原料药生产质量管理手册

沈阳抗生素厂编号：ZL398 页号：1/112 质量手册质量手册 QA Manual 版本号：00 颁发部门：质量部执行日期： 年 月 日 文件内容：文件内容： INDEX： 1、质量方针、质量方针 .4 Quality Policy.4 2、质量管理原、质量管理原 则则.4 Principles for Quality Assurance.4 3、定、定 义义.6 Definitions.6 4、人员管、人员管 理理.10 Personnel and Organization.10 5、培、培 训训.15 Training.1 5 6、厂、厂 房房.16 Premises16 7、消毒与卫生、消毒与卫生21 Sanitation and Hygiene.21 8、物料供应、物料供应.27 Materials Supply.27 9、生产文件与记录、生产文件与记录.30 Manufacturing - Documentation and Records.30 10、原料药生、原料药生 产产.39 Manufacture Of API.39 沈阳抗生素厂编号：ZL398 页号：2/112 质量手册质量手册 QA Manual 版本号：00 颁发部门：质量部执行日期： 年 月 日 11、质量文件与记录、质量文件与记录.52 Q.A. Documentation and Records.52 12、质控处文件与记、质控处文件与记 录录.63 Quality Control.63 13、检验报告、检验报告 单单.84 Certificate of Analysis.84 14、有效期和复检、有效期和复检 期期.84 编号：ZL398 沈阳抗生素厂 页号：3/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 Expiry and Retest Dating.84 15、留、留 样样.85 Reserve / Retention Samples. 85 16、仓储、仓储. .86 Warehousing and Distribution. 86 17、委托生产、委托生产/委托检验委托检验. 96 Contract Manufacture and Analysis. . 96 18、验证、验证. 99 Validations. 99 19、客户投诉与召回、客户投诉与召回. 106 Customer Complaints and Recalls. 106 20、自检、自检. 108 Self Inspection. . 108 21、产品质量回顾、产品质量回顾. .109 Product Quality Review. 109 22、变更控制、变更控制. 110 Change Control. 110 发放范围：发放范围： 全厂 编号：ZL398 沈阳抗生素厂 页号：4/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 文件复审：文件复审： 复 审 人 复审日期 复审意见 编审批过程：编审批过程： 起草人审核人批准人 部 门质保处质保处质量部总工程师 签 名 日 期 编号：ZL398 沈阳抗生素厂 页号：5/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 1、质量方针质量方针 Quality Policy ： “质量” 的定义是指为符合预定用途所具有的一系列固有特性的程度。质量体系是基 于一定的设备、人员基础上通过设计、文件化、执行及控制来实现预期质量、纯度、安 全性及稳定性等目标的系统。根据质量系统分工，各部门包括研发、生产、技术、仓储、 销售、质量和质检等部门分工合作，共同实现质量方针。质量管理体系主要包括验证、 GMP、文件、内审、培训及客户投诉。质量目标的最终实现是基于全员范围质量方针、 质量通则贯彻落实基础上实现的。 Our QUALITY philosophy is a synthesis or world guidelines, laws regulations and best human requirements, which enable us to cater to the best needs of our customers. The QUALITY system is designed, documented, implemented and controlled which is based on instrumentation, man power and management desire so as to give a assurance that the products manufactured by the company will be consistent in their intended use with respective to quality, purity, safety, efficacy and stability. It is monitored by a team responsible for validation, GMP, documentation, self-audits, training and market complaints. The ultimate QUALITY goal is achieved by every one adhering to quality policy and principle. 2、质量管理原则质量管理原则 PRINCIPLES FOR QUALITY ASSURANCE 2.1 我公司保证产品质量安全可靠，我厂质量管理能够实现质量目标。 We pledged to assure that its products and services are of high quality with regard to safety, properties of use and reliability.The management of Shenyang Antibiotic Manufacture is fully committed to supporting all necessary measures. 2.2 质量目标基于下列要求的制定： Quality Assurance comprises the totality of all measures desired to achieve this aim taking into 编号：ZL398 沈阳抗生素厂 页号：6/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 account （1）客户的需求 The needs of our customers （2）相关法规要求 The relevant legal requirements （3）工艺要求 The state of the art （4）内控质量标准。 The inhouse standards 2.3 产品质量的保证是研发、供应、生产、仓储、销售等部门必须各自制定并完成相应质 量目标从而实现的。 The quality assurance of products and services is therefore a company obligation, which must be shared by the departments for development, purchasing, manufacturing, distribution, marketing and by all other members. 2.4 质量部的职责： The Quality Assurance Departments Duty： （1）质量标准的建立及更新； Ensures that appropriate quality standards are set, maintained and kept upto date. （2）生产过程质量监督管理； Supervises the implementation of all necessary measures through the line / manufacturing functions. （3）提高全员质量意识。 Plays a leading role in promoting quality awareness throughout the company. 2.5 质量部的工作： The tasks of the Quality Assurance Department include: （1）生产及委托生产生产过程监督指导； Technical guidance and supervision to different manufacturing units owned by the company and third parties. （2）协调相关部门建立各项标准； 编号：ZL398 沈阳抗生素厂 页号：7/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 Setting standards in co-operation with all departments concerned. （3）生产储存及发运的全过程实施质量管理； Implementing quality assurance measures at all levels of manufacture, storage and distribution. （4）组织应对突发事件及产品召回； Organizing emergency and recall procedures. 2.6 质量部长直接向厂长汇报工作，独立于销售、生产、供应及研发部门。 Quality Assurance Department minister reports to Director of the company so as to ensure independence from marketing, manufacturing, purchasing and R （1） 文件及文件修正的批准。 The authorization of written procedures and other documents including amendments （2）生产环境的监督和控制。 The monitoring and control of the manufacturing environment （2） 厂区卫生 Plant hygiene （3） 工艺验证 Process validation （4） 培训 编号：ZL398 沈阳抗生素厂 页号：16/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 Training （5） 物料供应商、委托生产的批准和监管。 The approval and monitoring of suppliers of materials The approval and monitoring of contract manufacturers （6） 监管物料和成品的贮存条件。 The monitoring of storage conditions for materials and products （7） GMP 执行情况监管。 The monitoring of compliance with the requirements of GMP （8） 记录保存。 The retention of records （9）通过巡视、调查及取样监控可能影响产品质量的因素。 The inspection, investigation and taking samples in order to monitor factors which may affect product quality 5、培训、培训 TRAINING 5.1 应依照培训计划对生产、储存、检测相关人员进行培训（包括工艺员、机修人员、保 洁人员） 。 Training should be provided in accordance with a written programme for all personnel who are involved in production activities, storage functions, and control laboratories (Including technical, maintenance and cleaning personnel). 5.2 应定期培训 GMP 相关知识并对培训效果进行评估。 Training on Good Manufacturing Practices should be repeated periodically and its practical effectiveness should be assessed. 5.3 应对新进员工进行适应岗位要求的岗前培训。经评估岗位技能合格后方予以独立上岗 操作。评估记录应存档。 Newly recruited personnel should be given training appropriate to the tasks assigned to them. Their ability and knowledge to perform the assigned operations should be tested and evaluated before putting them to work independently. The records of evaluation should be kept in detail. 5.4 高风险操作区（如：高活性、高毒性、传染性、高致敏性物料的生产区）的工作人员 编号：ZL398 沈阳抗生素厂 页号：17/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 应接受专门培训。 Personnel working in areas where contamination is hazardous, e.g. areas where highly active, toxic or sensitizing materials are handled (should be given specific training appropriate to these activities. 5.5 质量保证的理念和质量过程控制方法应全员重点培训以提高质量管理工作理解和执行 能力。 The concept of quality assurance and all the measures capable of improving its understanding and implementation should be widely discussed during the training sessions. 5.6 培训管理制度由质量部长和总工程师审核批准后，执行相关培训记录存档。 Written training programmers should be available approved by Quality Assurance Manager and Production Manager as deemed appropriate. Training records should be kept in detail. 5.7 定期评估培训效果。 At definite intervals, assessment of training programmes effectiveness should be done. 6、厂房、厂房 PREMISES 6.1 一般要求 General Requirements 6.1.1 厂房选址、设计、布局、建造、改造和维护必须符合药品生产需求，应当能够最大 限度避免影响产品质量的污染和混淆，便于清洁、操作和维护。 Premises must be located, designed, constructed, adapted and maintained to suit the operations to be carried out and aimed to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid bulk-up of dust or dirt and in general, any adverse effect on quality of the product. 6.1.2 药品生产厂房应根据厂房及生产防护措施综合考虑选址。厂房所处的环境应当能够 最大限度地降低物料或产品遭受污染的风险。 Pharmaceutical manufacturing premises should be situated in an environment, which when considered together with measures to protect manufacture and storage, present minimal risk of causing contamination of materials and products. Pharmaceutical manufacture should also present minimal risk of environmental contamination via emissions, waste, etc. 编号：ZL398 沈阳抗生素厂 页号：18/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 6.1.3 应定期对厂房进行维护，确保厂房维护保养操作不危害人员和产品质量。根据清洁、 消毒规程进行清洁、消毒。 Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazards to the personnel and quality of the product. They should be cleaned and where applicable, disinfected according to the detailed written procedures. 6.1.4 生产、储存过程应配备相应照明、温度、湿度和通风设施并确保其不会直接或间接 影响产品质量、仪器设备精度。 Lighting, temperature, humidity and ventilation should be appropriate and such that they do not affect directly or indirectly either the product during their manufacture and storage or the accurate functioning of the equipment. 6.1.5 厂房应设计、建造、装配预防昆虫和其他动物的进入的设施，并定期维护。设置门 禁设施禁止非生产人员进入。 Premises should be designed, constructed, equipped and maintained to prevent entry of insects and other animals. Steps should be taken in order to prevent entry of unauthorized persons. 6.1.6 生产区、库房及实验室禁止其他部门工作人员穿行。 Manufacturing, storage and quality control areas should not be used as a means of access to other areas by personnel who do not work in them. 6.1.7 工作区域、走廊等不用于储存目的。 Working areas, corridors, etc. should not be used for storage purposes. 6.1.8 减少灰尘容易堆积的突出的臂架、架子、壁橱和设备或难以清洁的角落等清洁死角。 To reduce the accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be carefully designed to avoid uncleanable recesses. 6.1.9 气锁间的门禁止同时敞开。 Airlock doors should not be opened simultaneously. 6.2 仓储区域 Storage areas 6.2.1 仓储区域应具备足够的空间储存各类产品和物料，如原辅料、包装材料、半成品、 编号：ZL398 沈阳抗生素厂 页号：19/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 成品。放行、拒收、退货及召回的产品单独存放。 Storage areas should be of sufficient capacity to store various categories of products and materials: starting materials and packaging materials, bulk and finished products, products in quarantine, released, rejected, returned and recalled. 6.2.2 仓储区域设计和使用应确保良好的储存条件，定期清洁并维持在物料或产品保存所 需温湿度范围内。 Storage areas should be designed and adopted to ensure good storage conditions. They should be cleaned periodically and maintained within acceptable temperature and humidity limits suitable for materials or products being stored. 6.2.3 接、发货区应保证物料和产品免受外界天气的影响，接货区应允许物料入库前清洁。 Acceptance and dispatch bays should protect materials and products from the weather. Receiving bay should be designed and equipped to allow incoming materials to be cleaned before storage. 6.2.4 明确标示隔离区仅授权人员进入。 Quarantine areas must be clearly marked and their access restricted to authorized personnel. 6.2.5 原料和内包材应配备单独的取样区域。 There should be separate sampling area for starting materials and primary packaging materials. 6.2.6 拒收、召回、退货的物料或产品离存放，仅授权人员可以进入。 Separate segregated areas should be provided for storage of rejected, recalled or returned materials or products. The access to these areas should be restricted to authorized persons only. 6.2.7 易燃或其他有害物料适宜条件下单独存放以确保储存、取样和处理的安全。 Highly flammable or otherwise hazardous materials should be separately stored under appropriate conditions to ensure safety in storage, sampling and handling. 6.2.8 印字包材（如标签等）应该在安全条件下储存于独立密闭包装内，仅授权人员进入。 Printed text components (e.g. labels etc.) should be stored under secured conditions, in separate closed bundles or containers with access restricted to authorized personnel. 编号：ZL398 沈阳抗生素厂 页号：20/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 6.3 生产区域 Manufacturing Areas 6.3.1 对特定药品采用专用密闭设施预防交叉污染的风险。 In order to eliminate the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities should be available for the production of particular drugs. 6.3.2 厂房使用应确保按照生产操作流程分布，清晰界定洁净级别划分洁净区，确保厂房 符合洁净级别要求。 Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of operations and to the requisite cleanliness levels, which should be clearly identified and separated into cleanliness zones. 6.3.3 生产区过程控制检查应定期执行以预防产品生产出现风险。 Certain in-process control checks may be performed within the production area provided that they do not present any risk to the products being manufactured. 6.3.4 工作区域与转存区域应允许设备及物料合理定位避免批不同产品或不同批次产品混 淆或交叉污染。 Working space and in-process storage space should be adequate for orderly and logical positioning of equipment and materials to minimize the risk of confusion between different products or their components and of cross-contamination. 6.3.5 原料、内包材接触的环境其内表面（墙体、地面或天花板）应该光滑，无裂缝和接 头，无堆积尘埃，应能够简单有效地清洁和消毒。窗、门、阀门、管线等应充分密封。 棚顶通风口密封。 Where starting materials, primary packing materials are exposed to the environment, interior surfaces (of walls, floors, and ceilings) should be smooth, free from cracks and open joints, should not shred particles, should permit easy and effective cleaning and disinfecting.Windows, doors, entry of ducts, pipes, etc, should be adequately sealed. In the areas where dust is generated, voids above suspended ceilings should be sealed. 6.3.6 管线、照明设施、通风换气口等设施设计安装应尽量避免清洁死角及维护保养难以 进入的部位。 编号：ZL398 沈阳抗生素厂 页号：21/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean and as far as possible, they should be accessible from outside for maintenance purpose. 6.3.7 排水设施应当大小适宜，并安装防止倒灌的装置。应当尽可能避免使用明渠排水； 不可避免时，明沟宜浅，以便清洁和消毒。 Drains should be of adequate size and fitted with traps. Open channels should be avoided. If necessary, they should be shallow to facilitate cleaning and disinfecting. When not in use, they should be maintained dry. 6.3.8 生产区域配备空调净化系统确保空气高效流通（包括温度、压力、湿度和空气净化 过滤）以保证药品的生产环境符合要求。空气循环回风系统应充分过滤以避免产生交叉 污染。 Production areas should be effectively ventilated with air control facilities (including temperature, pressure, if necessary, humidity and filtration) appropriate to products handled, operations undertaken within them and to the external environment. Any recycled air should be adequately filtered to prevent cross-contamination. 6.3.9 产尘操作间（如称重、混合操作间）应采取专门的吸尘措施。 Local dust extraction system should be provided where dust is generated (e.g. weighing, mixing and processing operations). 6.3.10 通风和吸尘系统应经过确认并定期清洁和维护，过滤器更换的周期应明确规定，确 认和维护保养（包括滤芯更换）应在文件明确规定并且记录，记录存档。 Ventilation and dust extraction system should be qualified and regularly cleaned and maintained. Filter change intervals should be clearly specified. Qualification and maintenance (including filter change) should be documented and the records are maintained. 6.4 车间分析室 Laboratory Areas 6.4.1 实验室应与生产区分开。微生物实验室应与其他实验室分开。 Laboratories should be separated from production areas. Microbiological Laboratories should be separated from other laboratories. 6.4.2 实验室的设计应当确保其适用预定的用途，应提供足够的区域避免混淆和交叉污染。 编号：ZL398 沈阳抗生素厂 页号：22/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 Laboratories should be designed to suit operations to be carried out in them. Sufficient space should be provided to avoid mix-ups and cross-contamination. 6.4.3 设备、玻璃器皿、化学试剂、样品、留样和记录储存应设有足够的空间。 There should be adequate storage space for spare equipment, glassware, chemicals, samples, retained samples and records. 6.4.4 必要时应当设置专门的仪器室，保证灵敏度高的仪器免受震动、静电、潮湿或其他 外界因素的干扰。 Separate provision may be necessary to protect sensitive instruments from vibrations, electrical interference, humidity, etc. 6.4.5 以下物质单独存放： Provision should be made for separate storage of (1)待销毁的废料； Waste material awaiting disposal (2)成瘾性药物或精神麻醉类药物； Controlled drugs or narcotics (3)剧毒物质； Highly toxic substances (4)易燃溶剂与非易燃溶剂分离； Flammable solvents separate from non-flammable solvents 6.4.6 应该提供专门的空气流通和烟雾抽取设施； Separate ventilation and fume extraction facilities should be provided. 6.4.7 每个实验室正确配备灭火器及其他安全防火设备。 Appropriate fire fighting and other safety equipment should be available in each laboratory. 6.4.8 实验室日常使用应建立清洁/消毒规程。 There should be written cleaning / sanitation programme for all laboratories, appropriate for the work undertaken. 6.5 辅助区域 Ancillary Areas 编号：ZL398 沈阳抗生素厂 页号：23/112 版本号：00质量手册质量手册 QA Manual 执行日期： 见首页 6.5.1 食堂与休息区域应该与其他区域分开。 Canteen and rest areas should be separate from other areas. 6.5.2 用于更衣、盥洗、如厕目的的设施应适用使用者数量配备，便于使用。卫生间不应 该直接与生产区域相通，并提供水、肥皂、清洁剂和手烘干器或一次性毛巾。 Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users.Toilets should not directly communicate with production areas.Water, soap or detergent and air dryers or single use towels should be provided in washing facilities. 6.5.3 车间应该与成品区分离。在生产区存放的部件或工具，应该根据其用途保存在房间 或上锁的柜子里。 Workshops should be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for this purpose. 7、消毒与卫生、消毒与卫生 SANITATION AND HYGIENE 7.1 清洁和消毒流程 Cleaning and Sanitation Programmes 7.1.1 生产厂房保持清洁避免垃圾堆积和虫鼠害孳生。 Manufacturing premises should be maintained in a cleaned condition, free from accumulated waste, orderly, and free from insects and vermin. 7.1.2 以下内容需要文件规定： A written sanitation programme should be available for the premises, indicating: （1）应定期清洁保持干净的区域及清洁频次； areas to be cleaned and cleaning intervals （2）具体清洁流程和清洁使用的工具； detailed cleaning procedures to be followed and equipment to be used for cleaning. （3）清洁剂、消毒剂的选择、使用方法及定期更换避免产生抗性的规定； cleaning agents and disinfectants to be used including