8、2010版药品gmp变更控制培训讲义

变更控制,山德士（中国）制药有限公司 邓艳 2011-07-29,GMP 2010/中国GMP2010相关要求,第十章质量控制与质量保证第四节变更控制第二百四十条企业应当建立变更控制系统，对所有影响产品质量的变更进行评估和管理。需要经药品监督管理部门批准的变更应当在得到批准后方可实施。第二百四十一条应当建立操作规程，规定原辅料、包装材料、质量标准、检验方法、操作规程、厂房、设施、设备、仪器、生产工艺和计算机软件变更的申请、评估、审核、批准和实施。质量管理部门应当指定专人负责变更控制。第二百四十二条变更都应当评估其对产品质量的潜在影响。企业可以根据变更的性质、范围、对产品质量潜在影响的程度将变更分类（如主要、次要变更）。判断变更所需的验证、额外的检验以及稳定性考察应当有科学依据。第二百四十三条与产品质量有关的变更由申请部门提出后，应当经评估、制定实施计划并明确实施职责，最终由质量管理部门审核批准。变更实施应当有相应的完整记录。第二百四十四条改变原辅料、与药品直接接触的包装材料、生产工艺、主要生产设备以及其他影响药品质量的主要因素时，还应当对变更实施后最初至少三个批次的药品质量进行评估。如果变更可能影响药品的有效期，则质量评估还应当包括对变更实施后生产的药品进行稳定性考察。第二百四十五条变更实施时，应当确保与变更相关的文件均已修订。第二百四十六条质量管理部门应当保存所有变更的文件和记录。,通行国际参考法规,欧盟法规Commission Regulation (EC) No. 1084/2003Commission Regulation (EC) No. 1085/2003Regulations describe the need to control changes as they relate to drug product marketing authorizations美国FDA 法规Control of changes as they relate to market authorizationsHuman drug NDAs (21 CFR 314.70)Generic human drug ANDAs (21 CFR 314.97)Animal drug NADAs (21 CFR 514.8)Post-approval change guides (SUPAC, BACPAC, PAC-ATLAS)21 CFR 211 (Drug GMPs) and 21 CFR 820 (Device GMPs) - various parts describe the need to control changes,Definition定义 变更是什么？,Definition定义 变更控制是什么？,What our objective for set up change control? 建立变更控制的目的,Responsibility职责,Type of Change变更类型（total: 21）,Product formulation产品处方Manufacturing process (drug substance, drug products)生产工艺（原料药、制剂产品）Batch size批量Manufacturing, packaging and analytical equipment生产、包装和分析设备Facilities & Utilities设施和公用系统In-process control中间过程控制Starting material / Excipient / Intermediate起始物料/辅料/中间体,Type of Change变更类型（total: 21）,Primary packaging material内包装材料Secondary packaging (e.g. labels, leaflets, cartons, other printed items, etc.)外包装材料（例如：标签、说明书、纸盒、其他印刷的材料等）Technical changes related to labelling and artwork与标签和样稿相关的技术变更Analytical testing methods分析方法Analytical testing specifications质量标准Water systems水系统Cleaning and sanitization procedures清洁和消毒程序,Type of Change变更类型（total: 21）,Suppliers供应商Production site生产地点Stability (shelf life, retest period, storage and transport conditions)稳定性（有效期、复检日期、储存和运输条件）Quality and GMP related documentation与质量和GMP相关的文件Changes in Computer Systems and Software which may have an impact on system validation, product quality or GxP. 由于变更计算机系统和软件而影响系统验证、产品质量或GxPChange of supplier or third party; includes manufacturing, packaging, testing, warehousing, and distribution变更供应商或第三方，包括生产、包装、检验、仓储和分销商Change in release site(s)变更放行地点,Process Summary流程概要,Time limit for processing变更处理时限,Change Request and Evaluation变更申请和评估,Some deficiencies during audit/常发生的相关缺陷,Example of Recal l/产品召回案例l,PRODUCT产品Desmopressin Acetate Injection（醋酸去氨加压素注射液), 4mcg/mL unit dose pack ampulsRECALL召回号： # D-110-4RECALLING FIRM/MANUFACTURER召回企业：Abbott Laboratories, Abbott Park, IL by letter January 16, 2004. REASON原因：Unapproved New Drug: Manufacturing change did not have an ANDA pre-approval./生产工艺变更未经过ANDA预先批准DISTRIBUTION销售One lot distributed nationwide.In this case, the change may not have been evaluated through change control for registration requirements.此单案例，变更未遵循经过正式的变更控制程序实施注册要求评估,Example of Recall产品召回案例ll,PRODUCTButalbital(布他比妥), Aspirin, and Caffeine Capsules, (50mg Butalbital, 325mg Aspirin, 40mg Caffeine), 100 count bottles.RECALL # D-078-4RECALLING FIRM/MANUFACTURERLannett Co, Inc, Philadelphia, PA by telephone November 10, 2003. REASONANDA/NDA Discrepancies: Manufacturing process used an unapproved source of Butalbital./生产工艺使用的原料药未经批准DISTRIBUTIONOne lot distributed nationwide.Another case in which the change may not have been evaluated through change control for registration requirements.此单案例，变更未遵循经过正式的变更控制程序实施注册要求评估,Example-FDA warning letter FDA警告信,Searle, Ltd. (Puerto Rico) December 2002“Failure to follow your procedure related to your Change Control Program as required by 21 CFR 211.100(a). For example, many instances were reported as lacking the required signatures prior to the implementation of a change requested.”未遵循21CFR211.100(a)的变更管理程序。例如，很多案例显示在实施变更前缺少应有的签名。Changes should not be made until change requests are formally approved and documentation closed.变更申请正式批准前不得实施变更。,Example-FDA warning letter FDA警告信,Amgen (Colorado) May 2003“Construction of the _ and expansion of the support systems, which included making modifications to existing product process pipes, was conducted without adequate change control. There was no protocol describing the tests to be conducted or the data to be collected to ensure the new and existing pipes were clean and suitable for use. Furthermore, there was no documented review of data regarding the cleanliness