（原料的记录，中间体（IMIM），原料药的标识和），原料药的标识和包装材料包装材料每批交货的产品应包括：每批交货的产品应包括： - -制造商制造商/ /供应商的名称供应商的名称 - -标识和重量标识
181、和重量 - -供应商控制和识别码供应商控制和识别码 - -收货单上的归属码收货单上的归属码 - -收到的日期收到的日期 - -源于此的任何检测和结论源于此的任何检测和结论 - -使用物料的追溯使用物料的追溯 - -根据设定的标准，对标签和包装材料的审核；根据设定的标准，对标签和包装材料的审核； - -对以上材料的放行或不合格判定！对以上材料的放行或不合格判定！l l批准的主标签应便于比较！批准的主标签应便于比较！6.4 Master Production and Control InstructionsMaster production instructions for each IM/API
182、 should be -prepared -dated -signed by one person and independently checked by QUMaster production instructions should contain: -name of product including document reference code -complete list of raw materials and IMs -accurate statement of quantities needed or calculation -production location, mai
183、n equipment -detailed production instructions (sequences, process parameter ranges, sampling instruction, IPCs, time limits, expected yields -instructions for storage6.4 主生产和控制指令对每个中间体对每个中间体/ /原料药的主生产指令应该原料药的主生产指令应该 - -被准备被准备 - -标注日期标注日期 - -被签名并由质量部门的独立审核被签名并由质量部门的独立审核l l主生产指令应包括：主生产指令应包括： - -产品名称包括
184、文件引用代码产品名称包括文件引用代码 - -原料和中间体的完整清单原料和中间体的完整清单 - -需要的数量的准确描述需要的数量的准确描述 - -生产位置，主设备生产位置，主设备 - -具体的生产指令（顺序，工艺参数范围，取样指令，具体的生产指令（顺序，工艺参数范围，取样指令，IPCIPC，时间限制，预计产出），时间限制，预计产出） - -储藏指令储藏指令6.5 Batch Production and Control Records.should have complete information, checked before issuance for correct version, un
185、ique batch number.should contain: -dates and time (if appropriate) -identity of main equipment - identification of all materials used -actual results -sampling performed (SOP!) -signatures of person(s) performing the operation -IPC/laboratory test results -actual yield -description of packaging and
186、labels used -deviation/investigation if critical -results of release testing6.5 批生产和控制记录l l应有完整的信息，改版签发的审核，唯一的批号应有完整的信息，改版签发的审核，唯一的批号 l l. . 应包括：应包括： - -日期和时间（如果适当的话）日期和时间（如果适当的话） - - 主设备的标识主设备的标识 - - 使用的原料的标识使用的原料的标识 - -实际结果实际结果 - -取样操作（按取样操作（按SOPSOP！）！） - -操作人员签名操作人员签名 -IPC/ -IPC/化验室检测结果化验室检测结果 -
187、-实际产量实际产量 - -包装描述和使用的标签包装描述和使用的标签 - -偏差偏差/ /调查调查 - -放行检验的结果放行检验的结果6.6 Laboratory Control Records.should contain: -description of sample (name, batch number, date, quantity) -reference to test method -cross reference to preparation of reference standards, reagents and/or standard solutions -complete
188、record of all raw data (+ graphs/charts/spectra) -record of all calculations (units, conversion factors,.) -statement of test results, how do they compare with specs -date and signature of person(s) performing the tests -date and signature of a second person ( review for accuracy and completeness, c
189、ompliance with set standards)Records should be maintained also for modifications to test method, calibration of lab instruments, stability testing, OOS6.6 化验室控制记录应包括：应包括： - -样品描述（名称，批号，日期，数量）样品描述（名称，批号，日期，数量） - -检测方法参照检测方法参照 - -标准品，试剂和标准品，试剂和/ /或标准溶液配置的互相参照或标准溶液配置的互相参照 - -完整的原始数据（完整的原始数据（+ +图谱图谱/ /图
190、表图表/ /光谱）光谱） - -所有计算的记录（单位，转换系数）所有计算的记录（单位，转换系数） - -检测结果报告，与规格比较如何检测结果报告，与规格比较如何 - -检测操作人的签名和日期检测操作人的签名和日期 - - 另一人的签名和日期（对准确性，完整性，按照标另一人的签名和日期（对准确性，完整性，按照标准操作的审核）准操作的审核）l l对检测方法，化验室仪器校验，稳定性实验和对检测方法，化验室仪器校验，稳定性实验和OOSOOS的修改记录应该保存的修改记录应该保存6.7 Batch Production and Control Record ReviewWritten procedures
191、 should be established for review and approval to ensure compliance with set specs.Records of critical process steps should be reviewed and approved by QU before release or distribution.Deviations/investigations/OOS reports should be reviewed as part of the batch review before release.QU should rele
192、ase all IM that are shipped outside the control of the manufacturing company.6.7批生产和控制记录审核应建立书面的程序，以审核和批准，确定符合设定应建立书面的程序，以审核和批准，确定符合设定的规格的规格在放行或销售前，关键工艺步骤的记录应该被质量在放行或销售前，关键工艺步骤的记录应该被质量部门审核和批准部门审核和批准在放行前，偏差在放行前，偏差/ /调查调查/OOS/OOS报告应作为产品审核的一报告应作为产品审核的一部分部分质量部门对所有运出的中间体进行放行。质量部门对所有运出的中间体进行放行。7 Materials
193、 ManagementGeneral ControlsReceipt and QuarantineSampling and Testing of Incoming Production MaterialsStorageRe-evaluationDuring an audit the inspector will walk along the Flow of Materials“ from receipt to handover to production area and transfer to GMP area!7 物料控制总控制接收和待验外来物料的取样和检测储藏再评估审计的检查官可能会顺着
194、物料的流程，从接收审计的检查官可能会顺着物料的流程，从接收到运送到生产区域，到运送至到运送到生产区域，到运送至GMP区域！区域！7.1 General ControlsThere should be written procedures (SOPs) describing -receipt -identification -quarantine -storage -handling -sampling -testing -approval or rejection of all materialsSuppliers of critical materials should be evaluat
195、ed (audit)7.1 常规控制l l应该有书面的规程（应该有书面的规程（SOPSOP）规定）规定 - - 接收接收 - - 识别识别 - - 代验代验 - - 储藏储藏 - - 操作操作 - - 取样取样 - - 检测检测 - -所有物料的批准或拒收所有物料的批准或拒收l l关键物料的供应商应该被评估（审计）关键物料的供应商应该被评估（审计）7.1 General ControlsMaterials should be purchased against an aggreed specification approved by the QU.Suppliers should be app
196、roved by the QU.The supplier of critical materials should be known by the IM or API manufacturer.Changing the supplier of critical raw materials should follow the established Change Control Procedure!7.1 常规控制按照质量部门批准的规格采购物料按照质量部门批准的规格采购物料l l中间体或原料药的制造商应了解关键物料的供应中间体或原料药的制造商应了解关键物料的供应商商l l关键物料供应商的更换应该
197、遵循已建立的变更控关键物料供应商的更换应该遵循已建立的变更控制程序！制程序！7.2 Receipt and QuarantineUpon receipt and before acceptance each container should be visually checked for -correct labelling -container damage -broken seals -evidence of tampering or contaminationMaterials should be held under quarantineuntil they have been sam
198、pled, examined or tested and released for use.If incoming materials are mixed with existing stocks (tank, silo) they should be identified as correct, tested and released.Procedures should be in place to prevent discharging of incoming materials into the wrong existing stock.7.1 常规控制按照质量部门批准的规格采购物料按照
199、质量部门批准的规格采购物料l l中间体或原料药的制造商应了解关键物料的供应中间体或原料药的制造商应了解关键物料的供应商商l l关键物料供应商的更换应该遵循已建立的变更控关键物料供应商的更换应该遵循已建立的变更控制程序！制程序！7.2 Receipt and QuarantineIf bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination. -certificate of cleaning, testing, audit of the suppli
200、er (QMS).Large storage tanks/containers with attendant manifolds, filling and discharge lines should be identified/labelled!Each container should be identified with code, batch or receipt number.The status of each batch should be clearly seen through ist label(s). (Quarantine, sampled, released or r
201、ejected)7.2 接收和待验在接收前，应该目测每个容器的包装在接收前，应该目测每个容器的包装 - -正确的标识正确的标识 - -包装损坏包装损坏 - -封条损坏封条损坏 - -污染污染l l在物料被取样，检测或放行前，应该在待验状态下。在物料被取样，检测或放行前，应该在待验状态下。l l如果来料是和已有的库存混合的（储罐，筒仓），来如果来料是和已有的库存混合的（储罐，筒仓），来料应该确定是正确的，检验放行的。料应该确定是正确的，检验放行的。l l为避免来料误卸入储罐，为避免来料误卸入储罐，SOPSOP应放置在现场。应放置在现场。Sampling and Testing of Incomi
202、ng Production Materials At one test should be conducted to verify the identity of incoming materials. -Exception: Dangerous or highly toxic materials, processing aids, or internally transfered materials do not need to be tested if a Certificate of Analysis is obtained; specs o.k.! -Non-testing shoul
203、d be justified and documentedA suppliers CofA can be used instead of other testing if the supplier has been evaluated/audited by QU!Supplier approval should include the proof that material consisitently can meet the specs.Before reducing testing at least three batches should undergo full testing aga
204、inst the specs. At appropriate intervalls full testing should be conducted.来料的取样和检测l l至少要采用一种方式确定来料的特性至少要采用一种方式确定来料的特性 - - - -例外：如果有分析单或规格，危险的或巨毒物质，例外：如果有分析单或规格，危险的或巨毒物质，工艺助剂，或内部转运物质不需要检测，工艺助剂，或内部转运物质不需要检测， - -免检产品应该被确定并且记入文件免检产品应该被确定并且记入文件l l如果供应商是已经被质量部门审计和评估的，那么如果供应商是已经被质量部门审计和评估的，那么供应商的分析单就可以代替其
205、他的检测！供应商的分析单就可以代替其他的检测！l l供应商的批准应包括连续物料符合标准的证据。供应商的批准应包括连续物料符合标准的证据。l l在减少检测前至少有三批产品经过全检符合规格在减少检测前至少有三批产品经过全检符合规格l l在适当的间隙应进行全检在适当的间隙应进行全检SamplingSamples should be representative; SOP should define -number of containers , which part of container -amount of material to be takenA sampling plan should
206、be set based on criticality of the material, variability, past quality history, amount needed for analysis!Contamination during sampling should be avoided (defined location, sampling booth).Containers to be sampled should be carefully opened and reclosed and marked as sampled“.取样样品应该是具有代表性；SOP应该确定以下
207、内容 -容器号，容器的哪一部分 -取样的数量一个取样计划应以物料的重要性，易变性，过去的质量历史，分析需要的数量为基础！应避免取样的污染（确定 的位置，取样间）被取样的容器应被仔细的打开，再关闭，并标明“已取样”Storage conditions and times should prevent any negative effect on quality (appropriate clean storage area!)Materials to be stored in a manner to prevent degradation and contamination/cross-cont
208、aminationA first-in-first-out principle must be establishedMaterials in fibre drums boxes or bags should be stored off the floor (on pallets).There should be enough space for cleaning and inspectionIf materials are stored outside suitable containers should be used and labels must remain legible. Con
209、tainers should be appropriately cleaned before use.Rejected materials should be controlled under a quarantine system, labelled, to prevent their unauthorized use.Materials should be re-evaluated after prolonged storage or exposure to heat/humidity7.4 Storage 7.5 Re-evaluation避免对质量有任何消极影响的储存条件和时间（适当的
210、清洁的储藏区域！）物料要以避免降解，污染/交叉污染的方式储存。先进先出的原则必须建立纤维制成的盒子袋子桶应该离地储存（或着平行）应该有足够的清洗和检查空间如果物料储藏在室外，应该使用适当的容器，标签必须是清晰可读的。使用前容器应该是适当清洗的。不合格物料应在待验系统下控制，标识，以防止未经许可的使用。延长储存，暴晒或暴露在潮湿环境后，物料应再评估。7.4 储藏 7.5 再评估8. Production and In Process ControlsWeighing and measuring devices should have a suitable accuracy for their i
211、ntended use.Critical weighing, measuring, subdividing should be witnessed or equivalent control to be used (AM: which?)Actual yields should be compared with expected yields.The processing status of major equipment should be indicated (status label, computer control systems, etc.)Time limits if speci
212、fied should be met.Intermediates held for further processing should be stored under defined appropriate conditions!8. 生产和过程控制称量和测量装置应有适合目标使用的准确性称量和测量装置应有适合目标使用的准确性关键的称量，测量，细分设备应有专门机构的证关键的称量，测量，细分设备应有专门机构的证关键的称量，测量，细分设备应有专门机构的证关键的称量，测量，细分设备应有专门机构的证据或等量物的控制（官方的衡量：哪个？）据或等量物的控制（官方的衡量：哪个？）据或等量物的控制（官方的衡量：
213、哪个？）据或等量物的控制（官方的衡量：哪个？）实际产量应与期望产出相对比。实际产量应与期望产出相对比。主要设备的生产状态应被标明（状态标志，计算主要设备的生产状态应被标明（状态标志，计算机控制系统，等）机控制系统，等）时间限制，如果规格有规定时间限制，如果规格有规定需要进一步使用的中间体应在确定的适当环境下需要进一步使用的中间体应在确定的适当环境下储存！储存！In-process Sampling and ControlsIPCs should be established to monitor the progress and control the performance of the p
214、rocessing step. Ranges!Critical IPCs should be approved by the QU.Qualification/training of production personnel performing the IPCs should be documented.SOPs how to do IPCs, how to sample, etc. should be in place.IPC sampling should not cause any (cross-)contamination.OOS investigations not normall
215、y needed for IPC tests.中间控制和取样l l应建立中间控制以监控生产进程并控制工艺过程中应建立中间控制以监控生产进程并控制工艺过程中的操作。范围！的操作。范围！l l关键的中间控制应由质量部门批准关键的中间控制应由质量部门批准l l中间控制的验证中间控制的验证/ /操作人员的培训应有记录操作人员的培训应有记录l l中间控制的现场应有其中间控制的现场应有其SOPSOP，怎样取样，等，怎样取样，等l l中间控制不可导致任何污染或交叉污染中间控制不可导致任何污染或交叉污染l ltests. tests. 对于中间控制的检验，对于中间控制的检验，OOSOOS调查一般不常用调查一般
216、不常用Blending of Batches of Intermediates or APIsBlending is defined as the process of combining materials within the same specification to produce a homogeneous IM or API.OOS batches should not be blended with others to meet the set specification. Each batch to be tested and released!Blending process
217、 should be controlled and documented, the blended batch should be tested.The batch record should allow traceability to the individual batches.Where physical attributes of the API are critical validation is required to show homogeneity of the combined batch.If blending affects stability, stability te
218、sting needed.Expiry/retest date should be based on the oldest batch!中间体或原料药的混批混批是为了生产均一的中间体或原料药，混合相同混批是为了生产均一的中间体或原料药，混合相同规格产品的工序。规格产品的工序。OOSOOS批次不可与其他符合标准的批次混合。混合前批次不可与其他符合标准的批次混合。混合前的每一批都要检测并放行！的每一批都要检测并放行！混合工序应是受控的并有记录，混合的批次应被检混合工序应是受控的并有记录，混合的批次应被检测。测。批记录应可以追溯到混合前的小批批记录应可以追溯到混合前的小批原料药的混批是否能达到产品的
219、均一，是需要验证原料药的混批是否能达到产品的均一，是需要验证的重要验证项目，的重要验证项目，如果混合影响稳定性，需要进行稳定性实验如果混合影响稳定性，需要进行稳定性实验失效期失效期/ /复检期应按照时间最久的批次算！复检期应按照时间最久的批次算！ 9 Packaging an Identification Labelling of APIs and IMsWritten procedures needed for receipt, identification, quarantine, sampling, examination/testing and release.Packaging an
220、d labelling materials should conform to specs.Containers should protect against deterioration or contamination during transportation and storage.Containers should be clean (sanitized), for re-use without previous labels. Cleaning procedures to be defined!Access to the label storage should be limited
221、!Reconciliation of labels required: issued-used-returned!Printed labels should be controlled against specs.A printed label representative to be included in the batch record.9 9 中间体和原料药的包装和标识中间体和原料药的包装和标识l l需要为接收，鉴别，待验，取样，检测和放行建立需要为接收，鉴别，待验，取样，检测和放行建立规程。规程。l l包装和标签材料应符合规格。包装和标签材料应符合规格。l l在运输和储存中，容器应该
222、能防止变质或污染。在运输和储存中，容器应该能防止变质或污染。l l容器应清洁（消毒），容器循环使用时，上面没有容器应清洁（消毒），容器循环使用时，上面没有使用过的标签。要有确定的清洗程序！使用过的标签。要有确定的清洗程序！l l标签储藏库的进入应有限制！标签储藏库的进入应有限制！l l标签的管理：签发标签的管理：签发- -使用使用- -收回！收回！l l印刷的标签应按照标准控制。印刷的标签应按照标准控制。l l在批记录里要有一张有代表性的标签。在批记录里要有一张有代表性的标签。Packaging and Labelling OperationLabelling opreations desig
223、ned to prevent mix-ups.Labels for APIs, IMs should show: name or code, batch number, storage conditions (if critical).In case of leaving the manufacturers material management system: name and address of manufacturer, quantity, transport conditions/legal safety information, expiry date or retest date
224、.Packaging and labelling area should be inspected and released for operations; results to be recorded!Containers transported outside of the manufacturers control should be sealed in a manner that tampering/altering may be recognised by the recipient.包装和贴标签贴标签以防止混淆贴标签以防止混淆原料药和中间体的标识应表明：名称代码，批号，原料药和中间
225、体的标识应表明：名称代码，批号，原料药和中间体的标识应表明：名称代码，批号，原料药和中间体的标识应表明：名称代码，批号，储存条件（如果重要）储存条件（如果重要）储存条件（如果重要）储存条件（如果重要）例如物料管理系统中应标明：制造者名称和地址，例如物料管理系统中应标明：制造者名称和地址，例如物料管理系统中应标明：制造者名称和地址，例如物料管理系统中应标明：制造者名称和地址，数量，运输环境数量，运输环境数量，运输环境数量，运输环境/ /法定安全信息，有效期或复检期法定安全信息，有效期或复检期法定安全信息，有效期或复检期法定安全信息，有效期或复检期包装和贴标签区域应是检查合格的；检查结果要记包装和
226、贴标签区域应是检查合格的；检查结果要记录！录！运出制造商控制的区域以外的包装应是密封的，如运出制造商控制的区域以外的包装应是密封的，如果有搀杂或开封的行为，接收人可以识别出来。果有搀杂或开封的行为，接收人可以识别出来。Storage and DistributionFacilities with appropriate conditions should be available.Seperate areas should be assigned for quarantined, rejected, returned, recalled materials or alternative sys
227、tem!Only QU released materials should be dispatched to third parties and documented. SOP in place for recalls!Materials should be transported in a manner that does not affect their quality. Special conditions required to be stated on the label.The manufacturer should ensure that the transport compan
228、y knows and follows the transport and storage conditions.Transport of quarantine material to other units within the company und QU control is possible (SOP!). 储藏和销售设施应在适当的状态下设施应在适当的状态下为待验，不合格，收回，召回物料划出区分的区域为待验，不合格，收回，召回物料划出区分的区域或可选择的系统！或可选择的系统！只有质量部门放行的物料可以被发送到第三人或部只有质量部门放行的物料可以被发送到第三人或部门。门。SOPSOP放在
229、被召回物料附近！放在被召回物料附近！物料运输应选用不会影响其质量的方式。需要特殊物料运输应选用不会影响其质量的方式。需要特殊储存方式的应在标签上标明。储存方式的应在标签上标明。制造商应确定运输公司了解并遵照运输和储存条件制造商应确定运输公司了解并遵照运输和储存条件运输。运输。在制造商厂内，由质量部门控制，待验物料可以被在制造商厂内，由质量部门控制，待验物料可以被运往其他岗位。（有运往其他岗位。（有SOPSOP规定！）规定！）11 Laboratory ControlsGeneral requirements: adequate laboratory facilities, SOPs for s
230、ampling, testing, approval, rejection, recording and storage/archiving of lab data.Specs should be set and followed for all materials!Specs and test procedures should be the same as in registration/filing!Specs should include a control of the impurities (microbial count or endotoxins, if specified).
231、Lab controls to be followed and recorded at the time they are performed.OOs results to be investigated and reported (SOP!).Change Control SOP to be established and followed!Reagents and standard solutions to be labelled correctly (Use by“ dates)Defined procedures for primary reference standards, in-
232、house primary standard, secondary refernce standard to be in place!11 实验室控制常规要求：足够的实验室设施，取样常规要求：足够的实验室设施，取样SOPSOP，检测，批准，检测，批准，不合格判定，实验室数据的记录与归档不合格判定，实验室数据的记录与归档为全部物料建立规格并遵照规格执行！为全部物料建立规格并遵照规格执行！规格和检验程序应与注册申请的一致！规格和检验程序应与注册申请的一致！规格应包括对杂质的控制（细菌总数，内毒素，如果必规格应包括对杂质的控制（细菌总数，内毒素，如果必要）要）在操作同时，遵循化验室控制并记录。在操作
233、同时，遵循化验室控制并记录。不合格结果应被调查并报告（有不合格结果应被调查并报告（有SOPSOP！）！）建立变更控制建立变更控制SOPSOP并执行并执行溶剂和标准溶液要准确标记（在溶剂和标准溶液要准确标记（在.日使用）日使用）l l应当为基本标准品，内部标准品规定程序；二级标准品应在应当为基本标准品，内部标准品规定程序；二级标准品应在现场现场Testing of IMs and APIsAn impurity profile describing the identified and unidentified impurities of a typical batch should be es
234、tablished.The impurity profile should be compared in appropriate intervals against registration/historical data (annual review)!Validation of analytical procedures should be performed according to guidelines ICH Q2A and B.Certificates of Analysis should be issued on request.Stability monitoring shou
235、ld be in place. Stab data are the basis for retest or expiry dates and storage conditions!Stability packaging should simulate the storage/shipment or market container. Normally first three commercial batches should undergo stability testing. After that one batch/year.中间体和原料药的检测应建立杂质概况，描述确定的和未确定的杂质应建
236、立杂质概况，描述确定的和未确定的杂质杂质概况应在适当的间隙做，根据注册杂质概况应在适当的间隙做，根据注册/ /历史数据历史数据（年检）！（年检）！分析的验证程序应按照分析的验证程序应按照ICH Q2A and BICH Q2A and B的指南进行。的指南进行。应该按要求签发分析单应该按要求签发分析单稳定性的监控记录应在现场。稳定性数据是复检期稳定性的监控记录应在现场。稳定性数据是复检期或有效期和储存条件的根据！或有效期和储存条件的根据！稳定性的包装应模拟储藏稳定性的包装应模拟储藏/ /运输或商业包装。通常头运输或商业包装。通常头三批商业批次应用来做稳定性实验。之后每年加入三批商业批次应用来做
237、稳定性实验。之后每年加入一批。一批。Reserve/Retention SamplesThe packaging and holding of reserve samples is for future re-evaluation ic case of complaints, etc.Reserve samples should be retained for one year after the expiry date or three years after complete dispatch.The reserve sample should have the same packagin
238、g as the API or more protective!The quantity should allow at least two full analytical runs according two pharmacopeia or to specs requirements.留样l对保留样品的包装和处理是为了将来的投诉等情况的再评估l留样应在失效期后再保存一年或销售后保存三年l留样应该与原料药用相同的包装或保护更好！l留样数量应至少有两个全检（按药典或规格要求）的量12 ValidationValidation policy: The companys overall policy
239、 should be documented.Critical parameters should be identified during development; ranges for the reproducible operation should be defined.All critical (quality, purity) operation steps should be validated (based on risk analysis/ risk assessment).Validation documentation: Validation protocol, valid
240、ation report, variations to be documented with justification.Qualification: Before process validation DQ, IQ, OQ, PQ should be completed!Process validation (PV) is the documented evidence that the process, operated within established ranges, can reproducibly produce the specified quality of API/IM.1
241、2 验证l l验证方针：工厂应有整体方针的文件验证方针：工厂应有整体方针的文件l l在开放时应确定关键参数；应确定能重复操作在开放时应确定关键参数；应确定能重复操作 的的范围范围l l所有关键的（质量，纯度）操作步骤应是已验证的所有关键的（质量，纯度）操作步骤应是已验证的（根据风险分析（根据风险分析/ /风险评估）风险评估）l l验证文件：验证方案，验证报告，变化及评判应有验证文件：验证方案，验证报告，变化及评判应有文件规定。文件规定。l l验证：在工艺验证前，应完成验证：在工艺验证前，应完成验证：在工艺验证前，应完成验证：在工艺验证前，应完成DQ, IQ, OQ, PQ DQ, IQ, OQ
242、, PQ l l工艺验证（工艺验证（PVPV）是工艺，操作符合标准的证据，）是工艺，操作符合标准的证据，能够评估原料药能够评估原料药/ /中间体生产的重复性。中间体生产的重复性。DefinitionsDesign Qualification (DQ): documented verification that the proposed design of facilities, equipment, systems is suitable for the intended purpose.Installation Qualification (IQ): doc. verif. that the
243、 equipment/sytems, as installed or modified, comply with the approved design, the manufacturers recommendations and/or user requirements.Operational Qualification (OQ): doc. verif. that the equipment/systems, as installed or modified, perform as intended throughout the anticipated operating ranges.P
244、erformance Qualification (PQ): doc. verif. that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on approved process method and specifications.定义设计确认(DQ)：是对提议的设施、设备或系统适用于预期的目的的一种成文的确认。安装确认(I Q)：对安装好的和调整过的设备或系统符合已批准的设计、制造商建的议和/或用户的要求的成文的确认。操作确
245、认(OQ)：对安装好的和调整过的设备或系统能在整个预期的操作范围内按要求运行的成文的确认。性能确认(PQ)：是对设备及其辅助系统在相互连接后，能根据已获准的工艺方法和质量规格有效地、重现地进行运转的成文的确认。Approaches to Process Validation (PV)Prospective validation (preferred): should be completed before the final drug product manufactured from that API is marketed.Concurrent validation (possible):
246、 only limited number of batches have been produced; thorough monitoring and testing is required!Retrospective validation (exeption): well established process, no changes in quality (annual review!), no process/product failures, impurity profile existing!Three consecutive successful production batche
247、s should be manufactured.Critical process parameters should be controlled and monitored.PV should confirm the impurity profile, comparable or better than APIs in tox/pivotal studies!工艺验证方法（PV）前验证（首选）：应该在用该原料药制成的制剂产品销售前验证（首选）：应该在用该原料药制成的制剂产品销售前完成。前完成。同步验证（可能）：仅限于已经生产的批号；需要有充分同步验证（可能）：仅限于已经生产的批号；需要有充分
248、的监控和测试！的监控和测试！回顾性验证回顾性验证 ( (例外例外): ): 已建立的良好工艺已建立的良好工艺, , 质量没有变化质量没有变化 ( (年度回顾年度回顾!), !), 没有工艺没有工艺/ /产品不合格产品不合格, , 有杂质档案有杂质档案! !应当有连续三批合格的产品应当有连续三批合格的产品. .应当控制和监测关键的工艺参数应当控制和监测关键的工艺参数. .工艺验证应当确认杂质概况工艺验证应当确认杂质概况, , 比原料药在临床和毒理研究比原料药在临床和毒理研究的数据相似或更好的数据相似或更好! !ValidationSystems/processes should be perio
249、dically evaluated, in case of any critical changes revalidation should be conducted.Cleaning validation: where is a risk to API quality?; grouping based on solubility, difficulty of cleaning,is possible. Residue limits to be set based on potency and toxicity.Cleaning methods to be defined: swab, rin
250、se, steam extraction.Validated analytical methods should be used. Recovery rate from spiked surfaces should be 50%!Appropriate qualification of analytical equipment to be completed before validation starts.Computerised Systems should be validated (acc. to ICH).验证系统系统/ /工艺应是定期评估的，任何重要的变更都要再验工艺应是定期评估的
251、，任何重要的变更都要再验证。证。清洗验证：哪里会影响原料药的质量？根据溶解度，清洗验证：哪里会影响原料药的质量？根据溶解度，清洗的难易程度分组。清洗的难易程度分组。根据效价和毒性确定残留限度。根据效价和毒性确定残留限度。应使用已验证的分析方法。回收率应大于应使用已验证的分析方法。回收率应大于50%50%！在验证开始前，相应的分析设备确认应该完成。在验证开始前，相应的分析设备确认应该完成。计算机系统应被验证（根据计算机系统应被验证（根据ICHICH）13 Change ControlA formal change control system should be established and
252、followed (SOP). Decision tree is helpful.A change control team or QU should guide through the procedure for planning, reviewing, approving, final reports, follow up (registration, revalidation, etc.); minor-major change? Scientific rational should be written!When implementing approved changes, measu
253、res should be taken to update all affected documents!First batches produced or tested after the change should be evaluated.If necessary, samples of IMs/APIs should undergo stability studies (accelerated; added to monitoring schedule)Drug product manufacturers should be informed about the change; som
254、etimes formal approval is needed (contract!).13 变化控制应当建立并遵守（应当建立并遵守（ SOPSOP ）正式的变化控制的系统。判断树是）正式的变化控制的系统。判断树是有用的。有用的。应当有变化控制的队伍或质量部门在一下过程中予以指导：应当有变化控制的队伍或质量部门在一下过程中予以指导：计划，审核，审批，最终的报告，项目跟踪（注册，再验证计划，审核，审批，最终的报告，项目跟踪（注册，再验证等）等）; ; 次要的变更次要的变更? ? 应有书面的科学合理的材料应有书面的科学合理的材料! !实施已核准的变更时，应当采取措施确保所有受变更影响的实施已核准
255、的变更时，应当采取措施确保所有受变更影响的文件都已修订文件都已修订! !变更实施后，应当对变更之后生产或测试的头几个批次进行变更实施后，应当对变更之后生产或测试的头几个批次进行评估。评估。如有必要，可以将中间体或原料药的样品放入一个加速稳定如有必要，可以将中间体或原料药的样品放入一个加速稳定性计划，并性计划，并/ /或放入稳定性监测计划。或放入稳定性监测计划。应当将变更通知目前的制剂药制造商。应当将变更通知目前的制剂药制造商。有时候需要正式的审有时候需要正式的审批（合同！）批（合同！）14 Rejection and Re-Use of MaterialsRejected IMs and AP
256、Is can be reprocessed or reworked. The final disposition of rejected materials should be recorded.Reprocessing: Repeating a process step with addition of IM/API conforming or not conforming to specs. These steps like crystallization, distillation, filtration, milling, should be part of the establish
257、ed process.Continuation of a process step based on IPC results is not reprocessing“.Introducing of unreacted material back into a process is reprocessing“ but needs careful evaluation14 物料的拒收和再用拒收的中间体和原料药可以返工或再加工。拒收的中间体和原料药可以返工或再加工。应当记录不合格物料的最终处置情况。 返工返工: 将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或
258、其它合适的步骤(如蒸馏，过滤，层析，磨粉)。在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，不属于返工。将未反应的物料返回某一工序，并重复化学反应，这是进行返工，要仔细评估14 Rejection and Re-Use of MaterialsReworking: Proceessing of not conforming IM/API by others than established process steps.Before reworking an investigation on non conforming“ should be performed.Reworked bat
259、ches should be appropriately evaluated (testing, stability, all quality parameters!). Concurrent validation plus report is expected.Main focus should be put on impurity profile of reworked batches; if needed additional analytical methods should be used!Recovery of solvents, reactants, IMs,APIs is o.
260、k. as long procedures are defined, specs met and the use is documented!Returns should be identified, quarantined, reprocessed, reworked or destroyed; use or disposal should be recorded.14物料的拒收和再用重新加工重新加工: 中间体中间体/原料药的工艺与已建立的工艺步骤不同原料药的工艺与已建立的工艺步骤不同在重新加工前，应当对不符合的原因进行调查。重新加工的批号应当接受适当的评估重新加工的批号应当接受适当的评估（
261、检测，稳定性，所有检测，稳定性，所有的质量参数！）。通常还要有同步验证及报告。的质量参数！）。通常还要有同步验证及报告。主要的关注点应当在重新加工批号的杂质档案；如果需要应当有额外的分析方法！只要有成文的回收方法，并且回收的物料符合其使用标准，溶剂，反应物，中间体或原料药的回收是可以接受的!退货应当被标识，隔离，再处理，重新加工或销毁；使用或销毁应当被记录。15 Complaints and RecallsAll quality related complaints should be recorded and investigated according to the SOP!Records
262、 should contain: name , address of complainant, receiving date, reason, action taken, follow-up actions, response, final decision on IM/API batch.Records of complaints should be retained for evaluation of trends, frequencies, severity and basis for corrective actions.SOP for recalls should be establ
263、ished (when, why, who, information to whom, how is the recalled material treated?)In case of serious, life-threatening situations, local, national/international authorities should be informed.15 投诉和召回所有所有与质量相关的投诉，都应当根据与质量相关的投诉，都应当根据SOPSOP进行记录进行记录和调查！和调查！记录应当包括：姓名，投诉人地址，接到投诉的日期，原因，采取的措施，随后采取的措施，回复，对该
264、批中间体/原料药的最终措施投诉记录应当保存，旨在评估其变化趋势、涉及产品的发生频率及其严重性，以便采取纠正措施。应当建立召回的应当建立召回的 (何时，为何，何人，告知谁，如何对待召回的物料？)如果情况严重或可能威胁生命，则应当通知地方、国家或国际当局，并征求其建议。16 Contract Manufacturers (including Labs).should comply with GMP as defined in the guideline.Contract manufacturer and labs should be evaluated/ audited for GMP compl
265、iance.A written contract should describe in detail responsibilities, tasks, quality measures, flow of information.Where subcontracting is allowed, approval/evaluation of the contract giver is required!Manufacturing and lab records to be kept at the site where the activity occursAny changes should be
266、 reported to and approved by the contract giver.16 合同厂商 (包括实验室).应当遵守指南中的应当遵守指南中的GMP规定规定应当对协议制造商(包括实验室)进行评估，以确保符合GMP。应当有书面合同，详细规定各方的职责，任务，质量措施，信息交流。在允许分包的情况下，必须要有合同委托方事先的评估和核准！生产和分析记录应当保存在操作现场，并随时可得任何更改应当报告并得到合同委托方的批准。17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers.should comply
267、 with GMP as defined in the guideline!Traceability of distributed APIs/IMs should be ensured.QMS should be established.All operations should be performed under GMP controls to avoid mix-ups, (cross)-contamination, loss of identity, purity! Different packaging requires stability tests!.should transfe
268、r any quality/regulatory information to customer/manufacturer!Handling of complaints, recalls, returns should follow the SOPs!17 代理商, 经纪人, 贸易商, 分销商, 重新包装人和重新贴签人.应当应当按照指南的规定遵守遵守GMP!原料药和中间体的分发应当确保可追溯性分发应当确保可追溯性应当建立质量管理系统应当建立质量管理系统所有的操作都应当在GMP的控制下实施，以避免混和，（交叉）污染，标识丢失，纯度！不同的包装需要稳定性测试！.应当传达任何质量/药政的信息给客户/
269、工厂！投诉，召回，退货应当安装SOP处理！18 Specific Guidance for APIs Manufactured by Cell Culture/Fermentation.addresses specific controls for APIs/IMs manufactured by cell culture or fermentation using natural or recombinant organisms.All GMP principles of Q7A apply!Principles of fermentation for classical“ processe
270、s to produce small molecules and for processes using recombinant/non recombinant organisms to produce proteins/polypeptides are the same.Biotechnological process“ means the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce API
271、s.18 用细胞繁殖/发酵生产的原料药的特殊指南. 说明通过细胞繁殖或用天然或重组组织发酵生产的原料药或中间体的特殊控制运用所有运用所有GMP ，Q7A原理原理!用“经典的”生产小分子的发酵工艺的原理，和用重组/非重组的有机体生产蛋白质/多肽的工艺的原理是一样的。“生物工艺”是指用重组DNA、杂交瘤或其它技术产生或修饰的细胞或组织来生产原料药。APIs manufactured by Cell Culture/FermentationViral safety described in ICH Guideline Q5A: Quality of Biotechnological products
272、 Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.Cell Bank Maintenance and Record KeepingCell Culture and FermentationHarvesting, Isolation and PurificationViral Removal/Inactivation Steps (Q5A).用细胞繁殖/发酵生产的原料药的特殊指南ICH 指南Q5A生物制品的质量：生物制品的质量从人体或动物组织细胞
273、族得到的生物制品的病毒安全性评估”中描述的生物制品的病毒安全性。细胞库的维护和记录保持细胞繁殖和发酵收取、分离和提纯病毒的去除/灭活步骤 (Q5A)19 APIs for Use in Clinical TrialsThe controls used should be consistent with the stage of development (pre-clinical to clinical).Appropriate GMP concepts (approval!) should be applied.An independent QU should be established f
274、or release or rejection.Raw materials (CofA), packaging materials, IMs, APIs should be tested against set specs.Labelling should be controlled and should say for investigational use“.Equipment shoule be calibrated, clean and suitable.Facilities should ensure that (cross)-contamination can be avoided
275、.19 用于临床研究的原料药该控制应当与药品的开发阶段一致(临床前到临床)应当采取适当的GMP概念（批准的！）应当建立独立的质量部门来放行或拒收原料(CofA), 包装材料, 中间体, 原料药应当按设定的规格重新检测标签应当受控并且应当说是为“调查使用”设备应当经校验，清洁并适用设施应当确保能避免（交叉）污染19 APIs for Use in Clinical TrialsThe production of APIs should be documented (lab notebooks, batch records) in detail ( use of materials, proces
276、sing, observations). Yields can be more variable! Process validation should be conducted when batches are produced for commercial use.Changes are expected and should be adequately recorded.Laboratory controls should be scientifically sound (may not be validated in an early stage).A system should be
277、in place for retaining samples, setting of expiry/retest dates.Documentation should ensure appropriate information about equipment, facilities, processes, testing.A system for retaining all records should be used.19 用于临床研究的原料药原料药的生产应当详细（物料使用，工艺，观察）成文（实验室记录本、批记录。预期产量更具可变性！ 当进行商业性生产时应当按指南进行工艺验证变更是可预期的
278、变更是可预期的并应当被适当记录虽然在早期状态可能还没有验证，但是，实验室应当是科学，合理的。现场应当有一套留样的，有效期/复测时间设定的系统文件应当确保有适当的信息，文件应当确保有适当的信息，关于设备，设施，工关于设备，设施，工艺，检测艺，检测应当有一套保存所有记录的系统应当有一套保存所有记录的系统GMP (ICH Q7A) Compliance and Inspection for COS/CEPChange Control ProcedureDr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept Heidelb
279、ergGMP (ICH Q7A) Compliance and Inspection for COS/CEP变更控制程序Dr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergSubjects1.Change Control Definition2.Projects and Production Differences3.Technical Changes4.Changes of Processes5.Changes in technical projects/development proje
280、cts6.Change Control Procedure Example7.Deviations Definition8.Deviations - Measures to be taken9.Deviations - Documentation题目1.变化控制程序定义2.项目和生产区分3.技术变更4.工艺变更5.技术项目/开发项目中的变更6.变化控制程序实例7.偏差定义8.偏差处理措施9.偏差文件1. Change Control - DefinitionChange Control is a-planned-approved-documented-controlledprocedure c
281、oncerning any changes of a-formulation (qualities, quantities)-procedures (manufacruring, analytical)-equipment, technical system (air, water, filtration, etc.)-product-project1. 变更控制定义变更控制变更控制 是一个是一个-根据计划的根据计划的 - 通过批准的通过批准的 -有文件为证的有文件为证的 - 受控的受控的 程序中任何关于以下内容的程序中任何关于以下内容的 变化变化流程（质量，数量）流程（质量，数量）规程规程
282、（制造的，分析的）（制造的，分析的）设备，技术系统设备，技术系统 （空气，水，过滤，等）（空气，水，过滤，等）- 产品产品- 项目项目1. Change Control - DefinitionChange Control is a very important element in theQuality Assurance System / Qualizy Management System!Change Control is the evidence that changes-are planned and documented-reasons are clear/transparent
283、and can be traced back-are of a controllable risk-still lead to a finished product within set specifications1.变化控制定义在质量保证、质量管理系统中变化控制是个非常重要的因素！在质量保证、质量管理系统中变化控制是个非常重要的因素！变化控制是以下内容的证据变化控制是以下内容的证据变化是根据计划的，有文件为证的变化是根据计划的，有文件为证的原因清晰，且可以被追踪原因清晰，且可以被追踪有可控制的有可控制的 风险风险变化仍然导致合格的成品变化仍然导致合格的成品1. Change Control
284、 - DefinitionChange Control Documents describe and assess planned masuresif changes are conducted for-components of a product-the process or process environment (technical systems, utilities)-production methods-checking methods (IPC, analytical)-complex technical systems, computerised systems-techni
285、cal projects (equipment, facilities, turn key buildings)or any other change which can influence -product quality, -safety, -efficacyor which can change the production system1. 变更控制定义如果变更是由以下内容引起的，变化控制文件描述和评估计划的措施：产品成分工艺和工艺环境（技术系统，设施）生产方法检测方法（IPC，分析方法）综合技术系统，计算机化系统技术项目（设备，设施，关键建筑的变化）或者其它能够影响以下方面的变更：产
286、品质量，安全，效率或者变化能够改变生产系统Projects and Production - DifferenciesProduction Scope/Valid for: Routine production, Change Control Team to take decisions Longer time needed from start to final approvalDevelopment Project (New dosage form, new API) Valid after definition of product characteristics Project Tea
287、m to take decisions Realisation in short time, consequences to time schedule!?Technical Project Valid after a defined point in time specific for the project, e.g. after approval of URS FDS Frame for decisions for engineering to be defined for the project (approved by user and supplier) Realisation i
288、n short time necessary 项目和生产区别生产生产范围/验证：对日常生产由变更控制小组做决定从开始到最终批准需要较长的时间开发项目（新制剂，新原料药）开发项目（新制剂，新原料药） 确定产品特性后生效由项目小组做决定短时间实现，结果遵循时间进度技术项目技术项目 在确定的某点对于具体的某项目及时完成后生效。例如，在URS-FDS的批准后取决于该项目已确定的工程 （由使用者和供应商批准）在必要的较短时间内实现 Technical ChangesWhich systems/equipment to be included in Change Control“?-All systems
289、/equipment which have been qualifiedWhich changes require a requalification?-All changes which can have an influence to quality, safety, efficacy of the finished productThose changes have to be evaluated and approvedinternally (QA, ChangeControl Team).Some need approval by Health Autorities!技术变更变更控制
290、包括哪些系统变更控制包括哪些系统/设备？设备？所有己验证的系统/设备哪些变化需要再验证？哪些变化需要再验证？所有能够影响质量，安全，成品有效性的变更这些变更必须通过内部审核和批准（这些变更必须通过内部审核和批准（QA,变更控制小组）。变更控制小组）。有些需要通过官方机构的批准。有些需要通过官方机构的批准。3. Technical ChangesWhich technical changes have to undergo the Change Control Procedure? Removal of measuring points New lubricant, grease New too
291、ls Change of materials Change of seizes of containers Change of manufacturing steps/routine Installation of additional equipment (to improve transport) Changes in the water system (purification, storage, distribution, control, materials, etc.) Changes in providing media with contact to product (wate
292、r, air, clean steam, gases)3.技术变更哪些技术变更必须通过变更控制程序？哪些技术变更必须通过变更控制程序？测量点的去除测量点的去除新的润滑剂，油新的润滑剂，油新工具新工具材料的变更材料的变更容器大小的变更容器大小的变更制造步骤的变更制造步骤的变更附属设备的安装（为了便于运输）附属设备的安装（为了便于运输） 水系统的变更（纯化，储存，分流，控制，材料，等）水系统的变更（纯化，储存，分流，控制，材料，等） 接触产品的介质的变更（水，空气，清洁蒸汽，油）接触产品的介质的变更（水，空气，清洁蒸汽，油） 3. Technical ChangesWhich technical
293、changes/works dont have to undergoa Change Control Procedure? Exchange of parts for identical parts (type, material, function) Change of filters (material, type, mesh width) Maintenance work following SOPs Calibration Changes of transport equipment, which is not in contact with the primary packaging
294、 material.It should be carefully decided if a formal ChangeControl Procedure should be conducted!3. 技术变更哪些技术变更不必通过变更控制程序？哪些技术变更不必通过变更控制程序？ 更换相同零件（型号，材料，功能）更换相同零件（型号，材料，功能）更换过滤器（材料，型号，孔径）更换过滤器（材料，型号，孔径）按照按照SOP进行的维护工作进行的维护工作校验校验对于不接触原始包装材料的运输设备的对于不接触原始包装材料的运输设备的 变更变更正式的变更控制程序需要认真的确定才能被实施！正式的变更控制程序需要认真
295、的确定才能被实施！Changes of ProcessesWhich processes have to undergo the Change ControlProcedure?-All processes which have been validated (manufacturing, analytical methods, cleaning procedures).Which changes require a revalidation?-Significant changes which with a high probability have an influence to the
296、quality of the finished product.Those changes have to be evaluated and approvedinternally (QA, Change Control Team).Some need approval by Health Authorities.工艺变更哪些工艺必须通过变更控制程序？哪些工艺必须通过变更控制程序？所有已经被验证的工艺（制造，分析方法，清洗程序）所有已经被验证的工艺（制造，分析方法，清洗程序）哪些变更需要再验证？哪些变更需要再验证？有很高可能性影响成品质量的重大变更。有很高可能性影响成品质量的重大变更。这些变更必
297、须通过内部（这些变更必须通过内部（QA,变更控制小组）的评估和批准变更控制小组）的评估和批准有些变更需要通过官方部门的批准。有些变更需要通过官方部门的批准。Changes of ProcessesWhich changes require a revalidation? APIs/excipients: density, particle seize, specification (purity) Packaging material: glas quality, foils, closure systems, print procedures, etc) Processes: Blendin
298、g time, type of blender, temperatures, sterilisation, processing time, intermediate storage. Equipment for production (in contact with product): Automatic leak detection system, visual inspection system, welding procedure, material. measuring points, etc. Process environment: flow of material, water
299、 treatment, laminar air flow, air supply for clean rooms, etc. Change of the production facility or site of production.工艺变更哪些变更需要再验证？原料药/赋形剂：密度，颗粒度，规格（纯度）包装材料： 瓶质量，箔，密封系统，印制程序，等）工艺：搅拌时间，搅拌桨型号，温度，消毒，工艺时间，中间体储存产品设备（与产品接触的）自动检漏系统，目测系统。 焊接程序，材料，测量点，等。 工艺环境：物流，水处理，空气层流，洁净室的空气补给，等生产设施或生产地点的变更Changes in te
300、chnical projects/development projectsWhen should Change Control start in a project?-after GMP Design has been defined and approved: -end of phase DQ in technical projects (URS-FDS) -after definition and approval of product characteristics (decision by project team, QA should supervise)Who should be
301、involved?-Projectmanager, Projectteam (Registration, QC, Clinical Dev., Pharmaceutical Dev., Marketing, QA)-Projectmanagers for single modules/steps/project parts-Persons responsible for qualification, validation-User of equipment/system/facility/building-Technical/engineering department技术项目/开发项目的变更
302、一个项目的变更控制应从什么时候开始？一个项目的变更控制应从什么时候开始？在GMP设计已经确定和批准后 在技术项目的设计确认阶段后期 (URS-FDS)在产品特性被确定和批准后（在项目小组决定之后，QA应该监督管理）涉及哪些人？涉及哪些人？项目经理，项目小组（注册，QC， 临床部门，药学部门，市场，QA)负责单独模块/工序/项目步骤的项目经理验证，确认的负责人设备/系统/设施/建筑的使用者技术/工程部门Design Qualification in Project WorkEngineeringManufac- turingDelivery/InstallationCommiss-ioningS
303、tart-upTest RunsProcess Optimi-sationDQ/FDSRe-Val.PV / CVOQ/SATFATURSPQChange Control / RequalificationIQ/SATDetail RABasic RA项目工作中的设计确认 工程工程制造制造交货交货/安装安装试运行试运行试生产试生产工艺优化工艺优化DQ/FDSRe-Val.PV / CVOQ/SATFATURSPQ变更控制变更控制 / 再确认再确认IQ/SAT详细的详细的RA基础的基础的 RAChanges in technical projects/development projectsWh
304、ich changes/changes in planning have to undergo Change Control?-All changes/changes in planning which can influence quality of the finished product conducted at parts of equipment being in contact with product conducted at equipment supplying media which come in contact with product技术项目/开发项目的变更哪些变更哪
305、些变更/计划中的变更必须通过变更控制程序？计划中的变更必须通过变更控制程序？所有的变更所有的变更/计划中的变更计划中的变更哪些能够影响成品质量？哪些能够影响成品质量？ 对于接触产品的设备零件对于接触产品的设备零件 对于设备的补给媒介是接触产品的对于设备的补给媒介是接触产品的Changes in technical projects/development projectsDo all changes/changes in planning have to undergo Change Control?NoHow to find out if a change has to undergo Ch
306、ange Control? only possible with detailled knowledge of the process exact knowledge of factors influencing product quality exact knowledge of interplay of different factors of influenceOnly the user of an equipment, system, productionline, facility, etc. can take the final decision.For complex syste
307、ms,.team decision is recommended技术项目/开发项目的变更所有的变更/计划中的变更必须通过变化控制吗？不不怎样找到是否一个变更必须通过变更控制？只有在有详细的工艺信息时影响产品质量的准确信息只有在设备的使用者能够对系统，生产线，只有在设备的使用者能够对系统，生产线，设施等做最终决定的，设施等做最终决定的，对于综合系统对于综合系统.建议由小组做决定。建议由小组做决定。6. Change Control Procedure - ExampleDocumentation according to GMP RequirementsFill out the template
308、 Change Control/applicationApplication to be sent to CCTeam/CCCoordinator/QARegistration/Number, Change Control to be listed in a tablePeriodical evaluation of changes by CCTeam (QA, Head ofdepartment, further participants according to the kind of change6.变化控制程序实例符合符合GMP要求的文件要求的文件填充变更控制的模板/申请表申请递交至变
309、更控制小组/变更控制协调人/QA登记号，变更控制要列表变更控制小组（QA，领导部门，变更相应的参加部门）定期评估变更6. Change Control Procedure - ExampleDocumentation according to GMP RequirementsDecision and approval about measures to be taken, trials to beconducted, batch size to be defined, time schedule, etc.Information to be given to responsible coord
310、inator, employees.Conducting of all activities decided in the CCTeamCollection of data, summary ,evaluation of data, reportFinal decision to change or not or to conduct additional workDocumentation, Archiving6.变更控制程序实例符合符合GMP要求的文件要求的文件变更措施的决定和批准，采取的检测，确定的批量，时间表，等由变更控制小组决定的信息，由负责的协调人，员工实施收集数据，总结，数据评估
311、，最终决定变更与否的报告，或者采取其它措施的报告文件化，归档文件化，归档Deviations - Definition All events not compliant to routine/normal production/ manufacturing procedure All events /data found outside of established specifications (Out Of Specification Results, OOS ) Mistakes suddenly occured (reason unknown) or caused by misfunc
312、tion of equipment or caused by employees偏差定义所有不符合日常所有不符合日常/正常生产正常生产/制造程序规范的事件制造程序规范的事件 发现的超出规格的所有事件发现的超出规格的所有事件/数据数据（不合格结果，（不合格结果，OOS) 突然发生错误（未知）或由于设备的误操作或由员工导突然发生错误（未知）或由于设备的误操作或由员工导致。致。Deviation Measures to be taken Documentation of the deviation for Annual Batch Review Information of responsible
313、personnel (SOP!) Mistakes/deviations should not be held back Investigation to find the reason for mistakes/deviation Measures to avoid mistakes/deviations to be set and controlled ( increase IPC, check set ranges for manufacturing, check manufacturing instruction) Depending on deviation increase of
314、analytical investigations for batch release偏差采取的措施 偏差的年度批记录审核文件人员的职责信息(SOP!)错误/偏差不应该被隐瞒调查或为错误/偏差找到原因避免错误/偏差的措施要设定并且受控。（增加过程控制 ,检查制造的程序，检查生产指令） 根据偏差增加对放行批次的检测调查Deviation Documentation Remarks/description in batch documentation required Decision of Head of Production: stop or continue manufacturing; e
315、valuation if minor or major deviation; Is influence on product quality probable? Deviation report as enclosure and as information to QC and QA Documentation to be done according to GMP requirements偏差文件在需要的批记录上做注释和描述生产领导的决定：停止或继续制造；评估是否关键偏差；是否有可能影响产品质量？偏差报告作为附件和给QC,QA的信息文件要按照GMP的要求制作GMP (ICH Q7A) Com
316、pliance and Inspection for COS/CEP Validation of Cleaning Proceduresin Chemical API ProductionDr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergGMP (ICH Q7A) COS/CEP的遵循与检查的遵循与检查 化学原料药生产中的清洁过程验证Dr. Berthold Stemmle Pharma ConsultingAssociated Partner of Concept HeidelbergP
317、harmaceutical Technology, April 2005Warning Letter Report 2004There were a large number of violations of 211.67of 21 CFR . .18 out of 33 warning letters cite most deficiencies in Equipment cleaning and maintenance“.For Control of microbiological contamination“ the citationrose from 1 in 2003 to 11 i
318、n 2004.The proportion of warning letters to companies outsideThe US has increased.药物技术, 4月 2005警告信报告，2004有相当数量的 21 CFR 第211.67章节的缺陷.18 33封警告信中18封主要缺陷在与“设备清洁与维护”对“微生物污染的控制” ，引用2003年1月到2004年11月US以外的公司的警告信比重已经增长了Guidances, Regulatory RequirementsICH Q7A: Cleaning procedures should normally be validated
319、 In general, cleaning validation should be directed to process steps or situations where carryover of materials poses the greatest risk to API quality. In early production it may be unnecessary to validate equip. cleaning procedures where residues are removed by subsequent purification steps.APIC (A
320、PI Committee): Guide to Cleaning Validation in API Plants.指导, 药政要求ICH Q7A: 清洁程序应当被验证 一般来说，清洗验证应当直接针对工艺步骤，或携带物料对原料药质量造成最大风险的地方。 在较早的生产步骤中，对于残留物被下一步的精制步骤转移的地方，设备的清洗验证可以是不必要的。 清洗程序（应用于）APIC (API 委员会): 清洗验证在原料药工厂中的指导Guidances, Regulatory RequirementsICH Q7A - Bracketing accepted - Validated analytical p
321、rocedures to be applied - Determination of microbial load if necessary - Definition of time intervals for controling validity of cleaning proceduresValidation Protocol should include information about - Equipment (room, id-number, material) - Cleaning SOP - Acceptance limits - Analytical method (sam
322、pling method, sampling plan)指导, 药政要求ICH Q7A - 已接受的框架已接受的框架 - 已被验证的分析过程的运用已被验证的分析过程的运用 - 微生物负荷的判定如果必要的微生物负荷的判定如果必要的 - 间隔时间的界定，控制清洗程序的有效性间隔时间的界定，控制清洗程序的有效性验证方案应当包括这些信息验证方案应当包括这些信息 - 设备（房间，识别号码，物料）设备（房间，识别号码，物料） - 清洗清洗SOP - 接受的限度接受的限度 - 分析方法分析方法 (取样方法，计划取样方法，计划)Guidances, Regulatory RequirementsPIC: Cl
323、eaning has to cover previous products, cleaning agents, extraneous materials and microbiological contamination.One product trains dont require cleaning validation (but.)Polyproduction (multi purpose trains) have to be validated.Three subsequent cleaning procedures are required.Bracketing is accepted
324、.Acceptance limit should reflect strongest of the 3 criteria 1/1000 dose, 10 ppm, visual clean指导, 药政要求PIC: 清洗必须覆盖前面的产品，清洗媒介，外来的物料和微生物污染单品种连续生产不需要清洗验证（但是）多产品（多用途的生产链）必须验证三个后续的清洗程序是必需的接受的框架接受的限度应当反映最强的3个标准 1/1000 计量, 10 ppm, 目测清洁Guidances, Regulatory RequirementsFDA: Written instructions (SOPs) after
325、optimizing and final setting of cleaning procedure. if necessary dedicated equipment removal of residues of cleaning agents.Control of micro-organisms where appropriate Validation protocol (as part of the Validation Master Plan!) and report, approved by management.Risk based approach for limit setti
326、ng, why? 指导, 药政要求FDA: 在优化和最终设定清洗程序后形成书面的指在优化和最终设定清洗程序后形成书面的指令令(SOPs)如有必要需专用设备去除媒介的残留必要地方的微生物控制 管理层批准的验证方案（作为验证主计划的一部分）和报告风险，基于为限度设置的方法，为什么？Cleaning Validation in API ManufactureDefinition The process of providing documented evidence that the cleaning methods employed within a facility consistently c
327、ontrol potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels.It is necessary to validate cleaning procedures because - it is a customer requirement (ensures safety, purit
328、y) - it is a regulatory requirement in API manufacture - it assures through internal control the quality and compliance of the process 原料药制造中的清洗验证定义定义 成文的清洗程序必须要有证据来说明，用于设施上成文的清洗程序必须要有证据来说明，用于设施上的清洗方法能严格控制潜在的产品携带（包括中间的清洗方法能严格控制潜在的产品携带（包括中间体和杂质），洗涤剂和外来物料进入随后产品的水体和杂质），洗涤剂和外来物料进入随后产品的水平要在被预先决定的水平之下。平要在
329、被预先决定的水平之下。验证清洗程序是必要的，因为验证清洗程序是必要的，因为 - 客户要求 (确保安全，纯度) - 原料药制造的药政要求 - 确保通过内部控制质量，符合工艺 Dedicated Equipment (FDA, ICH Q7A)Stand-by times to be defined for cleaned/uncleaned equipment as well as time periods for campagne working. Time intervals for cleaning to be set. (degradation products, micro-organ
330、isms)APIs with high allergene potential (Penicillines, Cephalo- sporines)Pesticides (Herbicides, Fungicides, Insecticides) filters!, tarry or gummy residuesHigh active APIs (Steroids, Cytostatics)Infectious Material专用设备 (FDA, ICH Q7A)备用时间用来确定设备清洁/不清洁，也就是规模生产的有时间周期。设定用于清洁的时间间隔。（降级产品，微生物）有高过敏潜在的原料药（青霉
331、素，头苞菌素）农药(除草剂, 防霉剂, 杀虫剂) 过滤器！，柏油或胶的残留高活性的原料药（类固醇，细胞抑制剂）易传染物料Potential ResiduesPrecursors to the APIBy-products and/or degradation products of the APIThe previous productSolvents and other materials employed during manufactureMicro-organismsCleaning agents and lubricants, surfactants潜在残留原料药的前体副产品和/或原
332、料药的降解产品前面的产品在制造中使用的溶剂和其他物料微生物洗涤剂和润滑剂，表面活性剂Cleaning Validation Policy How to approach Cleaning Validation?It is advisable for API manufacturers to hold an official Cleaning Validation Policy.Specific department responsibilities should be outlined in this and it should be approved by senior management
333、.Definition of terms (swab, rinse, flush, wash.)Statement of company policy on validation of cleaning proc.Re dedication of equipment (dangerous, highly active)Analytical validation policyRational for the methods by which acceptance criteria are determinedRevalidation policy清洗验证方案怎样进行清洗验证在原料药的制造中制定一
334、个正式的清洗验证方案是恰当的由专门的部门负责，其职能应该由高级主管部门批准术语定义（擦拭，淋洗，冲洗，洗涤.)清洗程序验证中公司方针的声明关于设备的专用性（危险的，活性高的）检测验证方案方法的合理性，接受的标准是已确定的再验证方针Cleaning liquid5150R 1 / R 5 / R 9 + R 13R 4 / R 8 + R 12R 3 / R 7 + R 11R 2 / R 6 + R 13S 1S 2 + S 3S 4S 5 + S 6API Production TrainMungenast, Merck 清洗液5150R 1 / R 5 / R 9 + R 13R 4 /
335、R 8 + R 12R 3 / R 7 + R 11R 2 / R 6 + R 13S 1S 2 + S 3S 4S 5 + S 6API 生产链Mungenast, MerckTypical API Train Equipment Cleaning method Sampling Examples forSurfaces in m2Steering kettle Zentrifuge Filter housing Filter material Drying oven Tumble dryer Pipings 10-30 5 5 2-30 10 10 5典型的原料药制造链典型的原料药制造链设
336、备 清洗方法 取样 实例： 表面积 m2反应釜 离心机 过滤器 过滤材料 干燥烘箱 摇摆干燥器 管路 10-30 5 5 2-30 10 10 5Multi-Product EquipmentChemicalsPrecursors to APIsAPIsExcipientsFood additivesCosmetical substances多种产品使用的设备化学品原料药的前体原料药赋性剂食品添加剂化妆品物质Levels of CleaningThe degree or level of cleaning and validation depends on: - the equipment u
337、sage (dedicated or not) - the stage of manufacture (early, intermediate, final step) - the nature of the potential contaminants (toxicity, solubility ,.)The higher the potential for finished API contamination the greater the requirement to validate (ensure product safety!)Different levels possible b
338、ased on the stage of process beeing cleaned and the subsequent product manufacturedIt is the responsibility of the manufacturer to demonstrate that the level of cleaning and validation is adequate.Cleaning should be carried out as soon as practical after the end of processing and should leave the pl
339、ant in a suitable condition for next use.清洗水平清洁验证程度或水平取决于以下内容： - 设备的用法（专用或非专用） - 制造阶段（早期，中间体，成品阶段） - 潜在污染物的性质（毒性，可溶性.)成品污染的可能性越高，验证的要求则越高(确保产品的安全性！）不同工艺阶段的清洗和后续产品的制造决定了不同的清洗水平制造商负责证明清洗的水平和验证是充分的。实际加工完成后，就应该进行清洗，使厂房处于适用下一步使用的状态。API 2Step 1API 2Step 2API 1Step 1API 1Step 2API 1Step 3Cleaning Validatio
340、nLimit 10-100 ppmBulk BStep 1Bulk BStep 2Cleaning Limit 100-1000 ppmCleaning visually cleanLevels of Cleaning and Validation原料药 2步骤1原料药 2步骤2原料药 1步骤 1原料药 1步骤 2原料药 1Step 3清洗验证限度10-100 ppm原料药 B步骤1原料药 B步骤2清洗限度 100-1000 ppm清洗 目测洁净清洗水平和验证Levels of Cleaning and ValidationLevel 2 Product changeover of equip
341、ment used in final step Intermediates of one batch to final step of another Validation required - essentialLevel 1 Intermediates or final step of one product to intermediate of another Early step to intermediates in a product sequence Risk assessment: progression between level 0 and 2 depending on p
342、rocess and nature of contaminant based on scientific rational Level 0 in-campaign, batch to batch changeover No validation required清洗水平和验证水平水平 2在成品阶段产品更换使用设备。在成品阶段中间体由一种换为另一种。 验证要求 必须水平水平 1 中间体或成品步骤的一个产品变为另一个产品的中间体 在产品程序中早期的产品变为中间体风险评估：根据工艺和科学原理决定的污染性质，风险评估：根据工艺和科学原理决定的污染性质，水平级数在水平级数在0到到2 水平水平0 在连续生
343、产中，批与批的交替在连续生产中，批与批的交替无验证要求无验证要求Levels of Cleaning and ValidationProduct change over Acceptance limit ValidationPrecursor to final step API 10 ppm-100 ppm Yes 1/100-1/1000 dosePrecursor to intermediate 100 ppm-1000 ppm YES/NOof an API RA for APILater step to earlier step of Visual clean or NOthe sam
344、e API 1000 ppm, RA Early step to early step ofof the same APIPrecursor to chemical Visual clean NO(No GMP product“) 清洗水平和验证产品更换产品更换 接受标准接受标准 是否是否 验证验证前体到原料药的成品阶段 10 ppm-100 ppm 是是 1/100-1/1000 dose前体到一个原料药的中间体 100 ppm-1000 ppm 是是/否否 RA for API同一原料药的后期步骤到前期步骤 目测洁净或 否否 1000 ppm, RA 同一原料药的前期步骤到前期步骤前体到化
345、学品 目测洁净 否否(否 GMP 产品“) Elements of Cleaning Validation - Stage 1Name a validation team (Production, Engineering, QA/QC)Determine the most appropriate cleaning procedure for the equipment - Generate and establish acceptance criteria for the contaminant. - The cleaning method will be determined by the
346、process, the equipment, the cleaning agents and the cleaning techniques available. - All aspects of cleaning procedure should be clearly defined in SOPs be they manual, CIP or COP.清洗验证要素阶段1成立验证小组（生产，工程，QA/QC)决定最适当的设备清洗程序 - 针对污染建立可接受的标准 - 清洗方法由工艺，设备，洗涤剂和可行的清洗技术决定 - 清洗的所有方面应由SOP确定，是人工洗涤，CIP或COP清洗Eleme
347、nts of Cleaning Validation Stage 1Develop and validate the sampling and chosen analytical methods for the compound(s) being cleaned - Swab - Rinse - CondensateDetermine % recovery, limit of detection, limit of quantification, accuracy of method, reproducibility, stability over time,.清洗验证要素阶段1针对清洗的成分
348、，开发验证取样以及分析方法的选择 - 擦拭 - 淋洗 - 缩合确定回收率，最低检测限，定量限，方法的准确性，重现性，稳定性Elements of Cleaning Validation Stage 1Evaluate equipment surfaces and determine: - Worst case locations to sample (swab sampling) - Volume and type of rinse solvent to be employed (rinse sampling) - Equipment surface area, necessary to ca
349、lculate carry- over into subsequent batches.清洗验证的要素阶段1评估设备标明和确定： -样品位置最不易清洗（棉签取样） - 所用体积和淋洗溶液的类型（洗液取样） - 设备表面积，计算带入后续批次的数量Elements of Cleaning Validation Stage 2Develop a cleaning validation protocol for the product and the equipment being cleaned which should encompass: - Introduction - Scope - Equ
350、ipment - Cleaning procedure - Sampling procedures - Analytical testing procedure - Acceptance/Cleaning limits - Acceptance criteria for the validation清洗验证的要素 阶段 2为产品和需清洗的设备开发一个清洗验证方案，应该包括： - 介绍 - 范围 - 设备 - 清洗程序 - 取样程序 - 分析检测程序 - 接受的/洁净的限度 - 验证接受的标准Elements of Cleaning Validation Stage 3Interim Repor
351、t is required where there is a long period of time between manufacture of the validation runs! - Generate an interim cleaning validation report on a clean by clean basis detailing the acceptability of the cleaning procedure for the equipment and the product.清洗验证的要素 阶段 3需要临时的报告，因为在制造和验证实施之间有一段比较长的时间!
352、 - 依据针对产品和设备细化的可接受的清洁程序，产生临时的清洗验证报告Elements of Cleaning Validation Stage 4Generate cleaning validation report detailing the acceptability of the cleaning procedure for the equipment and the product. - give a detailed background and introduction to the cleaning validation study. - evaluate all data g
353、enerated with respect to set acceptance criteria for the study. - indicate the requirement if any for revalidation (period of time, change control,.)清洗验证的要素 阶段 4依据针对产品和设备细化的可接受的清洁程序，生成清洗验证报告 - 对清洗验证的研究给出详细的背景和介绍 - 依照为研究设定的标准对所有生成的数据评价 - 指出任何再验证的要求（时间周期，变化控制. ）Elements of Cleaning ValidationEstablish
354、ment of Acceptance CriteriaCleaning Validation should demonstrate that the procedure removes contaminants“ of the previous substance down to preset acceptable levels.The cleaning procedure does not contribute unacceptable levels of residual materilas to the equipment.The limits set are practical, ac
355、hievable and justifiable.Focus should also be given to partial reactants, by-products besides the principle reactant.Companies should decide on which residue(s) to quantify based on sound scientific rational.清洗验证的要素可接受标准的建立清洗验证应当证明，程序去除了以前的物质的污染，将它降低到了设定的可接受的水平清洗程序无助于设备残留物处于无法接受的水平限度的设定是实际的，可以达到的并且是
356、合理的也应该关注除主反应物以外的部分反应物，副产物公司应当用科学的根据为残留定量 Acceptance Criteria Chemical DeterminationGenerally residual API or intermediate is of greatest concernLimits can be based on toxicological or therapeutic data: - an Acceptable Daily Intake (ADI) + safety factor is calculated and converted to the max. allowab
357、le carryover - maximum of 1/1000 of lowest dose of previous product is allowed in maximum dose of following product. The validation protocol outlines how the limit per sample is set. - if no data for the API are available 10 ppm criterion (0.1 %) has to be established. (ICH: 0.1% of an individual un
358、known or 0.5% total unknown materials may be present in the product being tested)可接受的标准 化学判定通常，残留的原料药或中间体是最受关注的限度可以来源于毒理学或治疗数据： - 利用日摄入量安全系数可以计算转换出最大允许量。 - 前面产品的最低剂量的1/1000（最大），可以作为下一产品的最大剂量限度。验证方案须说明每个样品的限值是如何设定的。 - 如果该原料药没有可提供的数据，则10ppm的标准是必须的(0.1 %). (ICH:0.1的未知杂质或0.5未知总杂质是可以出现在被检测的产品中的)10 ppm Cr
359、iterion FDA StatementSome firms have incorrectly applied the 0.1% impurity identification threshold as acceptance limit.This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process of relat
360、ed compound and not extraneous impurities caused by cross contamination.0.1% criterion may be used depending on the stage of the process.Cleaning procedure should remove any cleaning agents introduced. Acceptance criteria absence of these materials within capabilities of assay and sampling method.Fi
361、rm must decide on Acceptance Criteria which are justifiable for their particular situation.10 ppm 标准 FDA 声明部分厂商不正确的运用了0.1的杂质识别阀值作为可接受的限度0.1的杂质阀值的运用是不适当的，因为该限度是为生产工艺中的相关物质而设定的杂质，并不指引起交叉污染的外来杂质根据于工艺阶段， 0.1% 的标准可以被使用清洗程序应当去除任何使用的清洗剂。可接受的标准-这些材料不存在-在取样方法和含量分析的能力范围内厂商必须针对他们的具体情况提出合理的可接受的标准Acceptance Crit
362、eria Physical DeterminationThere should be a provision during routine cleaning for a visual examination of the equipment, verifying that it is free of visible residues.The validation protocol should include this requirement as an additional acceptance criterion.White residues are visible on stainles
363、s steel surfaces if the amount exceeds 400 g/100 cm2 .Special attention should be given to areas that are hard to clean (agitator shafts, thermowells, discharge valves) and areas that would be difficult to verify on a routine basis.可接受的标准 物理判定应该有这样的条款：目测检查设备的日常清洗，检验其没有可见的残留验证方案应当包括这样的要求作为一项附加的可接受的标准
364、白色的残留在不锈钢的表面是可以看到的，如果数量超过400 g/100 cm2特别注意的是，应该划分出难清洗的区域（搅拌桨，温度计套管，卸料阀）和日常基础难检验的区域Acceptance Criteria Microbiological DeterminationAppropriate studies should be performed (swabs and/or rinse sampling) where the possibility of microbiological and endotoxin contamination of subsequent product is deeme
365、d possible and presents a product quality risk. (e.g. non-sterile APIs used to manufacture sterile products)Requirements in pharmacopoeal monographs have to be fulfilled.可接受的标准 微生物判定应当在有些地方进行适当的研究（拭擦和/或浸泡取样）：微生物和内毒素可能会污染接下来的产品，进而被认为存在质量风险（例如，非无菌的原料药用于制造无菌产品） 药典专论中的要求必须满足Cleaning ProceduresSOP for ea
366、ch piece of equipment and process must be prepared.Evaluate equipment design with respect to residues to be removed, the available cleaning agents and cleaning techniques when determining the optimum cleaning procedure for the equipment.Cleaning procedures should be detailed, operator independent i.
367、e. rugged and reproducible to avoid any inconsistencies during the cleaning process.清洗程序必须准备每一段的设备和工艺的SOP以残留的去除来评估设备的设计，以有效的清洗剂和清洗技术来确定针对设备的适宜的清洗程序清洗程序应当详细，操作工独立，例如有粗放性和可重复性在清洗过程中可以避免任何不一致Cleaning Procedures Equipment Parameters: - Identification of the equipment to be cleaned - Property of material
368、s - Difficult to clean areas (gaskets, filters, hoses, weld joint, ball cock/valve, pipings (with measuring devices!) - Ease of disassembly, fixed or notResidues to be cleaned: - Cleaning limits, calculation, criteria - Solubility of residues (water, organic solvents,) - Length of campaigns, stand-b
369、y times (wet residues should not begin to dry)清洗程序 设备参数: - 标明要被清洗的设备 - 物料的属性 - 难清洗的区域（垫圈，过滤器，胶管，焊接点，球阀，管道（带计量装置！） - 是否易拆卸，是否固定残留的清洗: - 清洗限度，计算结果，标准 - 残留的溶解度（水，有机溶剂, ） - 生产跨度，待用时间（湿的残留不可开始干燥）Cleaning proceduresCleaning agent parameters to be evaluated: - Preferably materials that are normally used in
370、 the process - Detergents available (use detergents only if absolutely required, minimize use/amount!) - Solubility properties (kind and amount of water, solvent) - Environmental considerations - Health and safety considerations清洗程序清洗剂参数的计算: -最好是工艺中正规使用的物料 - 除垢剂的使用 (除非必须，使用最少量的除垢剂) - 溶解度 (易溶于水，溶剂) -
371、 环境因素 - 健康安全因素Cleaning ProceduresCleaning Techniques to be evaluated: - Manual cleaning - CIP (Clean-in-place) - COP (Clean-out-of-place) - Semi automatic - Time considerations; cleaning time, stand-by time; instable products sould not degradate - Number of cleaning cycles - Temperature, pressure, s
372、team, special spray nozzles,.Other requirements if necessary to be defined清洗程序需要评估的清洗技术 - 人工清洗 - 自动封闭清洗 - 拆卸清洗 - 半自动 - 时间考虑；清洗时间，备用时间，不稳定产品不可降级 - 清洗循环次数 - 温度，压力，蒸汽，专门的喷孔其他需要特别要求的内容Cleaning Procedures - Documentation Detailed definition of levels of cleaning to be performedDetailed description of cle
373、aning methodsSOP should require to inspect and verify cleanliness prior to manufacture of next batch (to be recorded!)SOP should detail where verification of cycle parameters (if automated) and checklists(complex manual procedures) is necessarySteps needed to protect the equipment from contamination
374、 after cleaningSOP should require control that no water/traces of water is left in the equipment after cleaningDate of cleaning by whom, when, who did control, previous product, etc. to be recorded. 清洗程序-文件明确需要的清洗水平详细描述清洗方法SOP中需要明确清洁是优先于后续批次的生产的。（要有记录！）（如果是自动的），SOP中应明确循环参数的检验，（复杂的人工清洗过程中）检验清单是必需的设备清
375、洗后污染的防护措施SOP中需要明确在清洗后设备上没有水/水迹记录中应标明清洗人，时间，审核人，清洗前的产品等。Sampling Methods Regulatory GuidancePIC/S Guideline describes only two suitable sampling methods, Swab test and Rinse test. (No Placebo or Next product methods)FDA prefers the swab test or a combination of swab and rinse test. Rinse test only is
376、 judged as critical.Swab test to be prefered if surfaces are simple to reach.Complex equipment with hidden or problematic surfaces usually require the rinse test.In pharmaceutical production swab test is mostly used.In the API production surfaces are large and often not easy to reach; rinse test is
377、mostly used. 取样方法-规范指导PIC/S指导中只描述了两种适当的取样方法，擦拭检验和淋洗检验。（无无效对照剂或下一产品方法）FDA 较为看重擦拭检验或擦拭和淋洗结合检验。如果表面是容易擦到的，则擦拭检验是较好的方法。对于有隐藏部分或表面不易擦到的复杂设备通常要求用淋洗方法。在制剂生产中擦拭方法是最常用的。在原料药生产中，通常设备表面较大并且不易擦到，淋洗方法最常用。 Guide to Inspection of Validation of Cleanig Processes FDA 1993 There are two general types of sampling that
378、 have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions“1993年年FDA清洗程序验证检查的指导清洗程序验证检查的指导 “大体有两种可接受的取样方法。最理想大体有两种可接受的取样方法。最理想的是直接接触设备表面的方法。另一方法是的是直接接触设备表面的方法。另一方法是使用淋洗液使用淋洗液. ”SamplingTwo methods genera
379、lly employed: SWAB and/or RINSE sampling. Testing in next product to be explained,exceptionSWAB: sites must be chosen with care, should reflect worst case locations, result to be extrapolated to the total product surface area which leads to a worst case of potential carryover into subsequent product
380、.Employs physical as well as chemical forces; evaluate sampling technique!Swabbing efficiency (% recovery) must be determined (70%, 80%!)Ensure that swab extractables do not interfere with the sampling method Insoluble residues due to physical action can be sampled取样用两种方法取样：擦拭和/或淋洗。检测下一产品的方法需要解释，是例外
381、。 擦拭：位置必须仔细选取， 应选用位置最不好的地方，由此种最坏情形推导出全部产品表面积及可能带到后续产品中的最大可能性。使用的物理方法和化学方法并重 ；评估取样技术！擦拭效率（回收率%）必须确定(70%, 80%!) 确定擦拭的提取不会影响取样方法由于物理行为加入的不可溶解物质能够被取到。Swab TestAdvantages Normally accepted by FDA Will remove residues from surfaces with a high probability Simply to handle (after training of personnel!)Dis
382、advantages Analytics more complicated/expensive than with rinse test - determination of recovery rate - extraction of swab material Does not represent the whole surface Not applicable in contained systems with CIP擦拭检测优势 通常都能被FDA接受 通常除去表面残留的可能性最高，易操作（人员必须经过培训）劣势 检测复杂/比淋洗检测费用多 - 确定回收率 - 从擦拭物里提取 不代表整个表
383、面不适用于CIP设备的包装系统Swab Test Schlinggaze Tupfer (Wiper) (Firma Hartmann) Cleantip TX761 (Firma Texwipe) 5 ml volume for extractionDr. F. Schmidtke, Schering AG擦拭检测 Schlinggaze Tupfer (Wiper) (Firma Hartmann) Cleantip TX761 (Firma Texwipe) 提取量5ML Dr. F. Schmidtke, Schering AGSwab TestDefine material of s
384、wab (surgical gauze DIN 61630-VM 20 supplier (Hartmann), type Pagasling Nr. 3.Define swab area and swab technique (directions, pressure, with model, manually, with tweezers)Wetting of swabs with suitable solvent does increase recovery rate.Transport of swab (type and size of container, labelling)擦拭检
385、测确定擦拭材料（外科用纱布DIN 61630-VM 20 供应商(Hartmann), 型号： Pagasling Nr. 3.确定擦拭面积和擦拭技术（方向，压力，有模型，人工的，用镊子）用适当的溶剂湿润棉签可以提高回收率棉签的传送（容器的大小型号，标签）Sampling RINSE SAMPLINGThe solvent rinse occurs after cleaning has been completedNot direct as swabbing but covers the entire surface area including parts not accessible to
386、 swabs.Rinse method allows greater ease of sampling than swabbingA reduced number of samples is required to generate a carryover figure.取样淋洗取样在清洗完成之后再用溶剂淋洗不是直接擦拭而是遮盖住其他部分，包括不可被擦拭的地方/淋洗方法的取样要求比擦拭方法要随意的多。取样数减少Rinse TestAdvantage - Analytical determination easier, often sample can be used for detection
387、 - Represents the whole surface - Contained systems with CIP technique can be tested - solubility of residue(s) can be increased by adding solvents; additional solvent rinse is possibleDisadvantage - Is the residue really in the sample or still on the surface? - Results not reliable if residues are
388、not soluble in rinse media.淋洗检测优势 - 化验方法简便，通常样品能被用来检测。 - 代表整个表面 - 密封CIP 设备的包装系统能被检测 - 加入溶剂使残留物的溶解度加大；另外的溶剂淋洗是可行的。劣势 - 残留是真的在样品中还是留存在表面？ - 如果残留物不溶解在淋洗媒介中，结果就不可靠Typical API Train Equipment Cleaning method Sampling Examples forSurfaces in m2Steering kettle Zentrifuge Filter housing Filter material Dryi
389、ng oven Tumble dryer Pipings 10-30 5 5 2-30 10 10 5Fill with water, boil RinseWash, fill up, CIP Rinse/SwabWash, fill up Rinse/SwabDedicated!Wash/brush/wipe SwabWash, fill up Rinse/SwabWash, fill up, pump Rinse 典型的原料药设备链典型的原料药设备链设备 清洗方法取样 示例 表面积m2反应釜 离心机 过滤器 过滤材料 烘箱 摇摆干燥器 管路 10-30 5 5 2-30 10 10 5注水
390、，煮开 淋洗注满，设备自动清洗 淋洗/擦拭注满，清洗 淋洗/擦拭专用的!洗/刷/擦 擦拭注满，清洗 淋洗/擦拭注满，清洗 ，泵抽 淋洗/擦拭Analytical MethodsTo yield meaningful results from swab/rinse the analytical methods used should be validatedMethod is able to detect the target substance(s) at levels consistent with set acceptance criteriaWhere more than one sub
391、stance/residue is exspected (probably the normal case in API manufacturing) a method could be applied that is not specific but detects all residues together. Then additionally the assumption must be made, that the worst case ( most active/toxic) substance represents the whole residue.Practical appro
392、ach for industry: dry residue determination for non volatile impurities or TOC determination for water rinses.检验方法得出擦拭/淋洗样品结果的检验方法应是被验证过的。检测目标物质的方法符合标准。当不止有一种残留物质时（这可能是原料药制造通常状况），检测方法应该不是专用的，而是能检测出所有残留物的。而且必须假设某种最坏（最有活性的，最有毒的）物质代表全部残留。实用的方法：干残留决定不挥发杂质，TOC决定水淋洗Analytical MethodsThe analytical method
393、should include a calculation to convert the amount of residue detected in the sample to 100%.Stability of samples should be ensured for the time between sampling and testing if sample integrity could be affected.检测方法分析方法应包括一个把残留换算成百分比含量的计算如果样品是完整性易受影响的，应确定取样和检测的过程中样品的稳定性。Validation Protocols (VPs)VP
394、 is necessary to define the specific items and activities that will constitute a cleaning validation study. A Validation Master Plan should indicate the overall Cleaning Validation strategy for either the product range/equipment type/entire site.VP provides information about objective of the study:
395、- what cleaning process, product to be removed, equipment - rational for grouping products should be detailed - cleaning procedure should be defined (SOP) in detail: cleaning agents, soakage times, equipment parameters, number of cleaning cycles, etc.验证方案 验证方案是用以确定特定清洗验证中所必需进行的项目和行为。验证主方案应确定整体的清洗验证方
396、针，方针包括产品范围/设备型号/场所整体验证方案提供包括研究目的的信息 - 要清洗的工艺，要祛除的产物，设备 -产物的分类应具体 -SOP中应明确清洗程序：洗涤剂，浸泡时间， 设备参数，循环清洗的次数，等。 Validation Protocols (VPs)VP should provide the scope of the study: - which residues are to be tested for (rational), which not - why those residues (including cleaning agents), specific or non sp
397、ecific test (TOC) - how many times should the study be run before a report is compiled and recommendations madeVP should list process parameters to be verified, particularly necessary when automated or semi-automated cleanong techniques are to be employed.VP defines sampling and inspection procedure
398、 to be used - types of methods, where to be taken, how many, etc - an equipment sampling diagram should be referenced验证方案验证方案应提供研究的范围 - 需要检测哪些残留物，哪些不需要 - 为什么这些残留物（包括洗涤剂）要用专门的或非专用的检测方法（TOC） - 在起草报告前应该或推荐运行多少次进行研究尤其是使用自动或半自动清洗设备时是必须的。验证方案要确定取样和检查程序 - 方法的种类，在哪取样，取样多少，等 - 应参照设备取样图Validation Protocols (V
399、Ps)VP defines personnel responsibilities during the studyVP details test methods to be used ( to be referenced)VP gives rational about acceptance criteria (chem./phys.)VP defines how change control is appliedVP defines approval and signatures needed before the studyVP defines the time scheduleVP des
400、cribes recording and evaluation methods including statistical analysis methods验证方案验证方案应确定负责研究的人员验证方案应详细描述所使用的检测方法（要参考的方案）验证方案应确定合理的标准（化学的/物理的） 验证方案应变更控制怎样适用验证方案应研究前需要的批准和签名验证方案应确定时间计划验证方案应描述记录和评估方法包括统计分析方法Validation Reports (VRs)VR is necessary to present the results and conclusions and secure appro
401、val of the study; it includes:Summary/reference to procedures (clean, sample, test)Physical and analytical test results (or reference), as well as any pertinent observationsConclusions regarding the acceptability of the results, and the status of the procedure(s) being validatedRecommendations based
402、 on the results; revalidationApproval of conclusions; review any deviationsInterim reports on a batch by batch basis where neededVR should conclude an appropriate level of verification subsequent to validation验证报告验证报告必需有结果和结论，研究的批准；它包括：综述/程序的参考（清洗，取样，测试）物理的和分析的检测结果（或参考），相关的检查结论中包括结果的接受和已验证程序的状况根据结果得
403、出的建议；再验证结论的批准；审核偏差在批与批的数据后应有小节验证报告应确定验证后适当的生效标准。Minimum RequirementsIf company policy is not to validate all equipment cleaning procedures for all products then as a minimum requirement the validation policy should encompass worst case conditions to the procedure as: - removal of residues with great
404、est biological activity - removal of products with the least solubility (product grouping) - apply maximum idle time before cleaning - build equipment classes ( used most difficult to clean)Three consecutive successful cleaning validation runs needed to demonstrate reproducibility (if possible!)Equi
405、pment grouping (similiar size, design, construction) is possibleConcurrent validation when product is manufactured infrequently最低要求如果生产商的方针不是为所有设备做清洗验证，那么作为最低要求验证方针应围绕最差的例子做验证： -用最大生物活性去除残留 - 用最低溶解度去除产物（产物团） - 在清洗前，最长的闲置期 - 建立设备级别（使用最难清洗的）三个连续的清洗验证批次需要证明其重现性（如果可能）设备分组是可能的（相同批量，设计，建造）当产品的制造频率发生较少时，做同
406、步验证 Change Control / RevalidationValidated cleaning procedures to be included in the change control program.Change: equipment, product, process, cleaning procedure; review or revalidation has to be performed.Cleaning procedures should be monitored at appropriate intervals after validation to ensure
407、effecttiveness during routine production.Monitoring can be done by analytical testing and visual inspection, where feasible.Visual inspection can detect cross contamination concentrated in small areas difficult to reach! (mirror!)变更控制/再验证 清洗程序的验证要包括在变更控制程序中变更：设备，产品，工艺，清洗程序；须进行再验证。在验证后适当的间隙内，清洗程序应该被监
408、测，以此来确定在日常生产中的有效性。必要的地方，监测可以用目测和分析方法检验目测可以检查小面积难接触的地方的交叉污染（反光镜！）Summary CV Program contains the following ElementsDefine Equipment (ID No) and products (previous, following)Assess impact of this process on routine processesDetermine cleaning agent and method (detailed!)Determine acceptance criteria
409、for the residues/cleaning agents. Give scientific rational!Determine degree of evaluation required for validationDefine residues to be tested for based on solubilities/toxDevelop sampling and analytical methods for recovery and detection of residues (swab, rinse, HPLC, TOC, dry residue)Acceptance cr
410、iteria for the validationCompile and approve validation protocolPerform validation studies according with protocolCompile and approve a Validation Report documenting studies, conclusions and recommendationsDefine revalidation policy 概述-清洗验证方案包含下列要素确定设备（设备编码）和产品（前期，后期）评估在日常生产中的工艺影响。确定洗涤剂和方法（详细的！）确定对残
411、留物接受的标准/洗涤剂。要有科学根据！确定验证的程度和评估验证的要求根据溶解度/毒性确定残留物的检测确定取样和有回收率和残留物检测限的分析方法（擦拭，淋洗，HPLC，TOC， 干燥残渣）验证的接受标准起草和批准验证方案 根据验证方案进行验证研究起草和批准验证报告，文件审核，结论和建议确定验证方针Good Manufacturing Practice Inspectionsin API ProductionDr. Berthold Stemmle Pharma Consulting良好制造规范原料药生产的检查Berthold Stemmle 博士 药物顾问Objective and Purpos
412、e of GMP - InspectionsCheck and evaluation of QA-SystemsHow is quality produced into the API?Control of official requirements (following the law)Information in documents/dossiers for approval identical with procedures and documentatian within the firm? Compliance in all areas of QC, QA, Production?C
413、ontrol of current GMP status.Support the implementation of GMP measures.Inform management about deficiencies to ensure support for necessary corrections.Any improvements compared to previous inspections?Ensure a safe product of defined quality with no risk for the patients.GMP的目的和目标检查检查和评估QA系统生产出原料药
414、的质量如何？官方要求的控制（遵循法规）公司内部的文件信息/批准的规程和文件QC,QA，生产等所有的区域是否符合要求目前的GMP状态的控制支持GMP实施的措施把缺陷通知管理部门以确保整改措施的必要支持相比先前的检查是否有任何改进？以确定的质量确保安全的产品，以及患者的无风险Types of Inspections/AuditsSystem orientated QS system, documentation system, organisation of batch release, training of personell, handling of OOS results, deviati
415、ons, changes; definitions of interfaces in GMP areasProduct orientated Batch and QC documentation (compliance!), annual product reviewsMaterial flow orientated Receipt and quarantine production packaging distribution (with documentation)Documentation orientated Control of production and QC documenta
416、tion of one batch, SOPs, reports, log-books, raw data, quality manual, etc.检查/审计的类型系统导向系统导向系统，文件系统，批放行的组织，人员的培训， OOS的处理结果，偏差，变更；GMP分工的界定产品导向产品导向产品批次和QC文件（遵循指南！）年度产品回顾材料流程导向材料流程导向接收和待验生产包装分销（与文件一起）文件导向文件导向产品的控制和一批产品的QC文件，SOP，报告，日志，原始数据，质量手册，等GMP Inspection StepsPreparation (first impression, presenta
417、tion of company, key persons, responsibilities, organisation chart, 30 min)InspectionFinal discussion with findings (critical, mayor, minor) with time frame for corrections.Inspection report (no new findings!)Corrective measures with time schedule, responsibilitiesInform inspectors when all measures
418、 are completed; if required, documents have to be sent to the authorities.Inspectors will take a decision for re-inspections depending on quality of documents!GMP 检查步骤准备（第一印象，公司的介绍演示，关键人物，指责，组织机构图，30分钟）检查发现问题（重大的，主要的，次要的）的最后讨论，整改的时间框架检查报告（没有新的发现！）整改措施及其时间表，责任.当所有的措施完成后通知检查官；如果有要求，文件必须递交到官方部门根据质量文件，检
419、查官决定再检查！Inspection of API - DocumentationGeneral documentation in the firmAPI specific documentationSummarizing and evaluating product documentsContent of Annual Product Review“原料药的检查文件公司的总文件原料药专门的文件汇总和评估产品的文件产品年度回顾的内容General Documentation in the FirmCompanys organisation (organisation chart with fu
420、nctions, aereas of responsibility, job descriptions, deputies, list of signatures).Records of external and internal training measures.Blue print of building/facilities.Calibration and maintenance records (following plans!)List/hierarchy of all SOPsCleaning protocol for bulding and facilitiesCleaning
421、 procedures for facilities and equipment公司里总的文件公司的组织机构（组织机构及其功能图，指责区域，指责描述，代理人，签名表）外部的和内部的培训措施记录建筑/设施图校验和维护记录（根据计划！）所有SOP的清单/分级建筑和设施的清洗方案设施和设备的清洗程序API specific DocumentationFlow chart of synthesis or process including equipmentOfficial documentation at Health AuthoritiesManufacturing instruction and
422、 batch recordLists of raw materials for synthesis, solvents, reagents, excipients, packaging materialsList of suppliers including evaluation (audits!)List of equipmentBatch Flow SheetDocumentation of deviations, investigation, evaluationFinal batch evaluation by responsible production personBatch re
423、cord review (QS) plus signature原料药专门的文件包括设备的工艺合成路线图卫生部门的官方文件生产指令和批记录合成原料，溶剂，试剂，赋形剂，包装材料的清单供应商清单包括评估（审计！）设备清单批次流程单偏差的文件，调查，评估产品负责人的批产品最后评估批记录审核(QS)加签字API specific DocumentationOverview of changes with rational, History of ChangesApproval of changes in processes according to SOPDocumentation of change
424、s in manufacturing instructions with version controlsList of rejected batchesImpurity profile (by-products, degradation products, solventsIPCs, analytical testing procedures for APIs, intermediates, raw materials. Other control procedures?Critical process parameters as basis for validationSampling p
425、lans原料药专门的文件合理的变更审核，变更历史根据SOP，工艺变更的批准有版本控制的，制造指令的文件变更退货批次的清单杂质档案（副产品，降解产物，溶剂）IPC过程控制，原料药的分析检测程序，中间体，原料，其它控制程序？根据验证，关键的工艺参数取样计划Summarizing and Evaluating Product DocumentsQualification reports for main equipment/facilities (IQ, OQ)Validation protocol, -data, -reportCleaning validation for multi purpo
426、se equipmentAdditional validation reports for steps like blending, milling, drying, etc.Annual Product Review! with all batches manufactured 汇总和评估产品文件主要设备/设施的确认报告（IQ,OQ)验证方案，数据，报告多用途设备的清洗验证混批，粉碎，干燥等步骤的附加验证报告年度产品回顾！有所有生产的产品Content of Annual Product Review“Most important product specific documentation
427、Contents to be defined in a SOP (quality parameters, deviations, OOS results, etc.)Definition and rational for critical parameters (facility, process, testing procedure)List of batch dataList of all batches including evaluationTrend analysis of critical quality parametersList of all changes with eva
428、luation (Change Control!)List of deviations with evaluation (Failure Investig. Reports)List of OOS batches and evaluationList of complaints and recalls and evaluationList of stability data with evaluationPlanned measures/activities Continuation of listsFinal evaluation by QS with signature年度产品回顾的内容最
429、重要的产品专门的文件最重要的产品专门的文件内容要在SOP中确定（质量参数，偏差，OOS结果，等）关键参数的定义和根据（设施，工艺，检测程序）批数据清单所有批次清单包括评估关键质量参数的分析趋势所有变更与评估的清单（变更控制！）偏差与评估清单（不合格调查报告）OOS清单批次和评估投诉，召回和评估清单稳定性数据和评估清单计划的措施/行为 后续清单后续清单部门的最终评估及签名部门的最终评估及签名Inspection Tour through Buildings/FacilitiesStatus of facilities/equipment: product, batch, cleaned?All
430、needed instructions available, log-books showing calibration, maintenance, repair, cleaningLast step of API purification, packaging, sampling, labellingFilling room for final API according to GMP(air flow,cleaning)Cross contamination: where possible, how is it avoided?Mix-ups possible with previous
431、batches?Which data are generated, automatically. Raw data handlingCritical raw data double checkedLabelling of containers (labels not on the lid!)Stotrage area: Environment control, principle, quarantineOutside stored materials protected? SOPs available?Status label on materials: sampled, released,
432、rejectedIs ensured that only released material goes to production?在建筑/设施中的检查顺序设施/设备的状态：产品，批号，清洁？所有必要的指令，标明校验，维护，维修，清洁的日志都是得到的原料药纯化的最后步骤，包装，取样，贴标签根据GMP原料药成品的包装室（空气流，清洁）交叉污染: 在可能的地方，如何避免?可能与前面的批次混和?哪些数据是自动产生的？原始数据的处理关键的原始数据要双检容器标签 (标签不能在盖子上!)贮存区: 环境控制, 原则, 隔离户外贮存的物料的保护？有效的SOPs?物料的状态标识:取样, 放行, 拒收确保了只有放
433、行的物料进入生产?Inspection Tour through Buildings/FacilitiesRejected materials clearly labelled, stored in different storage areas?Are recovered solvents mixed with fresh solvents? Control?Quality of water taken for the process steps? Checks on regulary basis, system validated?Is feeding water used from we
434、lls, quality data? Flow chart.Are solvents filtrated before use in the final step?How are utilities (gases, air, compressed air, etc.) controlled? Specs available and followed?Are manufacturing activities recorded in parallel?在建筑/设施中的检查顺序不合格物理是清楚的标明的，储藏在不同的储藏区域中？回收溶剂与新溶剂混和？控制？工艺步骤用水的质量？日常检测，系统验证？饮用水
435、是从井里来的，质量数据？流程图在最终步骤中使用前，溶剂过滤了吗？如何控制工具（气体，空气，压缩气体，等）？有规定并遵守？制造行为与记录是同时的？FDA API Inspections, Main FocusCompliance of approved documentation with manufacturing and testing documentation, actual activities and behaviour.Is QS independent, upper management involved?Process Validation: protocol data rep
436、ort follow-upCleaning validation, how are cross-contaminations avoided?Annual Product ReviewFailure Investigation (in case of deviations or OOs-results)Change Control System (SOP followed?)Batch Record Review done by independent unit (QS)?Testing methods validated, impurity profiles set for APIs?Ong
437、oing stability tests running?GMP training of personnel done and reported (Plan!)Development report as basis for validation available?Validation of the water preparation system, + microbiologicalCalibration and maintenance of facilities/equipmentFDA 原料药检查，主要焦点批准的制造和检测文件，实际的活动还有行为的遵循是否QS部门独立，有高级管理人员参与
438、？工艺验证：方案数据报告跟踪清洗验证，如何避免交叉污染？年度产品回顾不合格调查（如偏差或OOS结果）变更控制系统（遵守SOP？）独立的单位（QS)审核批记录?验证的检测方法，为原料药设定杂质档案？进行中的稳定性试验在运转吗?GMP人员培训的实施和报告（培训计划！）发展报告是以有效的验证报告为基础的吗?水系统的验证，微生物检测设施/设备的校验和维护Mostly observed GMP Deficiencies during Inspections of API Manufacturer by FDALaboratory ControlsRecords/ReportsAPI StabilityEquipment CleaningWater SystemsWritten ProceduresProcess ValidationProcess ControlsFDA对原料药制造商检查中常发现的GMP缺陷化验室控制记录/报告原料药稳定性设备清洗水系统书面规程工艺验证工艺控制
