FDA-API-inspection-training.ppt

1、Conferences defined chemical properties and structure!,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 Manufacturing,Chemical synthesis: production of

2、API starting material- introduction of API starting material into process production of intermediate(s) isolation and purification- physical processing and packaging Derived from animal sources: collection of organ, fluid, or tissue cutting, mixing, initial processing introduction of the API startin

3、g material into process isolation. Extracted from plant sources: collection of plants cutting and initial extraction further extraction physical processing API consisting of comminuted or powdered herbs: collection cutting/comminuting physical processing and packaging Biotechnology-Fermentation/cell

4、 culture: establishment of master and working cell bank maintenance of working cell bank cell culture/fermentation isolation and purification physical processing and packaging Classical“ fermentation to produce an API: Establishment and maintenance of the cell bank introduction of the cells into fer

5、mentation,.,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 Scope,The company should designate

6、and document the rationale for the point at which proiduction of the API 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

7、steps determined to impact the quality of the API.(AM critical steps identified?) 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 excipi

8、ents/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，纯化和包装，原料药制造的GMP规则逐步严格。 物理过程，例如造粒，包衣，和赋形剂/零头的混和，粉碎，满足GMP的要求,API Starting Materials (API-SM),Responsibility of com

9、panies to propose 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 auth

10、orities will require 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

11、 GMP“ (not the API-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

12、，药政官方部门将要求原料药的起始物料有更详细的资料！（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），如用于半合成青霉素的6-APA是被FDA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！,API-SM,Where the proposed API-SM is close to the API ensure that details on the synthetic process and analytica

13、l 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 for supply of API-SM!,Any change i

14、n 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 materials,API-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

15、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-SM,Synthetic or semi-synthetic APIs API-SM is analytically fully controlled in terms of identity, assay and impurities! API produced by direct fermentation Describe micro-organ

16、ism 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-SM based on a scient

17、ific 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 Production Interna

18、l Audits Product Quality Review,2. 质量管理,原则 质量部门职责 生产部门职责 内部审计 产品质量审核,2. Quality Management - Glossary,Quality 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 required for their intended use and that

19、 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 size and structure of the organi

20、zation. 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 characteristics of a product or se

21、rviceand 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。 质量控制 (QC) 是否符合质量规格的检查或测试。 质量属性

22、: 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 Management,Quality Management System - QMS,System needed to implement Quality Managem

23、ent efficiently.,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,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.,The Quality Assurance System - QMSystem .recognizes and describes interfaces, responsibilities,competences, Interactions.,.ensures clear Inputs for tasks,质量保证系统QM系统 职责的识别和描述,管辖相互作用,确定明确的职责分配,Interfaces Milestones Info

24、rmation flow/Interactions Tasks Competences Responsibilities,QMS is the arrangement of,管辖 分界 信息流动/相互作用 任务 权限 职责,质量管理系统,QMS,Documentation System,GMP,Describes system related quality,Describes product related quality,QMS,文件系统,GMP,描述与质量相关的系统,描述与质量相关的产品,GMP + Processes = QMS,GMP,Product related Quality

25、Documented evidence,Process,A set of interrelated or interacting activities which transforms inputs into outputs.,QMS,Including time-axis Including interconnections,GMP +工艺 = QMS,GMP,与质量相关的产品 文件化的证据,工艺,一系列相关的或相互作用的，把输入转化为产出的活动,QMS,包括时间轴 包括相互联络,General Considerations,PIC GMP Chapter 1: Quality Manage

26、ment “. To achieve the quality 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,PIC GMP 第 1章: 质量

27、管理 “要达到质量目标必须有广泛设计的和正确实施的质量保证系统， 加之以GMP规范并如此质量控制。应该完全文件化并有效监督。”,QMS,General Considerations,Introduction ISO 9001: “It is emphasized that the quality system requirements specified in this International Standard are complementary - not alternative - to the technical (product) specified requirements.”,

28、GMP,概论,ISO 9001 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。”,GMP,Comparison QMS / GMP,GMP,high,low,Degree of Detail,Validity within the company,QMS,GLP,GCP,比较 QMS / GMP,GMP,高,低,程度详述,公司内部的有效性,QMS,GLP,GCP,CEFIC Activities,Document combining ISO and GMP Requirements,December 1997,CEFIC 活动,ISO

29、和 GMP 要求的文件 的组合,December 1997,2.1 Principles,Quality 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. QMS should cover organisational structure, proced

30、ures, 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 should be specified. All quality related activities

31、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 Principles,Any deviation from established procedures should be documented and expla

32、ined, 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 and related actions (complaints, reca

33、lls, 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

34、、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 9001 Responsibility of Senior Management Quality Management System Controlling of Contracts Steering of Design Steering of Documents and Data Materia

35、ls 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, Preservation and Distributio

36、n Steering of Quality Records and Documents Internal Quality Audits (Self Inspection) Training Maintenance Statistical Methods,质量管理系统, 根据DIN ISO 9001的原理 高级管理层的责任 质量管理系统 合同控制 设计操控 文件和数据的控制 物料管理 对客户提供产品的操控 产品的识别和追踪 工艺操控 检测 委托检测的控制 检测状态 缺陷产品的操控 纠正与预防措施 操作，储存，包装，保存和分发 质量记录和文件的操控 内部质量审计（自检） 培训 维护 统计方法,Re

37、quirements according to DIN EN ISO 9001 9001 / 4.10 Testing Final Testing according to QM protocol or written testing procedure previous checks with results within acceptance criteria performed no distribution before having conducted all defined tests and approval of data and documents Testing Recor

38、ds Evidence that quality testing according to defined acceptance criteria exists Sign/signature Released“ of responsible person/unit,依据 DIN EN ISO 9001的要求 9001 / 4.10 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 Manageme

39、nt System Principle The holder of a manufacturing authorization must ensure that medicinal products -fit for their intended use (effectiveness, safety, purity) -comply with the requirements of the marketing authorization -are no risk for patients due to inadequate safety, quality or efficacy. The at

40、tainment of this quality objective is the responsibility of senior management and requires the participation and commitment by -staff in different departments at all levels -the companys suppliers -the distributors To achieve the quality objective reliably there must be a comprehensively designed an

41、d correctly implemented system of Quality Assurance incorporating GMP and thus Quality Control. QA should be -fully documented and its effectiveness monitored - adequately resourced with competent personnel, sufficient premises, equipment and facilities.,EC GMP 指南 QMS 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 (

42、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 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 System,Cost Accounting nach British Standard,质量管理系统,费用单 nach British Standard,EC GMP Guid

43、eline Documentation Principle Good documentation constitutes an essential part of the QA System. Clearly written documentation prevents errors from spoken communication -permits tracing of batch history -facilitates the search for any mistakes in case of complaints -hands over experience -facilitate

44、s training of newly recruited employees and deputies of employees -verifies the knowledge of employees -ensures that compliance with marketing authorization dossier can be controlled easily -ensures unchanged constant quality. Specifications, Manufacturing Formulae and Instructions, Procedures, and

45、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 好的文件构成了QA系统的一个要点部分. 清晰的书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. 文件的易识别是最重要的,2.2 Re

46、sponsibilities of the QU(s),QU should be involved in all quality-related matters QU should review and approve all quality-rel. Documents The main responsibilities of the QU should not be delegated. These responsibilities should be described in writing.,Responsible To be done by the Q-Unit,2.2 质量部门（Q

47、U）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 由QU完成,2.22 Main Responsibilities of QU,Releasing or rejecting APIs, intermediates. Establishing a system to release or reject raw materials. Reviewing batch production, lab control records,. validation protocols and reports Making su

48、re that critical deviations/OOS are investigated, internal audits are performed, complaints are investigated and resolved, effective systems are used for maintaining and calibrating critical equipment, stability data to support retest, expiry dates, storage conditions are available. Approving specif

49、ications, master production instructions, procedures impacting quality of intermediates/APIs, contract manufacturer/labs, changes with impact to quality. Performing product quality reviews.,2.22 QU的主要职责,放行或退回原料药，中间体. 建立 放行或退回原料制度. 审核 批产品, 实验室控制记录,. 验证方案和报告 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

50、系统，提供支持复测，有效期，贮存条件的稳定性数据 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,2.3 Responsibility for Production Activities,Preparing, reviewing, approving and distributing manufacturing instructions (according to SOP). Producing intermediates/APIs acc. to preapproved instructions. Reviewing all batch

51、 records; complete, signed? Making sure that production deviations are reported, evaluated, critical investigated, conclusions recorded! .production facilities are clean, calibrations are performed and records kept, validation protocols and reports are reviewed and approved, .new/modified facilities

52、 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 fo

53、r APIs Regular internal audits to be performed (schedule!) Findings and corrective actions listed, recorded, followed-up Documentation Attention 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

54、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!,2.5 Annual Product Quality Review,.to be conducted to show consisitency of the process. Critical in-process control and API test results Critical reaction parameters to be evaluated (Dev. Report!) Batches that failed to meet specifica

55、tions Critical deviations, investigations, conclusions (impact?) Any changes to the processes, analytical methods, specs, equipment,. Quality related returns, complaints and recalls Adequacy of corrective actions (permanent change?) Results of the review should be evaluated, corrections, changes, re

56、validation, approvals needed? For inspectors it is very easy to check your QMS and product quality!,2.5 年度产品质量回顾,.被指导来表明工艺的一贯性 关键的工序间控制和原料药检测结果 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？ 检查员们能非常容易地检查你们的QMS（质量管理系统）和产品质量!,And w

57、hat about training?,培训是什么?,3 Personnel 3.1Personnel Qualification There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs. The responsibilities of all personnel engaged in the ma

58、nufacture of intermediates and APIs should be specified in writing. Training should be regularly conducted by qualified individuals and should cover at a minimum, the particular operations that the employee performs and GMP as it relates to the employees functions. Records of training should be main

59、tained. Training should be periodically assessed.,3 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 培训应当被定期评定,3.1 Personnel Qualification Training Objectives of GMP Training Define and explain what GMP means How to transfer GMP into daily practice Generate consciousness for