Technical Requirements for the Registration Dossier of EDMF/COS/CTD and Filing strategies in EU countries

EDMF/COS/CTD注册文件的技术要求 及在欧盟国家的文件编撰策略

Technical Requirements EDMF compilation in CTD format : a) Module 3.2. S. Drug Substance b) Module 2.3 Quality Overall Summary CEP Procedure versus the DMF Procedure Filing strategies in EU countries Certification of suitability to the monographs of the European Pharmacopoeia Procedure ,Submission of the Dossier, Content of the Dossier/Expert Report, Assessment, Timetable, Follow-up

技术要求 CTD格式的EDMF的编撰: CEP程序对DMF程序 针对欧洲药典专论的适应性证书 a) 模块 3.2. S. 药物物质 b) 模块 2.3 质量概述 CEP程序对DMF程序 在欧盟国家的文件编撰策略 针对欧洲药典专论的适应性证书 程序，文件递交，文件内容/专家报告，评估，时间表，后续工作

How to get the guideline from the Internet ? www.emea.eu.int Human medicine or vet medicine Guidance documents ICH QWP Approved guidelines Guidelines under discussion

如何从互联网得到指南? www.emea.eu.int 人用药或兽药 指南文件 ICH QWP 批准的指南 讨论中的指南

Filing strategies CEP ASMF/EDMF procedure ???

文件编撰策略 CEP ASMF/EDMF程序 ???

CEP Procedure versus the DMF Procedure Guideline on Summary of requirements for active substances in the quality part of the dossier Classification of active substances : New active substances used for the first time in a medicinal product Existing active substances not described in the European Pharmacopoeia Existing active substances described in the European Pharmacopoeia

CEP 程序对 DMF 程序 针对文件质量部分中活性物质要求的概述的指南 活性物质的分类: 在药品中第一次使用的新的活性成分 在欧洲药典中没有描述的现有的活性物质 在欧洲药典中有描述的现有的活性物质

Application for a marketing authorisation of a Medicinal Product requires information on the Active Substance (AS): Certificate of suitability to the Monograph of the European Monograph Active Substance Master File (ASMF ) procedure Full details of manufacture

药品市场许可申请 活性物质(AS)的要求信息: 针对欧洲药典专论的适应性证书 活性物质主文件 (ASMF ) 程序 完整的制造细节

Feasible ways to submit Depending on the classification of the AS For new active substances and substances not described in the Ph.Eur. : ASMF/EDMF For existing substances, descrribed in the Ph.Eur. : CEP or ASMF/EDMF The AS manufacturer provides either: No 1) CEP or No 2 the ASMF/EDMF (Applicants part be included in the MA)

可行的递交方式 取决于活性物质的分类 对于在欧洲药典中没有描述的物质和新的活性物质: ASMF/EDMF 对于在欧洲药典中描述的现有的活性物质: CEP 或 ASMF/EDMF AS 制造商提供下列两者中的一个: 第1， CEP或 第2， ASMF/EDMF (MA包括此申请部分)

Submission of the CEP Generally avoiding any subsequent reassessment AS manufacturer submits : copy of the most curent CEP Written asurance that no significant changes in the manufacturing method have taken place Applicant submits : Results of batch analysis demonstrating compliance with the Ph.Eur. Monograph

CEP的递交 通常应避免下列任何的重新评估 作为制造商递交: 最新的CEP的复印件 书面保证：在采用的制造方法中没有发生重大变更 申请人递交: 批分析结果要证明符合欧洲药典专论的要求

ASMF/EDMF procedure Guideline on Active Substance Master File procedure : CPMP/QWP/227/02 Terms European Drug Master File (EDMF) and Active Substance Master File (ASMF) are interchangable Overview EDMF content Template letter of access and covering letter

ASMF/EDMF程序 活性物质主文件程序的指南: CPMP/QWP/227/02 欧洲药物主文件(EDMF)和活性物质主文件(ASMF)的条款可以通用 EDMF内容概览 准阅信和封面信的模板

ASMF/EDMF procedure Overall content of the ASMF/EDMF as indicated in NTA/CTD format Module 3 AP contains information non-condidental RP contains remaining information such as : Detailed information on the manufacturing steps (reaction conditions, temperature etc.) Evaluation of critical steps Quality control during manufacture Validation

ASMF/EDMF程序 按照NTA/CTD格式模块3的指示做ASMF/EDMF的全部内容 AP包含非保密的信息 RP包含剩余的如下信息: 制造步骤的详细信息 (反应条件，温度，等等) 关键步骤的评估 制造中的质量控制 验证

ASMF/EDMF Submission EDMF can only be submitted in support of an MAA EDMF Holder should submit to the MA holder: Copy of the latest version of the AP Copy of the QOS Letter of access AP contains information non-condidental EDMF Holder should submit to the authorities Complete EDMF with covering letter Letter of access

ASMF/EDMF递交 EDMF只能在MAA的支持下递交 EDMF的持有者递交到 MA的持有者: AP的最近版本的复印件 QOS的复印件 EDMF持有者应当把AP包含的非保密内容的准阅信递交到官方部门 有封面信的完整EDMF 准阅信

ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

Preparation and Filing of EDMF/ASMF for COS/CEP applicationies

申请COS/CEP的 EDMF/ASMF文件制作

Technical Requirements EDMF compilation in CTD format : a) Module 3.2. S. Drug Substance b) Module 2.3 Quality Overall Summary CEP Procedure versus the DMF Procedure Filing strategies in EU countries Certification of suitability to the monographs of the European Pharmacopoeia Procedure ,Submission of the Dossier, Content of the Dossier/Expert Report, Assessment, Timetable, Follow-up

技术要求 CTD格式的EDMF的编写： CEP程序对DMF程序 欧洲药典专论的适应性证明 a) 模块 3.2. S. 药物物质 b) 模块 2.3 质量综述 CEP程序对DMF程序 欧盟国家的文件编排策略 欧洲药典专论的适应性证明 程序，文件的递交，文件目录/专家报告，评估，时间表，跟踪执行

Certification procedure Application at the EDQM (European Directorate for the Quality of Medicines) How to apply ? Application form Procedere Timetable

COS证明程序 在EDQM申请（药品质量欧洲理事会） 怎样申请？ 申请表 程序 时间表

CEP Certification of suitability to the monographs of the Ph. Eur. Scope : CEP is intended for substances for which a monograph ( general or specific) has been adopted Organic or inorganic ( active or excipients) Substances produced by fermentation Products with the risk of TSE The CEP certifies that by applying the relevant monograph (if necessary with annex ) it is possible to ensure that all possible impurities from this particular route of manufacture can be fully controlled.

CEP欧洲药典专论的适应性证明 范围： CEP是针对那些已经被某个专论（大体的或详细的）所采用的物质 有机的或无机的（活性成分或赋形剂） 发酵产生的物质 有TSE风险的产品 通过应用相关的专论（附件，如果必要）CEP证明，从特别的制造路线生产的所有可能的杂质都是能够被完全控制的。

How to Apply ?

如何申请？

Submission Submission of one SINGLE copy of the full dossier QOS in addition to paper copy , electronic submission preferably in WORD format or read-write pdf Samples of 1-2 representative commercial batches (about 10 g) Application format and Annex 1 – 5

递交 递交整个文件的一份拷贝 QOS部分除了用文本文件，电子文本的递交最好用WORD文本或pdf 取1-2批有代表性的商业批次的样品(约10g) 申请格式和附件1-5

Annexes Annex 1 Letter of Authorisation ( if applicable) Annex 2 Letter of agreement ( if manufacturer not CEP holder) Annex 3 Declaration that manufacture of the substance is according to the dossier and GMP rules Annex 4 Letter of declaration of willingness to be inspected Annex 5 Letter of declaration regarding the use of material of human or animal origin

Annexes 附件二协议书(如果制造商不是CEP 的持有人) 附件一 授权信(如果适用) 附件三 所提交文件中的药物是按照GMP规则制造的. 附件四 愿意接受检查的声明信 附件五关于使用源于人或动物材料的声明信

Content of the Dossier Revised Guideline implemented by 1 September 2005 PA/PH/CEP (04) 1 3 R January 2005 : Quality Overall Summary QOS 2.3 according to the Notice to Applicants Volume 2 B Summary of the content of the dossier Discussion about the ability of the EP monograph to control the quality of the drug , in particular the declared potential impurities,or the necessity for alternative methods Justification where testing for possible impurities are omitted Imp. not detected in any batches or not present due to a particular production

文件目录 2005年九月一日生效的修订版指南PA/PH/CEP (04) 1 3 R January 2005 : 质量综述QOS2.3根据<申请人通知>卷2B 文件内容的概述 讨论关于用欧洲药典专论的要求来控制药物质量的能力 特别是药典公布的潜在杂质,或替代方法的必要性 省略对可能杂质的检测的理由 在任何批次中不检测的或由于某种特别的产物而不存在的杂质

Content of the Dossier General information 3.2.S 1 Commercialisation history of the substance : licensing history for medicinal products in Europe that contain the substance defined here Declarations : Annexes 1-5 Annex 3, applied GMP should comply the ICH Q7A , if available a copy of the GMP certificate If other parties are involved , details of their involvement , site addresses Manufacturer of the final substance performs purification only, declarations on GMP and willigness to be inspected should be provided for the contract manufacturer

文件目录 一般信息 3.2.S 1 物质的商业化历史:在欧洲药用产品的许可历史包括这里定义的物质 声明:附件1-5 附件3,应用的GMP应符合ICH Q7A,如果有,GMP证书的复印件 如果涉及第三方,详细的牵涉内容,地址 如果制造商仅是由纯化得到最终物质的,那么GMP的声明和愿意接受检查的声明应由合同制造商提供

Content of the Dossier Nomenclature General properties 3.2.S 1.3 : Physical characteristics , in case more than one grade .e.g. special particle size, compacted, particular polymorphic form one CEP only possible in case general specification is identical , otherwise different CEP with sub title Mixtures ( as explained in Substances for pharmaceutical ) API plus excipient only accapetable if this is defined in the monograph Claims regarding sterility etc. with reference to the monograph, freedom of pyrogens only if monograph foresees this

文件目录 化学名 常规属性 3.2.S 1.3 : 物理属性,当不只一种级别时,如,特殊的颗粒度,压缩的,如果一般的规格是确定的,一个多态形式只能有一个CEP ,否则,有副标题的不同CEP 混合物( 见药物物质的解释)原料药加赋形剂只有在药典专论中有确认才是可接受的. 关于无菌等的声明,参考专论,如果专论预见到焦精,而焦精的免用的声明

Content of the Dossier Manufacturer 3.2. S.2.1 If different sites are involved for asingle defined process for manufacture or testing , this should be explained Make clear which production step is conducted at which sites Names and addresses of each site should be given

文件的目录 制造商 3.2. S.2.1 如果一个单独的已确定的制造工艺或检测涉及不同的现场,这需要解释. 明确哪个生产步骤是在哪个现场进行的. 须给出每个现场的名称和地址

ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ARED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

Content of the dossier for chemical purity and microbiological quality

文件内容 化学纯度和微生物质量

Description of the manufacturing process and Process controls 3.2.S 2.2 Flow Chart incl. Structural formula for starting material and all intermediates Include all steps of the process, from starting material to the isolated intermediates to the drug substance Detailed description: solvents , reagents ,catalysts , reaction conditions, inf. on intermediates, quantities of all materials for a batch of commercial batch size, yields for isolated intermediates Specific emphasis on purification Max. batch size with experience acquired , reference to batches in the dossier In case of pilot scale batches yet, CEP can be granted providing scale up is immediately reported to the EDQM.

制造工艺和工艺控制的描述3.2.S 2.2 流程图包括起始物料和全部中间体结构式 包括从起始物料到分离中间体再到得到药物物质的所有工艺步骤 详细描述：溶剂，试剂，催化剂，反应条件，中间体的信息，一个商业生产批次的所有材料的数量，分离出的中间体的产量 尤其强调纯度 经验中所获得的最大批量，参考文件中的批次 仍处在中试批次中，如果批放大后立即报告EDQM，也可以获得CEP

Description of the manfacturing process and Process controls 3.2.S 2.2 For sterile products , variable or alternative batch sizes to be justified Isemi-synthetically manufactured API , fermented starting material well characterised, possible carrying impurities Declaration of use/non use of material of animal origin Different manufacturing sites and methods or alternatives could be described in one dossier , in case proof is given for each case sepcification and imp. Profile is exactly the same Responsibilities of different sites In case of alternative processes, batch analysis results to be presented to demonstrate no significant diff. in impurity profiles Re-processing , if re-application of a step already used

制造工艺和工艺控制的描述 3.2.S 2.2 对于无菌产品，可变的或交替的批量要被评估 半合成制造的原料药，已经完全定性的发酵起始物料，可能的运载杂质。 使用或未使用源于动物的材料声明 不同的或替代的制造地点和方法，如果对每种情况的规格和杂质都有证据，可以在一个文件中进行描述。概况是完全相同的。 不同现场的责任 如果有替代工艺，提出的批分析结果要证明在杂质概况中没有重大的差别。 再加工，再申请，如果一个工艺步骤已经使用

Description of the manfacturing process and Process controls 3.2.S 2.2 Re-working –application of steps different from the described process not acceptable Recovery ( mother liquors or filtrates ) of reactants, intermediates or final substance , acceptable in case of approved procedures Recovery of the substance without further purification is re-working, not acceptable Blending of production batches to obtain larger size is acceptable, providing each incorporated batch is individually tested and meets specification, prior to blending

制造工艺和工艺控制的描述 3.2.S 2.2 与所描述的工艺不同的步骤的返工申请不可接受 如果规程经过批准，回收的（母液或滤液）反应物，中间体或最终物质可接受， 没有进一步纯化的回收物质进行返工，不可接受 如果每个混合前的小批都是被独立检测过的，并且符合标准，混合小批以获得大批是可接受的，

Schematic description AS SM 1 catalyst Solvent SM 2

图解 AS SM 1 催化剂 溶剂 SM 2

3.2.S.2.3 Control of materials Specification of raw materials and solvents , appropriate In case a class I solvent could be present in a solvent , specification and test method; e.g Benzene in Toluol Starting material : justification, characterisation, specification , including potential impurities Discussion of possible carrying through of impurities Analytical test methods description In case the synthesis of API consits of only one or a few steps , manufacture of the staring material should be given If more than one supplier of the starting material is used, batch analysis results from the API manufactured from the different suppliers to be given

3.2.S.2.3 物料控制 原料和溶剂的规格，适当的 如果在溶剂中可能有一类溶剂应注明其规格和检测方法；如：甲苯中的苯 起始物料: 评定，性状，规格，包括潜在杂质 讨论运行中可能的杂质 分析检测方法的描述 如果原料药的合成仅有一步或几步构成，起始物料的制造应详细描述 如果所使用的起始物料的供应商不只一个，从不同的供应商生产而来的原料药的批分析结果应被提供。

3.2.S 2.4 Control of Critical steps and intermediates : Critical steps definition: where process conditions , test requirements or other relevant parameters must be controlled within the predetermined limits to ensure that AS meets specification Description of In Process controls Intermediates : Information on the quality and control of intermediates

3.2.S 2.4 关键步骤和中间体的控制： 关键步骤的定义：工艺条件，检测要求或其他相关参数必须控制在预先确定的限度内的以确保AS符合标准 过程控制的定义 中间体 : 质量信息和中间体的控制

3.2.S.2.5 Process validation and/or evaluation Process Validation should be provided as appropriate: Sterilisation process, including filtration and aseptic processing In case the monograph indicates specific additional requirements compliance should be demonstraeted For biological substances , specific microbial grade, suitable inactivation should be demonstrated 3.2.S 2.6 Manufacturing process development Description and discussion

3.2.S.2.5 工艺验证和/或评估 3.2.S 2.6 制造工艺开发 应提供适当的工艺验证： 消毒工艺，包括过滤和无菌工艺 如果药典专论中指出专门附加的要求，准则应该被证明 对于生物物质，专门的微生物指标，适当的失活应当被证明 3.2.S 2.6 制造工艺开发 描述和讨论

3.2.S.3 Characterisation 3.2.S 3.1 Elucidication of Structure and other Characteristics : Evidence of chemical structure : Elemental analysis, IR spectra, NMR, MS, UV spectra Evidence of structure of key intermediates, X-Ray christallography, optical rotation Physico-chemical Characteristics : Polymorphism, Melting point, DSC Solubility pKa and pH values

3.2.S.3 性状 3.2.S 3.1 结构分析和其他性状： 化学结构的证据： 元素分析，红外光谱，核磁共振，质谱，紫外光谱 关键中间体的结构证据，X-射线晶型图，旋光度 物理化学特性 : 多态性，熔点，DSC 溶解度 pKa 和 pH 值

3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Requirements concerning related substances according to the general monograph Substances for Pharmaceutical Use (2034) and the Guideline Control of impurities of pharmacopoeial substances ( QWP 1529/04) should be met Possible impurities considered as potential impurities arising from the synthesis should be discussed , indicating origin ( staring material, reagent, solvent,catalyst, intermediate or degradation product Discussion of possible routes of degradation Analytical methods ( LOD and LOQ)

3.2.S.3 性状 3.2.S 3.2 杂质 : 关于相关物质的要求，根据总的专论《药品使用的物质（2034）》 应符合《 药品物质的杂质控制指南》 ( QWP 1529/04) 应该对可能的杂质进行讨论，对认为是在合成中出现的潜在杂质，指出杂质起源（起始物料，试剂，溶剂，催化剂，中间体或降解产物 讨论降解可能的路线 分析方法 ( LOD 和 LOQ)

3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Suitability of the methods of the monograph to control the quality of the substance must be discussed and demonstrated Additional impurities above the reporting threshold demonstrating that Ph. Eur Method is suitable If Ph. Eur, method not suitable alternative test method including validation is required Chromatograms for production batches, with peak area results Additional related substances , identification and qualification accord. to the Guidance Imp. In new Drug Substances ( ICH/2737/99)

3.2.S.3 性状 3.2.S 3.2 杂质: 必须讨论和证明药典规定的原料药质量控制方法的适应性 添加的杂质在报告的阈值之上，以此证明欧洲药典的方法是合适的 如果欧洲药典的方法不适应，则需要替代的检测方法，并包括其相关的验证。 生产批次有峰面积结果的图谱 附加的相关物质，鉴别和验证符合《在新原料药中的杂质的指南》 ( ICH/2737/99)

3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Other impurities : residuals of toxic reagents, residues of acids or bases should be discussed Consider relevant guidelines Residual catalysts , possible carryover, justified control limits required

3.2.S.3 性状 3.2.S 3.2 杂质 : 其它杂质：有毒试剂的残留，酸或碱的残留应被讨论 考虑相关的指南 催化剂残留，可能的运行产物，所要求的合理的控制限度

3.2.S.4 Control of the Active substance 3.2.S 4.1 Specification : Description Identification Impurities Assay Additional tests Reference to : Impurities testing guideline ( ICH/2737/99) Note for Guidance on Specifications ( ICH /367/96) In case monograph under revision , new draft will be taken into consideration

3.2.S.4 活性物质的控制 3.2.S 4.1 规格： 描述 鉴别 杂质 含量 附加的检测 参考：杂质检测指南 ( ICH/2737/99) 关于规格的指南的注解( ICH /367/96) 如果专论在审核中，可以考虑新的草案

Specification of the Active Substance ICH/367/96 Note for Guidance on Specifications: Guidance for setting acceptance criteria Justification of specifications Selection of test procedures , pharmacopoeial tests ICH/2737/99 Impurities testing guideline Classification of impurities; residual solvents, starting material, intermediates, by-products, degradation products Reporting impurities, quantitative results numerical terms ! Reporting threshold, identification threshold, qualification threshold NMT 2g/day Ident. 0.1 %, Qualif. 0.15 % MT 2g/day Ident. 0.05 %, Qualif. 0.05 %

活性物质的规格 ICH/367/96规格指南的注释 ： ICH/2737/99 杂质检测指南 建立可接受的标准的指南 规格的说明 检测规程，药典检测方法的选择 ICH/2737/99 杂质检测指南 杂质的分类；残留溶剂，起始物料，中间体，副产物，降解产物 报告杂质，以数据定量的结果！ 报告阈值，鉴别阈值，验证阈值 NMT 2g/天， 鉴别的 0.1 %, 数量 0.15 % MT 2g/天，鉴别的 0.05 %,数量 0.05 %

3.2.S.4 Control of the Active substance 3.2.S 4.2 Analytical Proecedures Details of the analytical procedures In case of TLC methods in the monograph , suitability to detect imp. at relevant threshold ( 0.05% or 0.03 % acc. Max. daily dose) TLC method only accepted in rare cases , Requirements of suitability , detection and quantification limit have to be considered

3.2.S.4 活性物质的控制 3.2.S 4.2 分析规程 分析规程的详细内容 如果是在专论中的TLC方法，在相关阈值内杂质检测的适应性( 0.05% 或 0.03 % 根据日常最大计量) 仅在很少的情况下，可接受TLC方法 应考虑适应性，检测限和定量限的要求

3.2.S.4 Control of the Active substance 3.2.S 4.3 Validation of Analytical Procedures Reference to validation of analytical methods (ICH 381/95 and ICH 281/95); Typical chromatograms For additional methods acc. To the general methods of the Ph. Eur, like for residual solvents applicability is sufficient

3.2.S.4 活性物质的控制 3.2.S 4.3 分析规程的验证 分析方法验证的参考 (ICH 381/95 和ICH 281/95); 典型的图谱 对于附加的方法，根据欧洲药典的一般方法，象残留溶剂，适应性就足够了

3.2.S.4 Control of the Active substance 3.2.S 4.4 Batch Analysis Description of batches and results of batches Results below 1 % for related substances should be reported with 2 digits Present actual figures whenever possible instead of only ‚complies‘ Analytical results from min. 2 batches, maximum batch size Results should include : Date of manufacture, batch size and batch number, place of manufacture, results of analytical test, use of batches

3.2.S.4 活性物质的控制 3.2.S 4.4 批分析 批次描述和批次结果 结果小于1％的相关物质应用2位数报告 现在的实际数据，每当可能时只是代替“遵守” 分析结果从最少2批到最大批数量 结果应当包括: 制造日期, 批大小和批号, 制造地点, 分析检测结果, 批的使用

3.2.S.4 Control of the Active substance 3.2.S 4.5 Justification of Specification See Note for Guidance on Specification, impurity testing guideline, residual solvents 3.2.S 5 Reference Standards or Materials Specifications, full analytical and physico-chemical charcterisation, impurities etc. Reference substances ( primary and secondary) incl. full analytical results or Ph. Eur. CRS 3.2.S 6 Container Closure System Description of bulk storage container closure Specification of primary packaging material ( e.g. Poleythylene bags) ad secondary packaging ( e.g. fibre drums, metal drums)

3.2.S.4 活性物质的控制 3.2.S 4.5 规格的解释 3.2.S 5 对照品或对照物 3.2.S 6 容器密闭系统 查看指南中有关规格，杂质检测指南，残留溶剂的注解 3.2.S 5 对照品或对照物 规格，完整的分析和物理化学特性，杂质等 对照品（基准和二级）包括完整的分析结果或EP标准品 3.2.S 6 容器密闭系统 存放物料的密闭容器的说明 第一层包装材料（例如聚乙烯袋）和第二层包装（例如纤维桶，金属桶）的规格

3.2.S 7 Stability 3.2.S 7.2 Post approval stability Protocol and commitment Retest period may be attributed based on extrapolation , see NfG on stability testing 3.2.S 7.3 Stability Data Detailed results in tabular format, Stability testing according to ICH guideline information on the analytical procedures ( validation if necessary )

3.2.S 7 稳定性 3.2.S 7.2 公布批准的稳定性方案和执行 3.2.S 7.3 稳定性数据 复测周期可以基于外推法来定性，参见NfG 稳定性试验 3.2.S 7.3 稳定性数据 以表格形式的详细结果 根据ICH指南进行稳定性试验 基于分析规程（如果必要须验证）的信息

References Notice to applicants (NTA) Volume 2 B CTD Module 3 S Guideline on the chemistry of new active substances Validation of analytical methods , Analytical procedures methodology ICH Stability testing, photostability testing ICH Impurities testing guideline , residual solvents ICH. Note for Guidance on Specifications

参考文献 通知申请者 (NTA) 第2册 B CTD 模块 3 S 新活性物质化学部分指南 ICH 分析方法验证, 分析规程方法学 指南中关于规格的注意

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

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Application form – Request for New Certificate of Suitability

申请表－－ 新适应性证书的要求

Certification procedure Application at the EDQM (European Directorate for the Quality of Medicines) How to apply ? Application form Procedere Timetable

证明程序 申请EDQM (European Directorate for the Quality of Medicines) 如何申请 ? 申请表 程序 时间表

How to Apply ?

如何申请 ?

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

Technical Advice to Applicants and Holders of Certificates of Suitability (CEP)

对适应性证书(CEP)的 申请者和持有者的 技术建议

Technical Advice Request for Technical advice for CEP : Write a letter to EDQM Mention the name and address of the applicant Make reference to the relevant Ph.Eur. Monograph Name of the substance /material If applicable number of the corr. CEP Charge of 1000 €

技术建议 CEP技术建议的要求: 写信给EDQM 陈述申请者的名字和地址 制作与欧洲药典专论相关的参考 物质/物料的名字 1000 €（欧元）费用

Technical Advice Payment should include ref. To ‘Technical Advice’ Follow instructions at EDQM website Submission either by email to certification@pheur.org or EDQM certification Unit 226 Avenue de Colmar ( entrance rue Schertz) F-67029 Strasbourg France Technical questions or questions about the planning of the procedure Phrase Questions clearly add necessary supplementary information

技术建议 付款方式应当包括参考 ‘技术建议’ EDQM网站上的遵循指令 可以选择用电子邮件递交到certification@pheur.org 或EDQM认证部门： 226 Avenue de Colmar ( entrance rue Schertz) F-67029 Strasbourg France 技术询问或关于程序计划的询问 询问语句清晰，加上必要的补充信息

Technical Advice EDQM will organize provision of the advice in a hearing Hearings must be booked in advance Takes place at EDQM Once a month, next meetings October 6, November 3 and December 1st Note : Procedure does not replace the submission or assessment of the CEP application

技术建议 注意: 程序并不代替CEP申请的递交或评定 EDQM将在一场听证中组织建议的条款 听证必须预先登记 在EDQM发生 每月一次, 下次会议十月六日, 十一月三日和十二月1日 注意: 程序并不代替CEP申请的递交或评定

Hearing at EDQM

在 EDQM 听证

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

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Procedure for Revision / Renewals of Certificates of Suitability (CEP)

适应性证书(CEP)的修订/更新程序

Revision / Renewal Guideline on Requirements for Revision/Renewal of certificates : Holder of a CEP shall inform the EDQM of any change in the information Classification of changes : three categories Notification (N)/minor (R or T)/major Note : any change not classified as notification or minor change should be classified as a Major Change

修订/更新 证书的修订/更新要求的指南: CEP的持有者应当把任何变更信息告知EDQM 变更的分类: 三类 通知 (N)/次要的 (R or T)/主要的 注意: 任何没有被《通知》或次要变更归类的变更应当被归类为主要变更

Revision / Renewal Documentation to be provided : Justification of the change Application form, enclosing a comparative list of updated sections Specific documents as described in the Guideline on Requirements for Revision/ renewal of certificates

修订/更新 须提供的文件: 变更的说明 申请表，包括一个更新章节的对照表 在证书的修订/更新要求的指南中有对具体文件的描述

Revision / Renewal Notifications (N) : Change in name or address of CEP holder or the name of the manufacturer Change in name or address of the manufacturing site Deletion of any manufacturing site Deletion of a manufacturer of any intermediate/staring material Change in batch size of final substance, intermediate up to 10 fold to original batch Change in batch size downscaling

修订/更新 通知 (N) : CEP持有者的名字或地址，或者制造商名字的变更 制造场所的地址或名字变更 任何制造场所的删除 任何中间体/起始原料的制造商的删除 最终物质，中间体比原始批次扩大10倍的，批量的变更 批量缩减的变更

Revision / Renewal Notifications (N) : Minor Change to a test procedure Tightening of the specification limits Change in the code product/reference number or in the brand of the final substance Amendment to stability data further to a commitment Removal of the re-test period from the CEP TSE certificate , deletion of source country etc.

修订/更新 通知 (N) : 检测程序的次要变更 规格限度的严格化 产品代码/参考号或最终产品商标的变更 修订稳定性数据进一步到稳定性声明 从CEP上去除复检期 TSE证书，删除原料国家等内容

Revision / Renewal Minor Changes/Revisions (R) : Minor Change in manufacturing process, conditions : no change in imp. Profile, not sterilisation step, synthetic route remains the same Change in batch size of substance or intermediate more than 10 fold , conditions :changes in manufacturing process only necessitated by scale up, no biological or sterile product, change does not affect reproducibility a test procedure

修订/更新 次要变更/修订(R) : 制造工艺的次要变更，条件： 杂质概况，非消毒步骤没有变更，合成路线保持相同 原料药或中间体的批量变更超过10倍，条件：工艺的变更只有在扩大规模，非生物的或非无菌产品时是可行的，变化不影响到检测程序的再现性

Revision / Renewal Minor Changes/Revisions (R) : Specification of the final substance /intermediate /reagent , addition of a new test parameter change or replacement of a test procedure Conditions: change is not a result of unexpected events, new test procedure not a novel non-standard technique, new test procedure validated ,test results of at least two batches Change in the manufacturer or addition of a new manufacturer of starting material or intermediate , conditions: specifications and route of synthesis identical,not a biological substance,test results of 2 batches

修订/更新 次要变更/修订 (R) : 最终物质/中间体/反应物的规格，增加的新的检测参数的变更或检测程序的替换，条件: 变更不是意外事件的结果，新检测程序不是异常的非标准技术,新检测程序被验证，至少两批的检测结果 在制造商内或新起始原料或中间体制造商的增加的变更, 条件：规格和合成路线确认，非生物物质，两批检测结果

Revision / Renewal Minor Changes/Revisions (R) : For “double” CEP chemical purity and TSE risk , change in source of material Conditions: no change in manufacturing process, specification remains the same, substance not biological Change in the manufacturing site or addition of a new site for the finished substance conditions: quality control specifications, method of preparation, detailed route of synthesis are identical, not a biological substance

修订/更新 次要变更/修正： 由于“双”CEP化学纯和TSE风险，对原料的变更 条件：制造工艺没有变更，规格保持相同，非生物物质 变更制造现场或附加一个新的生产成品的场所 条件：质量控制规格，准备方法，详细的合成路线确定，非生物制品

Revision / Renewal Minor Changes/Revisions (R) : Change in the Re-test period of the final substance and /or storage conditions Conditions: stability studies accord. to the relevant guidelines, change not result of unexpected events , substance not biological Additional Minor Changes for TSE certificates

修订/更新 次要变更/修订： 最终物质复检期的变更和/或储藏条件的变更 条件：根据相关的指南进行稳定性研究，变更不是源于不可预料事件的发生，非生物制品 因为TSE证书附加的次要变更

Revision / Renewal Procedure : Notifications: Determination of validity of a notification within 2 weeks, If notification incomplete , request rejected, no asking for additional questions , applicant has to resubmit Multiple simultaneous notifications possible: max 3 changes, fees and deadlines are increased

修订/更新 程序： 通知：在两周内确定一个通知的生效 如果通知未完成，要求被拒绝，不可有其它的问题，申请人不得不重新递交 多个内容同时通知的可能：最多3个变更，费用和截止日期增加

Revision / Renewal Procedure : Minor Changes: T 0 , within 5 days after receipt, letter of acknowledgement of receipt T 30 days either approval and revised certificate or request for additional information New T 0 at receipt of additional information, new T 30 and approval or rejection Multiple changes: max 3 changes, fees and deadlines are extended increased

修订/更新 程序： 次要变更: T 0 ，在接收后5天内，确认接受信 T 30 ，批准并修改证书的日期或要求附加信息的日期 多项变更：最多3个变更，费用和截止日期相应的增加

Revision / Renewal Procedure : Major Changes: T 0 , within 5 days after receipt, letter of acknowledgement of receipt T 90 days either approval and revised certificate or request for additional information ( clock stop) New T 0 when response received at EDQM , new T 30 and approval or rejection Multiple changes: only one major together with minor/or notification is possible

修订/更新 程序： 主要变更： T 0 ，在接收后5天内，确认接受信 T 90，批准并修改证书的日期或要求附加信息的日期（计时停止） 新T0当收到EDQM的回复，新T 30和批准或退回 多种变更：只有一个主要变更和次要变更/或通知是可行的

Revision / Renewal Procedure : Quinquennial renewal: Application 6 months prior to expiry date T 0 , within 5 days after receipt, letter of acknowledgement of receipt T 120 days either approval and renewed certificate or request for additional information ( clock stop) If clock stop applicant to submit within 30 days New T 0 when response received at EDQM , new T 30 and approval or new request for information

修订/更新 程序： 五年一次的更新： 有效期前6个月的申请 T 0 ，在接收后5天内，确认接受信 如果计时停止，申请人要在30日内递交 新T0当收到EDQM的回复，新T 30和批准或退回

Revision / Renewal Monograph revisions : Letter by EDQM to applicant : Holder is requested to submit an update to the dossier within 30 days T 0, receipt and start of evaluation no letter from EDQM T 120 days acknowledgement of valid data or request for additional information ( clock stop) If clock stop applicant to submit within 30 days New T 0 when response received at EDQM , new T 30 and approval or new request for information

修订/更新 专论修订： EDQM给申请者的信： 要求持有者在30天内递交一个更新的文件 T 0，接受和评估开始，没有EDQM的来信 如果计时停止，申请人要在30日内递交 新T0当收到EDQM的回复，新T 30和批准或对内容的新要求

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str ALFRED E. TIEFENBACHER (GmbH & Co) Van-der-Smissen-Str. 1 22767 Hamburg Germany Tel.: +49-40-441809-0 Fax.: +49-40-441809-26 Mail.: info@tiefenbacher.com www.tiefenbacher.com

Conferences & Trainings on GMP and Regulatory Affairs

讲座&培训 GMP及药政

The Organisation CONCEPT HEIDELBERG Founded on 1 April 1978 Europe‘s leading institute of further education for the pharmaceutical industry - in the field of production, QA and regulatory affairs 240 GMP/FDA Compliance Courses per year Exclusive co-operation with the European Compliance Academy Office in Heidelberg

CONCEPT 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 independent 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.org

www.gmp-compliance.org

www.gmp-compliance.org

The CONCEPT HEIDELBERG Speakers Team Quality Control Dr Günter Brendelberger Analytics / Pharmaceutical Law Dr Gerhard Becker Hygiene / Microbiology Dr Karl-Friedrich Nieth GMP, ISO 9000 QM Systems Oliver Schmidt Production / IT Systems Dr Andreas Mangel Validation Sven Pommeranz Biotechnology / Microbiology Dr Ulrich Herber Pharmaceutical Engineering Harald Martin APIs / Regulatory Affairs Dr Barbara Jentges GMP Compliance Dr Berthold Stemmle Medical Devices / Quality Management Dr Heinrich Prinz IT Management Peter Dollenbacher

CONCEPT HEIDELBERG 的演讲队伍 质量控制 Günter Brendelberger 博士 分析方法/药物法律 Gerhard Becker 博士 卫生 / 微生物 Karl-Friedrich Nieth 博士 GMP, ISO 9000 QM系统 Oliver Schmidt 生产 / IT 系统 Andreas Mangel 博士 验证 Sven Pommeranz 生物工程 / 微生物 Ulrich Herber 博士 制药工程 Harald Martin 原料药 / 药政 Barbara Jentges 博士 GMP 遵守 Berthold Stemmle 博士 医疗器械 / 质量管理(QM) Heinrich Prinz 博士 IT 管理 Peter Dollenbacher

Europe‘s most important API Conference with EU Commission and FDA Speakers

欧洲最重要的原料药会议－ 与欧盟委员会和FDA讲演人一起

GMP (ICH Q7A) Compliance and Inspection for COS/CEP GMP for Active Pharmaceutical Ingredients (APIs) ICH Q7A, Annex 18 to EU Guide to GMP Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

GMP (ICH Q7A) 遵守 COS/CEP检查 原料药的GMP (APIs) ICH Q7A, 欧盟GMP指南附件18 Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

General The guideline was published by the EMEA (European Agency for Evaluation of Medicinal Products). Pharmaceutical manufacturers should only use APIs manufactured according 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 inspectors 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

Table of Contents Introduction Quality Management Personnel Buildings and Facilities Process Equipment Documentation and Records Materials Management Production and In-Process Controls Packaging and Identification Labelling of APIs and Intermediates Storage and Distribution Laboratory Controls Validation Change Control Rejection 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 Contents Complaints and Recalls Contract Manufacturers (including Laboratories) Agents, Brokers, Traders, Distributers, Repackers, and Relabellers Specific Guidance for APIs manufactured by Cell Culture/Fermentation APIs for Use in Clinical Trials Glossary

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. „Manufacturing“ 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 safety aspects or environmental aspects. Does not define registration/filing requirements or modify pharmacopeial requirements

1. 介绍 1.1 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. Introduction 1.2 Regulatory Applicability 1.3 Scope When 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 Scope The guide applies to the manufacture of APIs for use in human drug products. APIs manufactured 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 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 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 starting 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 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 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 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 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 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 companies 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 authorities 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 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，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 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 for 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 materials

任何在合成路线，检验控制或规格中的变更， 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-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-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 Production Internal 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 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 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 characteristics 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

Quality Management System - QMS Glossary: Quality Management Coordinated activities to direct and control an organization throughout all areas and processes with regard to quality. Quality Management System - QMS System needed to implement Quality Management efficiently.

词汇表：质量管理 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 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, Quality Control Technical Services Production competences, Interactions. ...ensures clear Inputs for tasks

质量保证系统－QM系统 职责的识别和描述 质量控制l 技术服务 生产 管辖相互作用 确定明确的职责分配

QMS is the arrangement of… Interfaces Milestones Information flow/Interactions Tasks Competences Responsibilities

质量管理系统 管辖 分界 信息流动/相互作用 任务 权限 职责

QMS Documentation System GMP Describes system related quality Describes product related quality

QMS 描述与质量相关的系统 文件系统 GMP 描述与质量相关的产品

GMP Process QMS GMP + Processes = QMS A set of interrelated or interacting activities which transforms inputs into outputs. Product related Quality Documented evidence QMS Including time-axis Including interconnections GMP + Processes = QMS

GMP 工艺 QMS GMP +工艺 = QMS 一系列相关的或相互作用的，把输入转化为产出的活动 与质量相关的产品 文件化的证据 包括时间轴 包括相互联络 GMP +工艺 = QMS

General Considerations PIC GMP Chapter 1: Quality Management “... 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 QMS 第 1章: 质量管理 “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，

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.” GMP

“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。” 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 Degree of Detail Validity within the company low GCP GLP high Validity within the company

比较 QMS / GMP 低 QMS GMP 程度详述 GCP GLP 高 公司内部的有效性

Document combining ISO and GMP Requirements CEFIC Activities CEFIC Working Party on GMP and Quality Assurance Document combining ISO and GMP Requirements Quality Management System for Active Pharmaceutical Ingredients Manufacturers integrating GMP into ISO 9001 December 1997

要求的文件 的组合 CEFIC 活动 ISO 和 GMP Quality Management System CEFIC Working Party on GMP and Quality Assurance ISO 和 GMP 要求的文件 的组合 Quality Management System for Active Pharmaceutical Ingredients Manufacturers integrating GMP into ISO 9001 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, 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 should 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 Principles Any deviation from established procedures 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 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 9001  Responsibility of Senior Management  Quality Management System  Controlling of Contracts  Steering of Design  Steering 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, Preservation and Distribution  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  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

Requirements 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 Records 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 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 Management 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 attainment 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 company’s suppliers --the distributors To achieve the quality objective reliably there must be a comprehensively designed and 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 (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 Guideline 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 --facilitates 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 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 Responsibilities 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（QU）的责任 职责  由QU完成 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

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 sure 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 specifications, 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 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 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 for 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 specifications 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, revalidation, 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 what 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 manufacture 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 employee’s functions. Records of training should be maintained. 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 GMP Improve qualification of personnel Motivate personnel Increase safety of APIs/ drug products

3.1 人员资质 – 培训 GMP 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 Qualification Training of Personnel Contents and definitions of a training program Wherefore? Define training issues and objectives! 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 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/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 for training  How to maintaine/archive the training record

3.1 人员资质 – 人员培训 培训记录应当包括以下内容:  培训日期  范围：产品，质量控制，等等  目标  老师的名字  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 by supervisor / superiour about Working hours, break times, How to behave in case of absence Manual for personnel Safety instructions Information about hygiene, SOPs, log- books, clothing, hands washing GMP according to a checklist Waste discarding packaging materials drug products waste containers/bags Environment How to handle solvents and cleaning agents Information about Company’s drug products Special manufacturing Health condition In case of any change superiour to be informed Introduction to Head of Production and colleages during demonstration of future working place Head of Production Colleages Signature of trainer: Employee’s signature ........................................ Date ............................... ................................ aus: Haffner et al. - Schulung von Mitarbeitern Pharm.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: 员工签字 ........................................ 日期 ............................... ................................ aus: Haffner et al. - Schulung von Mitarbeitern Pharm.Ind. 56, Nr. 8 (1994)

3.1 Training of Personnel Introduction to and information about working place; important SOPs to be read, understood and followed: Practical learning by doing Working place/area: ........................................................ from: ............. until: ............. Documents received: ........................................................... ........................................................... SOP ........................................................... Read and understood: Employee’s signature ..................................... Date nach: Haffner et al. - Schulung von Mitarbeitern Pharm.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： 动手的实际学习 工作场所/区域: ........................................................ 从: ............. 至: ............. 收到的文件: ........................................................... ........................................................... SOP ........................................................... 阅读并理解: 员工签字 ..................................... 日期 nach: Haffner et al. - Schulung von Mitarbeitern Pharm.Ind. 56, Nr. 8 (1994)

3.1 Training of Personnel Heard 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 doesn’t teach his employees how to think but that they have to think. (D. Goeudevert)

3.1 人员培训 听到不等于理解; 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 changed 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 storage 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 Hygiene 3.3 Consultants Personnel suffering from 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 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 person’s inclusion would not jeopardize the safety or quality of the APIs. 3.3 Consultants ..should have sufficient education, training, experience Records should be kept stating name, address, qualifications, and type of service provided.

3.2 人员卫生 3.3 顾问 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，地址，资质和提供服务的类型

4 Buildings and Facilities 5 Process Equipment 4.1. Design and Construction 4.2. Utilities 4.3. Water 4.4. Containment 4.5. Lightning 4.6. Sewage and Refuse 4.7. Sanitation and Maintenance 5.1. Design and Construction 5.2. Equipment Maintenance andCleaning 5.3. Calibration 5.4. Computerized Systems

4 厂房和设施 5 工艺设备 4.1. 设计和建筑 4.2. 公共设施 4.3. 水 4.4. 隔离防护 4.5. 灯光 4.1. 设计和建筑 4.2. 公共设施 4.3. 水 4.4. 隔离防护 4.5. 灯光 4.6. 污水和垃圾 4.7. 卫生设施和维护保养 5.1. 设计和建筑 5.2. 设备维护与清洗 5.3. 校验 5.4. 计算机系统

4 Buildings and Facilities 5 Process Equipment "Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, 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, cleaning, sanitization (where appropriate), and maintenance . "

4 厂房与设施 5 工艺设备 “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"

Statements - Requirements Prevent mix-ups or cross contamination!! GMP starts with the design of facilities ! DQ-IQ-OQ-PQ!! There is no room classification for (non sterile) API’s ! Appropriate filtration of incoming air! Closed systems are the preferred option ! Dedicated production areas for penicillins, 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 : Other Control system.

说明 – 要求 预防混淆或交叉污染!! 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 : 其它的控制系统.

Statements - Requirements 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 laboratories ! Appropriate measures for recirculated air ! (Recorded controls with signatures or documentation with Facility Management System Higher standard (GMP) in areas where API is exposed to environment !

说明 – 要求 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)!

Minimize risks of contamination and cross-contamination 4.2 Utilities Minimize risks of contamination and cross-contamination All 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 pressure), 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)

4.2 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) 污染和交叉污染的风险最低化 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）

Questiones to ask about the HVAC Which filters are used ? How are they controlled? Is there 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 a separate ventilation system ? HVAC = Heating, Ventilation, Air Condition

有关 HVAC 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 Guide International Society Pharmaceutical Engineering www.ispe.org

工程指南 International Society Pharmaceutical Engineering www.ispe.org

ISPE model open product handling closed critical criticality Level II protected Level III controlled product handling Level I no requirements Level I no requirements closed Non critical critical criticality

ISPE 模型 级别 II 保护 级别 III 受控 开放 产品处理 级别 I 不作要求 级别 I 不作要求 密闭 非关键 关键 重要性

Critical Steps Last filtration / isolation, purification Final drying, milling, sieving, coating Final packing of the API Critical steps can be also in earlier stages ! Steps after which a process failure or contamination with other substances can not be compensated any more !

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，不能采取任何补偿的步骤!

Requirements for level I (general) Well maintained chemical plant Orderly and clean Equipment and pipework identified and labelled Lightning to facilitate operations, cleaning and maintenance Waste containers and pipes clearly labelled Normal working dress

级别 I 的要求(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

Requirements for level II (protected) Area where measures have been taken to prevent contamination Normally no air recirculation Controlled direction of air flow Separate cubicles Separation of units Local dust extraction

级别 II 的要求 (保护) 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

Requirements for level III (controlled) Area with defined and controlled room standards Standard must be adequate to prevent any contamination of the product Minimum F9 air filter, better HEPA filter Cleaning and monitoring schedule (SOPs!!) Restricted access SOPs should be in place for the use of rodenticides, insecticides, fungicides, fumigating agents, cleaning and sanitizing agents to prevent contamination of equipment, materials, APIs.

级别 III 的要求 (受控) 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。

Requirements for level III (controlled) Easy to clean: Smooth surface, stainless steel. No cracks, no joints. Minimum equipment in room. Access control Dress code Documented cleaning and monitoring program.

级别 III 的要求 (受控) 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

Options for level II (protected) exhaust reactor 1 reactor 2 filter cristallizer centrifuge air intake (filtered)

级别 II 的选择 (保护) 排风 反应釜 1 反应釜 2 过滤器 结晶釜 离心机 进风 (过滤)

Options for level II and III air intake (filtered) exhaust charge hole reactor

级别 II 和 III的选择 进风 (过滤) 排风 卸料口 反应釜

Options for level III (controlled) Whole room as 'clean room‚ (GMP) e.g. final packing of API easy to handle, clear standard difficult to fit in old plants high investment and revenue cost Part of room as 'clean room' e.g. charging, seeding, sampling, final packing cheap option, but oftern extra ventilation system necessary

级别 III的选择 (受控) 整个房间作为“洁净室”(GMP) 部分房间作为“洁净室” 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 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 Flow air intake HEPA- FILTER PRODUCT 'clean room' normal plant area

级别 III 的例子: 开放式层流气流 进风 高效 过滤器 产品 ‘洁净室' 普通厂房区

Examples for Level III : 'clean room' with positive pressure air intake Clean corridor principle HEPA- FILTER dp = 10 - 12 PA dp = 12 - 15 PA 'clean room' (packing) transit corridor normal plant area

级别 III 的例子: 带正压的“洁净室” 洁净走廊的原理 进风 普通厂房区 高效 过滤器 ‘洁净室' (包装) 输送 走廊 dp = 10 - 12 PA dp = 12 - 15 PA ‘洁净室' (包装) 输送 走廊 普通厂房区

4.3 Water "Water 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 place. 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 Cleaning Schedules and procedures should 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 validation 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 Aspects EC - Guide to Good Manufacturing Practice for Medicinal Products: „Measuring, weighing, recording 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 should 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： ISPE-指南 (Vol. 1, 化学原料药) „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 “ (第3章 „房屋和设备“, 3.41) ISPE-指南 (Vol. 1, 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 “ (第9.4章 校验)

5.3 Calibration - Regulatory Aspects ICH - Q7A GMP for APIs „Control, 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 critical equipment should be known and verifiable ...“

5.3校验 – 药政方面 „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行校验... 针对 APIs的 ICH - Q7A GMP „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行校验... …应当了解并核实关键设备当前的校验状态...“

Calibration - Regulatory Aspects Central Requirements in GMP-Guidelines: Measuring 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: 测量仪器... .... 必须校验 .... 在适当间隔内 .... 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 Basics Calibration: 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 deviation to the smallest possible value with support from references that may be applied to optimise accuracy.

校验基础 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 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: 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 Basics Do all instruments in the production process have to be calibrated? No, only those instruments which are related to the product-/process quality and safety have to be calibrated Critical instruments Critical instruments are identified during Risk Analysis and Design Qualification.

校验基础 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 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: 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

Elements of Calibration Master-SOP Logbook Cal.Record Calibration SOP Elements of Calibration Calibration- Label Calibration Protocol Cal.Plan Calibration Work Trained Employees Testing Equipment

校验要素 主-SOP 日志 校验记录 校验SOP 校验标签 校验要素 校验方案 校验计划 校验工作 受训练的员工 测试仪器

Elements of Calibration Master-SOP should contain: Definitions Responsibilities Information concerning the structure of Calibration-SOP’s Description of equipment to be calibrated (List of all) Documentation Procedures Control over Reference Instruments How to define Calibration Intervals Guidelines, Standards and References

校验要素 主-SOP 应当包括: 定义 职责 关于校验结构的信息-SOP’s 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

Calibration Example of an instrument list :

校验 仪器列表样张 :

Elements of Calibration Calibration-SOP should contain: Detailed description of calibration procedure(s) Reference standard to be used and reference conditions Detailed description of instrument/measuring device Estimation of uncertainty of measured data Interval of calibration cycle Instructions for the documentation of calibration(s) ---Calibration records (template as enclosure) ---Records to be made in the logbook ---Calibration Certificates ---Calibration labels (template as enclosure)

校验要素 校验SOP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 Calibration Calibration records should contain: Identification of the instrument that has been calibrated (ID-No) Who performed the calibration? Date of the calibration Identification of the reference instrument that has been used Actual and specified conditions Next calibration date (Re-calibration) Calibration label attached to equipment/instrument

Elements of Calibration 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

Re-calibration (Date) Elements of Calibration Calibration Labels Identification (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 colours Summary-Labels for complex systems Labels should be robust and resistant to product and cleaning- / disinfecting agents XY Pharma Calibration Ident No. _________________ Date_______ Performed by___ _________ Re-calibration (Date)

校验要素 XY 药业 校验 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 XY 药业 校验 ID No. _________________ 日期_______ 执行人___ 再校验 (日期) _________

Calibration Label ? Status is for everybody visible Production 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 ? 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 ! 总是怀疑的看待校验报告! 标签应当在SOP中记录成文。

Elements of Calibration Recording in the logbook Date/time Observation/ Activity Signature Action taken (if necessary) Signature / Date Approval (Signature/Date) Calibration Sensor ID 0815 Record 098/12 _41/2000 Adjustment was necessary

校验要素 日志中的记录 Calibration Sensor ID 0815 Record 098/12 _41/2000 Date/time Observation/ Activity Signature Action taken (if necessary) Signature / Date Approval (Signature/Date) Calibration Sensor ID 0815 Record 098/12 _41/2000 Adjustment was necessary

Elements of Calibration Calibration-Plan Schedule of all calibration activities - by type of equipment - by production units/areas - ... Print-out of calibration orders and instructions Identification and follow-up of calibration activities Activities can be controlled by Commercial Software  Calibration Data Base GMP-compliant maintenance requires a Calibration Plan

校验要素 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

Elements of Calibration Trained employees Employees 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 SOP‘s in context with calibration Operating manuals of the instruments Documentation of Calibration/logbook recording General GMP and Change Control Procedures

校验要素 负责校验工作的员工应当至少有下面所列的训练: 受过培训的员工 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

Set the calibrated status Qualification and Calibration Calibration work is a prerequisite to get Qualifacation completed and to ensure GMP compliance!! Qualification Process Questions concerning calibration - Which measuring instruments are quality related? Risk Analysis Engineering - Possibility of calibration in the necessary accuracy and in the right range? DQ Installation IQ - Measurement correctly installed? - Calibration certificate from manufacturer available? Com-missioning OQ - Calibrated according to SOP? - Calibration certificate / label present? PQ Set the calibrated status Routine 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 有关验证的问题 得到已校验的状态 检验风险 - 哪些测量的设备是与质量相关的？ 检验风险 工程 - 在必要的准确度和量程中校验的可能性？ DQ 安装 IQ 衡量是否准确安装？ - 是否有可能从制造商处得到证书？ 任务 OQ 是否根据SOP校验了？ -是否提供校验证书/标签？ PQ 得到已校验的状态 日常生产

Calibration - Summary / Conclusion Calibration is a crucial part of the Quality Assurance Process Calibration plays an important role in all phases of a production line‘s life cycle Design  Qualification  Production Setting the appropriate 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 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… … 减少因不合格产品产生的化验费用 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… … 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 Computerized Systems GMP 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 maintanance. 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.

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。 5.4 计算机系统 相关的计算机系统必须验证 标准的（已验证的）软件 必须建立准入控制 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 建立操作，控制，数据储存和维护的SOP 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：另一个人的复核或系统复核是需要的。

Good Practices for Computerised Systems PIC/S Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme PI 011-1, 20 August 2003 Good Practices for Computerised Systems in regulated „GXP“ Environments Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

PIC/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 Consulting Associated Partner of Concept Heidelberg

Table of Contents Part One – Preamble: Purpose, Scope, Introduction Part 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) --Functional 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 Contents Part Three – System Operation/Inspection/References --Change management --Change control and error report system --System security, including back-up --Data changes – 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-系统操作/检查/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 Records 6 6. Documentation and Records 6.1 Documentation System and Specifications All documents related to manufacture should be prepared, reviewed, approved and distributed according to written procedures; 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 responsibilities! 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. Retention 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21 CFR 11 所有文件的分发，改版和撤回应该有维护 修改历史的控制。SOP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： 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 Pecifications During retention period, documents should be readily availablewhere needed 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 used, 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 Pecifications 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便于找到。这个在检查中可能是很重要的！

6.1 Documentation System and Specifications When entries are made in records, these should be made indelibly 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 out

6.1 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

6.1 Documentation System and Specification Specifications should be established and documented for --raw materials, intermediates, APIs, --labelling and packaging 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. 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 --原料，中间体，原料药 --标识和包装材料 --对于材料可能影响到质量的，如工艺助剂，垫圈，过滤器,.. 对于有工艺监测控制限和行动限的IPC，应建立OOS调查，以避免中间控制的偏差。SOP中应描述！ 文件中的电子签名应鉴定（如向美国市场供应， 应遵循21 CFR part 11 ）

6.2 Equipment Cleaning and use Record Records 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 these 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，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，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！ 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！！

6.3 Records of Raw Materials, Intermediates (IM), API Labelling and Packaging Materials Records 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 labels 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 原料的记录，中间体（IM），原料药的标识和包装材料 每批交货的产品应包括： --制造商/供应商的名称 --标识和重量 --供应商控制和识别码 --收货单上的归属码 --收到的日期 --源于此的任何检测和结论 --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； --对以上材料的放行或不合格判定！ 批准的主标签应便于比较！

6.4 Master Production and Control Instructions Master production instructions for each IM/API should be --prepared --dated --signed by one person and independently checked by QU Master 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, main equipment --detailed production instructions (sequences, process parameter ranges, sampling instruction, IPCs, time limits, expected yields --instructions for storage

6.4 主生产和控制指令 对每个中间体/原料药的主生产指令应该 --被准备 --标注日期 --被签名并由质量部门的独立审核 主生产指令应包括： --产品名称包括文件引用代码 --原料和中间体的完整清单 --需要的数量的准确描述 --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，IPC，时间限制，预计产出） --储藏指令

6.5 Batch Production and Control Records ..should have complete information, checked before issuance for correct version, unique 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 labels used --deviation/investigation if critical --results of release testing

6.5 批生产和控制记录 应有完整的信息，改版签发的审核，唯一的批号 .. 应包括： --日期和时间（如果适当的话） -- 主设备的标识 -- 使用的原料的标识 --实际结果 --取样操作（按SOP！） --操作人员签名 --IPC/化验室检测结果 --实际产量 --包装描述和使用的标签 --偏差/调查 --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 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, compliance with set standards) Records should be maintained also for modifications to test method, calibration of lab instruments, stability testing, OOS

6.6 化验室控制记录 应包括： -样品描述（名称，批号，日期，数量） -检测方法参照 -标准品，试剂和/或标准溶液配置的互相参照 -完整的原始数据（+图谱/图表/光谱） -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，按照标准操作的审核） 对检测方法，化验室仪器校验，稳定性实验和OOS的修改记录应该保存

6.7 Batch Production and Control Record Review Written procedures 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 release 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，确定符合设定的规格 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 在放行前，偏差/调查/OOS报告应作为产品审核的一部分 质量部门对所有运出的中间体进行放行。

7 Materials Management General Controls Receipt and Quarantine Sampling and Testing of Incoming Production Materials Storage Re-evaluation During 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物料的流程，从接收到运送到生产区域，到运送至GMP区域！

7.1 General Controls There should be written procedures (SOPs) describing --receipt --identification --quarantine --storage --handling --sampling --testing --approval or rejection of all materials Suppliers of critical materials should be evaluated (audit)

7.1 常规控制 应该有书面的规程（SOP）规定 -- 接收 -- 识别 -- 代验 -- 储藏 -- 操作 -- 取样 -- 检测 --所有物料的批准或拒收 关键物料的供应商应该被评估（审计）

7.1 General Controls Materials should be purchased against an aggreed specification approved by the QU. Suppliers should be approved 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 中间体或原料药的制造商应了解关键物料的供应商 关键物料供应商的更换应该遵循已建立的变更控制程序！

7.2 Receipt and Quarantine Upon receipt and before acceptance each container should be visually checked for -correct labelling -container damage -broken seals -evidence of tampering or contamination Materials should be held under quarantineuntil they have been sampled, 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 中间体或原料药的制造商应了解关键物料的供应商 关键物料供应商的更换应该遵循已建立的变更控制程序！

7.2 Receipt and Quarantine If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination. -certificate of cleaning, testing, audit of the supplier (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 rejected)

7.2 接收和待验 在接收前，应该目测每个容器的包装 -正确的标识 -包装损坏 -封条损坏 -污染 在物料被取样，检测或放行前，应该在待验状态下。 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。 为避免来料误卸入储罐，SOP应放置在现场。

Sampling and Testing of Incoming 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 should be justified and documented A 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 against the specs. At appropriate intervalls full testing should be conducted.

来料的取样和检测 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，工艺助剂，或内部转运物质不需要检测， - -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， -免检产品应该被确定并且记入文件 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他的检测！ 供应商的批准应包括连续物料符合标准的证据。 在减少检测前至少有三批产品经过全检符合规格 在适当的间隙应进行全检

Sampling Samples should be representative; SOP should define --number of containers , which part of container --amount of material to be taken A sampling plan should 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”

7.4 Storage – 7.5 Re-evaluation 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-contamination A first-in-first-out principle must be established Materials in fibre drums boxes or bags should be stored off the floor (on pallets). There should be enough space for cleaning and inspection If materials are stored outside suitable containers should be used and labels must remain legible. Containers 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/humidity

7.4 储藏 – 7.5 再评估 避免对质量有任何消极影响的储存条件和时间（适当的清洁的储藏区域！） 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。

8. Production and In Process Controls Weighing and measuring devices should have a suitable accuracy for their intended 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 specified 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 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？） 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，计算机控制系统，等） 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储存！

In-process Sampling and Controls IPCs should be established to monitor the progress and control the performance of the processing 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 normally needed for IPC tests.

中间控制和取样 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！ 关键的中间控制应由质量部门批准 中间控制的验证/操作人员的培训应有记录 中间控制的现场应有其SOP，怎样取样，等 中间控制不可导致任何污染或交叉污染 tests. 对于中间控制的检验，OOS调查一般不常用

Blending of Batches of Intermediates or APIs Blending 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 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 testing 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，混合相同规格产品的工序。 OOS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！ 混合工序应是受控的并有记录，混合的批次应被检测。 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均一，是需要验证的重要验证项目， 如果混合影响稳定性，需要进行稳定性实验 失效期/复检期应按照时间最久的批次算！

9 Packaging an Identification Labelling of APIs and IMs Written procedures needed for receipt, identification, quarantine, sampling, examination/testing and release. Packaging and 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! 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 中间体和原料药的包装和标识 需要为接收，鉴别，待验，取样，检测和放行建立规程。 包装和标签材料应符合规格。 在运输和储存中，容器应该能防止变质或污染。 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！ 标签储藏库的进入应有限制！ 标签的管理：签发-使用-收回！ 印刷的标签应按照标准控制。 在批记录里要有一张有代表性的标签。

Packaging and Labelling Operation Labelling opreations designed 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. 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 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） 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/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；检查结果要记录！ 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。

Storage and Distribution Facilities with appropriate conditions should be available. Seperate areas should be assigned for quarantined, rejected, returned, recalled materials or alternative system! 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 company 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 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！ 只有质量部门放行的物料可以被发送到第三人或部门。SOP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运输。 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SOP规定！）

11 Laboratory Controls General requirements: adequate laboratory facilities, SOPs for sampling, 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). 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-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SOP，检测，批准，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！ 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，如果必要） 在操作同时，遵循化验室控制并记录。 不合格结果应被调查并报告（有SOP！！） 建立变更控制SOP并执行 溶剂和标准溶液要准确标记（在...日使用） 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

Testing of IMs and APIs An impurity profile describing the identified and unidentified impurities of a typical batch should be established. 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 should 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 杂质概况应在适当的间隙做，根据注册/历史数据（年检）！ 分析的验证程序应按照ICH Q2A and B的指南进行。 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或有效期和储存条件的根据！ 稳定性的包装应模拟储藏/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。之后每年加入一批。

Reserve/Retention Samples The 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 packaging 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 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 留样应在失效期后再保存一年或销售后保存三年 留样应该与原料药用相同的包装或保护更好！ 留样数量应至少有两个全检（按药典或规格要求）的量

12 Validation Validation policy: The company‘s overall policy 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, validation 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.

12 验证 验证方针：工厂应有整体方针的文件 在开放时应确定关键参数；应确定能重复操作 的范围 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/风险评估） 验证文件：验证方案，验证报告，变化及评判应有文件规定。 验证：在工艺验证前，应完成DQ, IQ, OQ, PQ 工艺验证（PV）是工艺，操作符合标准的证据，能够评估原料药/中间体生产的重复性。

Definitions Design 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 equipment/sytems, as installed or modified, comply with the approved design, the manufacturer‘s 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. Performance 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): 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 batches 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完成。 同步验证（可能）：仅限于已经生产的批号；需要有充分的监控和测试！ 回顾性验证 (例外): 已建立的良好工艺, 质量没有变化 (年度回顾!!), 没有工艺/产品不合格, 有杂质档案! 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. 工艺验证应当确认杂质概况, 比原料药在临床和毒理研究的数据相似或更好!!

Validation Systems/processes should be periodically 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, rinse, 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/工艺应是定期评估的，任何重要的变更都要再验证。 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。 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50%！ 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ICH）

13 Change Control A formal change control system should be established and 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, measures 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; sometimes formal approval is needed (contract!).

13 变化控制 应当建立并遵守（ SOP ）正式的变化控制的系统。判断树是有用的。 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：计划，审核，审批，最终的报告，项目跟踪（注册，再验证等）; 次要的变更? 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性计划，并/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。有时候需要正式的审批（合同！）

14 Rejection and Re-Use of Materials Rejected IMs and APIs 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 established 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 evaluation

14 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。应当记录不合格物料的最终处置情况。 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 Materials Reworking: Proceessing of not conforming IM/API by others than established process steps. Before reworking an investigation on „non conforming“ should be performed. Reworked batches 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.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: 中间体/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（检测，稳定性，所有的质量参数！）。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 Recalls All quality related complaints should be recorded and investigated according to the SOP! Records 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 established (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 所有与质量相关的投诉，都应当根据SOP进行记录和调查！ 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 (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 compliance. 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 occurs Any changes should be 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GMP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 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 transfer 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 17 代理商, 经纪人, 贸易商, 分销商, 重新包装人和重新贴签人 ..应当按照指南的规定遵守GMP! 原料药和中间体的分发应当确保可追溯性 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/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“ processes 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 APIs.

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GMP ，Q7A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/Fermentation Viral safety described in ICH Guideline Q5A: Quality of Biotechnological products – Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. Cell Bank Maintenance and Record Keeping Cell Culture and Fermentation Harvesting, Isolation and Purification Viral 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 Trials The 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 for 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.

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 Trials The production of APIs should be documented (lab notebooks, batch records) in detail ( use of materials, processing, 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 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，关于设备，设施，工艺，检测 应当有一套保存所有记录的系统

GMP (ICH Q7A) Compliance and Inspection for COS/CEP Change Control Procedure Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

GMP (ICH Q7A) Compliance and Inspection for COS/CEP 变更控制程序 Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

Subjects Change Control – Definition Projects and Production – Differences Technical Changes Changes of Processes Changes in technical projects/development projects Change Control Procedure – Example Deviations – Definition Deviations - Measures to be taken Deviations - Documentation

题目 变化控制程序－－定义 项目和生产－－区分 技术变更 工艺变更 技术项目/开发项目中的变更 变化控制程序－实例 偏差－定义 偏差－处理措施 偏差－文件

1. Change Control - Definition Change Control is a --planned --approved --documented --controlled procedure concerning any changes of a --formulation (qualities, quantities) --procedures (manufacruring, analytical) --equipment, technical system (air, water, filtration, etc.) --product --project

1. 变更控制－定义 变更控制 是一个 --根据计划的 -- 通过批准的 --有文件为证的 -- 受控的 程序中任何关于以下内容的 变化 －流程（质量，数量） －规程 （制造的，分析的） －设备，技术系统 （空气，水，过滤，等） -- 产品 -- 项目

1. Change Control - Definition Change Control is a very important element in the Quality Assurance System / Qualizy Management System! Change Control is the evidence that changes --are planned and documented --reasons are clear/transparent and can be traced back --are of a controllable risk --still lead to a finished product within set specifications

变化控制－定义 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 －原因清晰，且可以被追踪 －有可控制的 风险 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 －变化是根据计划的，有文件为证的 －原因清晰，且可以被追踪 －有可控制的 风险 －变化仍然导致合格的成品

1. Change Control - Definition Change Control Documents describe and assess planned masures if 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 --technical projects (equipment, facilities, turn key buildings) or any other change which can influence --product quality, -safety, -efficacy or which can change the production system

1. 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： －产品质量，安全，效率 或者变化能够改变生产系统

Projects and Production - Differencies Scope/Valid for: Routine production, Change Control Team to take decisions Longer time needed from start to final approval Development Project (New dosage form, new API) Valid after definition of product characteristics Project Team 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 in short time necessary

项目和生产－区别 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） 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 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 Changes Which systems/equipment to be included in „Change Control“? --All systems/equipment which have been qualified Which changes require a requalification? --All changes which can have an influence to quality, safety, efficacy of the finished product Those changes have to be evaluated and approved internally (QA, ChangeControl Team). Some need approval by Health Autorities!

技术变更 变更控制包括哪些系统/设备？ －所有己验证的系统/设备 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（QA,变更控制小组）。 有些需要通过官方机构的批准。

3. Technical Changes Which technical changes have to undergo the Change Control Procedure? Removal of measuring points New lubricant, grease New tools 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 (water, 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？ 测量点的去除 新的润滑剂，油 新工具 材料的变更 容器大小的变更 制造步骤的变更 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） 接触产品的介质的变更（水，空气，清洁蒸汽，油）

3. Technical Changes It should be carefully decided if a formal Change Which technical changes/works don‘t have to undergo a 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 material. It should be carefully decided if a formal Change Control Procedure should be conducted!

3. 技术变更 正式的变更控制程序需要认真的确定才能被实施！ 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） 更换过滤器（材料，型号，孔径） 按照SOP进行的维护工作 校验 对于不接触原始包装材料的运输设备的 变更 正式的变更控制程序需要认真的确定才能被实施！

Changes of Processes Which processes have to undergo the Change Control Procedure? --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 quality of the finished product. Those changes have to be evaluated and approved internally (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？ －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？ －有很高可能性影响成品质量的重大变更。 这些变更必须通过内部（QA,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。

Changes of Processes Which changes require a revalidation? APIs/excipients: density, particle seize, specification (purity) Packaging material: glas quality, foils, closure systems, print procedures, etc) Processes: Blending 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 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 technical projects/ development projects When 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 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 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？ －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 Work Basic RA Detail RA Engineering Process Optimi-sation Manufac- turing Delivery/ Installation Commiss-ioning Start-up Test Runs URS DQ/FDS FAT IQ/SAT OQ/SAT PQ PV / CV Re-Val. Change Control / Requalification

项目工作中的设计确认 工程 试运行 试生产 工艺优化 制造 URS DQ/FDS FAT IQ/SAT OQ/SAT PQ PV / CV 基础的 RA 详细的RA 工程 交货/安装 试运行 试生产 工艺优化 制造 URS DQ/FDS FAT IQ/SAT OQ/SAT PQ PV / CV Re-Val. 变更控制 / 再确认

Changes in technical projects/ development projects Which 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/计划中的变更必须通过变更控制程序？ －所有的变更/计划中的变更 哪些能够影响成品质量？ 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

Changes in technical projects/ development projects Do all changes/changes in planning have to undergo Change Control? No How to find out if a change has to undergo Change Control? only possible with detailled knowledge of the process exact knowledge of factors influencing product quality exact knowledge of interplay of different factors of influence Only the user of an equipment, system, production line, facility, etc. can take the final decision. For complex systems,...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 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， 设施等做最终决定的， 对于综合系统..建议由小组做决定。

6. Change Control Procedure - Example Documentation according to GMP Requirements Fill out the template Change Control/application Application to be sent to CCTeam/CCCoordinator/QA Registration/Number, Change Control to be listed in a table Periodical evaluation of changes by CCTeam (QA, Head of department, further participants according to the kind of change

6.变化控制程序－实例 符合GMP要求的文件 填充变更控制的模板/申请表 申请递交至变更控制小组/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 - Example Documentation according to GMP Requirements Decision and approval about measures to be taken, trials to be conducted, batch size to be defined, time schedule, etc. Information to be given to responsible coordinator, employees. Conducting of all activities decided in the CCTeam Collection of data, summary ,evaluation of data, report Final decision to change or not or to conduct additional work Documentation, Archiving

6.变更控制程序－实例 符合GMP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，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

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 misfunction of equipment or caused by employees

偏差－定义 所有不符合日常/正常生产/制造程序规范的事件 发现的超出规格的所有事件/数据 （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致。

Deviation – Measures to be taken Documentation of the deviation for Annual Batch Review Information of responsible 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 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; evaluation 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) Compliance and Inspection for COS/CEP Validation of Cleaning Procedures in Chemical API Production Dr. Berthold Stemmle Pharma Consulting Associated Partner of Concept Heidelberg

GMP (ICH Q7A) COS/CEP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 Consulting Associated Partner of Concept Heidelberg

Pharmaceutical Technology, April 2005 Warning Letter Report 2004 There were a large number of violations of § 211.67 of 21 CFR . ..18 out of 33 warning letters cite most deficiencies in „Equipment cleaning and maintenance“. For „Control of microbiological contamination“ the citation rose from 1 in 2003 to 11 in 2004. The proportion of warning letters to companies outside The 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 Requirements ICH Q7A: Cleaning procedures should normally be validated 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 (API 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 Requirements ICH Q7A - Bracketing accepted - Validated analytical procedures to be applied - Determination of microbial load –if necessary - Definition of time intervals for controling validity of cleaning procedures Validation Protocol should include information about - Equipment (room, id-number, material) - Cleaning SOP - Acceptance limits - Analytical method (sampling method, sampling plan)

指导, 药政要求 ICH Q7A - 已接受的框架 - 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 - 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 - 设备（房间，识别号码，物料） - 清洗SOP - 接受的限度 - 分析方法 (取样方法，计划)

Guidances, Regulatory Requirements PIC: Cleaning has to cover previous products, cleaning agents, extraneous materials and microbiological contamination. One product trains don‘t require cleaning validation (but..) Polyproduction (multi purpose trains) have to be validated. Three subsequent cleaning procedures are required. Bracketing is accepted. 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 Requirements FDA: Written instructions (SOPs) after 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 setting, 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 Manufacture Definition The process of providing documented evidence that the cleaning methods employed within a facility consistently control 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, purity) - 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 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。 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-organisms) APIs with high allergene potential (Penicillines, Cephalo- sporines) Pesticides (Herbicides, Fungicides, Insecticides) filters!, tarry or gummy residues High 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 Residues Precursors to the API By-products and/or degradation products of the API The previous product Solvents and other materials employed during manufacture Micro-organisms Cleaning agents and lubricants, surfactants

潜在残留 原料药的前体 副产品和/或原料药的降解产品 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. 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 policy Rational for the methods by which acceptance criteria are determined Revalidation 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

API Production Train Cleaning liquid Mungenast, Merck 5150 S 1 S 4 R 1 / R 5 / R 9 + R 13 R 4 / R 8 + R 12 R 3 / R 7 + R 11 R 2 / R 6 + R 13 S 1 S 2 + S 3 S 4 S 5 + S 6 Mungenast, Merck

API 生产链 清洗液 Mungenast, Merck 5150 S 1 S 4 S 2 + S 3 R 2 / R 6 + R 13 R 1 / R 5 / R 9 + R 13 R 4 / R 8 + R 12 R 3 / R 7 + R 11 R 2 / R 6 + R 13 S 1 S 2 + S 3 S 4 S 5 + S 6 Mungenast, Merck

Typical API Train Examples for Surfaces in m2 Equipment Cleaning method Sampling Steering kettle 10-30 5 2-30 10 Zentrifuge Filter housing Filter material Drying oven Tumble dryer Pipings

典型的原料药制造链 实例： 表面积 m2 设备 清洗方法 取样 反应釜 10-30 5 2-30 10 离心机 过滤器 过滤材料 干燥烘箱 摇摆干燥器 管路

Multi-Product Equipment Chemicals Precursors to APIs APIs Excipients Food additives Cosmetical 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 Cleaning The degree or level of cleaning and validation depends on: - the equipment usage (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 based on the stage of process beeing cleaned and the subsequent product manufactured It 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 plant 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。

Levels of Cleaning and Validation API 2 Step 1 API 2 Step 2 API 1 Step 1 API 1 Step 2 API 1 Step 3 Cleaning Validation Limit 10-100 ppm Bulk B Step 1 Bulk B Step 2 Cleaning Limit 100-1000 ppm Cleaning visually clean

清洗水平和验证 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 1 Step 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

Levels of Cleaning and Validation Level 2 Product changeover of equipment used in final step Intermediates of one batch to final step of another Validation required - essential Level 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 process 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 验证要求 – 必须 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0到2 无验证要求 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 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， 水平级数在0到2 水平0 在连续生产中，批与批的交替 无验证要求

Levels of Cleaning and Validation Product change over Acceptance limit Validation Precursor to final step API 10 ppm-100 ppm Yes 1/100-1/1000 dose Precursor to intermediate 100 ppm-1000 ppm YES/NO of an API RA for API Later step to earlier step of Visual clean or NO the same API 1000 ppm, RA Early step to early step of of the same API Precursor to chemical Visual clean NO (No „GMP product“)

清洗水平和验证 产品更换 接受标准 是否 验证 前体到原料药的成品阶段 10 ppm-100 ppm 是 1/100-1/1000 dose 产品更换 接受标准 是否 验证 前体到原料药的成品阶段 10 ppm-100 ppm 是 1/100-1/1000 dose 前体到一个原料药的中间体 100 ppm-1000 ppm 是/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 1000 ppm, RA 同一原料药的前期步骤到前期步骤 前体到化学品 目测洁净 否 (否 „GMP 产品“)

Elements of Cleaning Validation - Stage 1 Name 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 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

Elements of Cleaning Validation – Stage 1 Develop and validate the sampling and chosen analytical methods for the compound(s) being cleaned - Swab - Rinse - Condensate Determine % 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，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 1 Evaluate 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 calculate 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 2 Develop a cleaning validation protocol for the product and the equipment being cleaned which should encompass: - Introduction - Scope - Equipment - 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 3 Interim Report 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!! - 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 4 Generate 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 generated 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 Validation Establishment of Acceptance Criteria Cleaning 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, achievable 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 Determination Generally residual API or intermediate is of greatest concern Limits can be based on toxicological or therapeutic data: - an Acceptable Daily Intake (ADI) + safety factor is calculated and converted to the max. allowable 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 unknown 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 Criterion – FDA Statement Some 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 related 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. Firm 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 Criteria – Physical Determination There 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 stainless steel surfaces if the amount exceeds ~400 µg/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 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 µg/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 Determination Appropriate studies should be performed (swabs and/or rinse sampling) where the possibility of microbiological and endotoxin contamination of subsequent product is deemed 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 Procedures SOP for each 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.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 materials - Difficult to clean areas (gaskets, filters, hoses, weld joint, ball cock/valve, pipings (with measuring devices!!) - Ease of disassembly, fixed or not Residues to be cleaned: - Cleaning limits, calculation, criteria - Solubility of residues (water, organic solvents,…) - Length of campaigns, stand-by 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 procedures Cleaning agent parameters to be evaluated: - Preferably materials that are normally used in 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) - 环境因素 - 健康安全因素

Cleaning Procedures Cleaning 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, steam, 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 performed Detailed description of cleaning methods SOP 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 necessary Steps needed to protect the equipment from contamination after cleaning SOP should require control that no water/traces of water is left in the equipment after cleaning Date 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！） 设备清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 Guidance PIC/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 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 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 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FDA清洗程序验证检查的指导 “大体有两种可接受的取样方法。最理想的是直接接触设备表面的方法。另一方法是使用淋洗液... ”

Sampling Two methods generally employed: SWAB and/or RINSE sampling. Testing in next product to be explained,exception SWAB: 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. 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。 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 Test Advantages Normally accepted by FDA Will remove residues from surfaces with a high probability Simply to handle (after training of personnel!) Disadvantages 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 不代表整个表面 不适用于CIP设备的包装系统

Swab Test Dr. F. Schmidtke, Schering AG Schlinggaze Tupfer (Wiper) (Firma Hartmann) Cleantip TX761 (Firma Texwipe) 5 ml volume for extraction

擦拭检测 Dr. F. Schmidtke, Schering AG Schlinggaze Tupfer (Wiper) (Firma Hartmann) Cleantip TX761 (Firma Texwipe) 提取量5ML

Swab Test Define material of swab (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 SAMPLING The solvent rinse occurs after cleaning has been completed Not direct as swabbing but covers the entire surface area including parts not accessible to swabs. Rinse method allows greater ease of sampling than swabbing A 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 Test Advantage - Analytical determination easier, often sample can be used for detection - 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 possible Disadvantage - Is the residue really in the sample or still on the surface? - Results not reliable if residues are 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 Examples for Surfaces in m2 Equipment Cleaning method Sampling Steering kettle Fill with water, boil Rinse Wash, fill up, CIP Rinse/Swab Wash, fill up Rinse/Swab Dedicated!! Wash/brush/wipe Swab 10-30 5 2-30 10 Zentrifuge Filter housing Filter material Drying oven Tumble dryer Pipings Wash, fill up, pump Rinse

典型的原料药设备链 示例 表面积m2 设备 清洗方法 取样 反应釜 注水，煮开 淋洗 注满，设备自动清洗 淋洗/擦拭 注满，清洗 淋洗/擦拭 注水，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 10-30 5 2-30 10 离心机 过滤器 过滤材料 烘箱 摇摆干燥器 管路 注满，清洗 ，泵抽 淋洗/擦拭

Analytical Methods To yield meaningful results from swab/rinse the analytical methods used should be validated Method is able to detect the target substance(s) at levels consistent with set acceptance criteria Where more than one substance/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 approach 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 Methods The analytical method 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 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: - 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 specific test (TOC) - how many times should the study be run before a report is compiled and recommendations made VP 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 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 (VPs) VP defines personnel responsibilities during the study VP details test methods to be used ( to be referenced) VP gives rational about acceptance criteria (chem./phys.) VP defines how change control is applied VP defines approval and signatures needed before the study VP defines the time schedule VP describes 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 approval of the study; it includes: Summary/reference to procedures (clean, sample, test) Physical and analytical test results (or reference), as well as any pertinent observations Conclusions regarding the acceptability of the results, and the status of the procedure(s) being validated Recommendations based on the results; revalidation Approval of conclusions; review any deviations Interim reports on a batch by batch basis where needed VR 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 Requirements If 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 greatest 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!) Equipment grouping (similiar size, design, construction) is possible Concurrent 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，做同步验证

Change Control / Revalidation Validated 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 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 Elements Define Equipment (ID No) and products (previous, following) Assess impact of this process on routine processes Determine cleaning agent and method (detailed!) Determine acceptance criteria for the residues/cleaning agents. Give scientific rational! Determine degree of evaluation required for validation Define residues to be tested for based on solubilities/tox Develop sampling and analytical methods for recovery and detection of residues (swab, rinse, HPLC, TOC, dry residue) Acceptance criteria for the validation Compile and approve validation protocol Perform validation studies according with protocol Compile and approve a Validation Report documenting studies, conclusions and recommendations Define 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 – Inspections in API Production Dr. Berthold Stemmle Pharma Consulting

Berthold Stemmle 博士 药物顾问 良好制造规范－原料药生产的检查 Berthold Stemmle 博士 药物顾问

Objective and Purpose of GMP - Inspections Check and evaluation of QA-Systems How 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? Control 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/Audits System orientated QS system, documentation system, organisation of batch release, training of personell, handling of OOS – results, deviations, changes; definitions of interfaces in GMP areas Product orientated Batch and QC documentation (compliance!!), annual product reviews Material flow orientated Receipt and quarantine – production – packaging – distribution (with documentation) Documentation orientated Control of production and QC documentation 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，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 产品批次和QC文件（遵循指南！！）年度产品回顾 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 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 Steps Preparation (first impression, presentation of company, key persons, responsibilities, organisation chart, 30 min) Inspection Final discussion with findings (critical, mayor, minor) with time frame for corrections. Inspection report (no new findings!) Corrective measures with time schedule, responsibilities Inform inspectors when all measures 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，检查官决定再检查！

Inspection of API - Documentation General documentation in the firm API specific documentation Summarizing and evaluating product documents Content 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 Firm Company‘s organisation (organisation chart with functions, 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 SOPs Cleaning protocol for bulding and facilities Cleaning 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 Documentation Flow chart of synthesis or process including equipment Official documentation at Health Authorities Manufacturing instruction and batch record Lists of raw materials for synthesis, solvents, reagents, excipients, packaging materials List of suppliers including evaluation (audits!) List of equipment Batch Flow Sheet Documentation of deviations, investigation, evaluation Final batch evaluation by responsible production person Batch record 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 Documentation Overview of changes with rational, History of Changes Approval of changes in processes according to SOP Documentation of changes in manufacturing instructions with version controls List of rejected batches Impurity profile (by-products, degradation products, solvents IPCs, analytical testing procedures for APIs, intermediates, raw materials. Other control procedures? Critical process parameters as basis for validation Sampling plans

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 Documents Qualification reports for main equipment/facilities (IQ, OQ) Validation protocol, -data, -report Cleaning validation for multi purpose equipment Additional 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 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 data List of all batches including evaluation Trend analysis of critical quality parameters List of all changes with evaluation (Change Control!) List of deviations with evaluation (Failure Investig. Reports) List of OOS – batches and evaluation List of complaints and recalls and evaluation List of stability data with evaluation Planned measures/activities Continuation of lists Final evaluation by QS with signature

《年度产品回顾》的内容 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 部门的最终评估及签名

Inspection Tour through Buildings/Facilities Status of facilities/equipment: product, batch, cleaned? All needed instructions available, log-books showing calibration, maintenance, repair, cleaning Last step of API purification, packaging, sampling, labelling Filling room for final API according to GMP(air flow,cleaning) Cross contamination: where possible, how is it avoided? Mix-ups possible with previous batches? Which data are generated, automatically. Raw data handling Critical raw data double checked Labelling of containers (labels not on the lid!) Stotrage area: Environment control, principle, quarantine Outside stored materials protected? SOPs available? Status label on materials: sampled, released, rejected Is 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 确保了只有放行的物料进入生产?

Inspection Tour through Buildings/Facilities Rejected 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 wells, 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 Focus Compliance of approved documentation with manufacturing and testing documentation, actual activities and behaviour. Is QS independent, upper management involved? Process Validation: protocol – data – report – follow-up Cleaning validation, how are cross-contaminations avoided? Annual Product Review Failure 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? Ongoing stability tests running? GMP training of personnel done and reported (Plan!!) Development report as basis for validation available? Validation of the water preparation system, + microbiological Calibration and maintenance of facilities/equipment

FDA 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？ 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 FDA Laboratory Controls Records/Reports API Stability Equipment Cleaning Water Systems Written Procedures Process Validation Process Controls

FDA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