原料药生产质量管理办法

1、文件内容：INDEX：1、质量方针 .4 Quality Policy.42、质量治理原则.4 Principles for Quality Assurance.43、定义.6Definitions.64、人员治理.10Personnel and Organization.105、培训.15Training.156、厂房.16Premises.167、消毒与卫生.21Sanitation and Hygiene.218、物料供应.27Materials Supply.279、生产文件与记录.30Manufacturing - Documentation and Records.3010、原料药

2、生产.39Manufacture Of API.3911、质量文件与记录.52Q.A. Documentation and Records.5212、质控处文件与记录.63Quality Control.6313、检验报告单.84Certificate of Analysis.8414、有效期和复检期.84Expiry and Retest Dating.8415、留样.85Reserve / Retention Samples. 8516、仓储. .86Warehousing and Distribution. 8617、托付生产/托付检验. 96Contract Manufacture a

3、nd Analysis. . 9618、验证. .99Validations. 9919、客户投诉与召回. .106Customer Complaints and Recalls. 10620、自检. 108Self Inspection. . 10821、产品质量回忆. .109Product Quality Review. 10922、变更操纵. 110Change Control. 110发放范围：全厂文件复审：复 审 人复审日期复审意见编审批过程：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 期质量方针Quality Policy：“质量” 的定义是指为符合预定用途所具有

4、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、执行及操纵来实现预期质量、纯度、安全性及稳定性等目标的系统。依照质量系统分工，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。质量治理体系要紧包括验证、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 en

5、able 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

6、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.质量治理原则PRINCIPLES

7、FOR QUALITY ASSURANCE2.1我公司保证产品质量安全可靠，我厂质量治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

8、求的制定：Quality Assurance comprises the totality of all measures desired to achieve this aim taking into 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 standards2.3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 qualit

9、y 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

10、 standards are set, maintained and kept upto date.（2）生产过程质量监督治理；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 Depar

11、tment include:（1）生产及托付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；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治理；Implementing quality assurance measures at all levels of m

12、anufacture, 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 & D departments. 2.

13、7遵守有关部门各项法律法规要求。Promise to observe all the relevant authorities on quality assurance matters. 3、定义DEFINITIONS3.1批Batch使用一定数量的物料通过一步或多步生产操作，生产出均质的、符合质量标准的产品的量。在连续生产中，批量能够定义为一定数量或一段时刻内生产的产品的集合。A specific quantity of material produced in a process or series of processes so that it is expected to be hom

14、ogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity of by the amount produced in a fixed time interval.3.2批号Batch Number一组唯一对应、用于区分不同产品或物料从进厂到交付出厂过程，便于追溯生产全过程的

15、数字、字母和/或符号的组合。A unique combination of numbers, letters, and/or symbols that identifies a batch( or lot) and from which the production and distribution history can be determined.3.3批生产和操纵记录Batch production and control record基于技术转移文件依照生产工艺流程编写的、用于描述给定批次产品其原料及生产过程的文件。A document stating the materials us

16、ed and the operations carried out during the processing of a given batch. It should be based on the technology transfer document and Method and be compiled as the manufacturing operation proceeds.3.4批包装记录Batch Packaging Record基于技术转移文件并按照包装操作过程编写的用于描述指定批次成品、包材及包装过程的文件。如需分步骤包装，每步分不记录。A document (or do

17、cuments) stating the finished product and packaging materials used, and the processes carried out during the packaging of a given batch. It should be based on the technology transfer document and be compiled during the packaging operation. A batch may be packaged in several parts, each with its own

18、complete set of packaging documentation/records.3.5校验Calibration体现仪器设备经检定符合相关标准限度要求的材料。The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.3.

19、6操纵程序Control Procedure规定原料、包装材料、过程产品、成品质量标准和检测方法的文件。A document giving specifications and test procedures for starting materials, packaging materials, In process, finished products.3.7原料药Active pharmaceutical ingredient(Drug substance)用于药品生产，作为活性中间体提供药理活性或直接阻碍药物在疾病的诊断、治愈、缓解、治疗、预防，阻碍机体的结构与功能的物质或混合物。An

20、y substance or mixture of substances intended to be used in the manufacture of a drug(medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the d

21、iagnosis, cure , mitigation, treatment, or prevention of disease or to affect the structure and function of the body.3.8药品生产质量治理规范 Good Manufacture Practice（GMP）药品生产质量治理规范（GMP）是定义并有效组织生产操作以确保持续稳定地生产出符合预定用途和注册要求的药品的操作规范。Good Manufacturing Practice is the definition and organization of manufacturing o

22、perations to ensure that products are consistently produced, tested, and controlled to the quality standards appropriate to their intended use and in accordance with the registered requirements.3.9过程操纵In-process Control在生产过程中监管并调整工艺以确保原料药符合质量标准的行为。Checks performed during production in order to monit

23、or and, if appropriate, to adjust the process and /or to ensure that the API conforms to its specification.3.10主生产和治理记录Master production and control record描述药品生产的起始物料及其数量、生产操作过程操纵细节（一般除包装外）的文件。A document stating the starting materials, with their quantities, to be used in the manufacture of a medici

24、nal product, together with a description of the manufacturing operations including details of specific in-process controls, but normally excluding packaging information3.11主包装指令Master Packaging Instruction用于描述物料包装过程使用的包材、包装方式、包装过程操纵细节的文件。包括贴标签或唛头等的操作。A document listing the components to be used for

25、a stated container or package together with a description of the method of packaging and with details of specific in-process controls. The instructions may include the method of assembling the component parts.3.12包装材料Packaging Material用于产品包装的物料，一般不包括苫布、集装箱等。Any material used in the packaging of a pr

26、oduct. The term is not normally extended to cover the outer packaging or delivery cases used for the transportation or shipment of orders. 包材分类：The Classification for packing material：直接接触产品的包装材料，即内包材；Packaging materials which come in contact with the product (often called Primary Packaging Material

27、s)中级包装材料，外包材；Secondary packaging materials（3） 其他包装材料。Other packaging materials3.13确认Qualification验证设备或辅助设施正确安装、正常运转、能够实现预期效果的操作。确认是验证的一部分，但仅有确认验证并不是完整的工艺验证。Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected

28、results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.3.14质量保证Quality Assurance质量保证是以保证产品质量达到预期要求为目的，组织和治理活动的总和。质量保证协调GMP与其他外在因素如原始设计和实际进展等的资源配置。Quality Assurance is the sum total of the organized arrangements made with the ob

29、ject of ensuring that products will be of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of these rules, e.g. original design and development.3.15隔离Quarantine在未决定物料批准或拒收之前，物料应单独存放或其他有效措施隔离的状态。The

30、status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.3.16半成品Semi-finished Product完成所有生产步骤预备包装产品（即散装产品）A product, which has completed all stages of production, and is ready for packaging (Also known as bulk product).3.17标准操作规

31、程Standard Operating Procedure (SOP)经审批、可作为批生产文件补充规定的通用操作标准（如设备操作、维护与清洁、区域清洁、环境操纵、取样和检验等）。A written authorized procedure, which gives instructions for performing operations not necessarily specific to a given product or material, but of a more general nature (e.g. equipment operation, maintenance and

32、 cleaning, cleaning of premises and environmental control, sampling and inspection, etc).Certain Standard Operating Procedures may be used to supplement the product-specific Batch production documentation. 3.18原料Starting Material除包材外用于生产药物的原料、辅料、中间体等物料。Any substance used in the manufacture of a medi

33、cinal product, but excluding packaging materials. A starting material is sometimes known as a raw material or an ingredient, although not all starting materials necessarily remain as ingredients of the final product. 3.19验证Validation有效保证某一工艺、方法或系统可持续产生符合既定标准的文件程序。A documented program that provides a

34、 high degree of assurance that a specific process , method , or system will consistently produce a result meeting pre-determined acceptance criteria.4、人员治理PERSONNEL ORGANISATION4.1通则General Requirements4.1.1人事处应为各部门配备足够数量的胜任相应工作能力、培训、经验、专业技术资格和治理技能方面要求的职员。There should be sufficient number of personn

35、el at all levels with the ability, training, experience and whatever necessary professional / technical qualifications and managerial skills appropriate to the tasks assigned to them.4.1.2建立组织机构图，明确各负责人职责权限。质量相关的工作职责不应存在空缺或重叠。There should be an organization chart and all responsible persons should h

36、ave their duties clarified and adequate authority to carry out their responsibilities. There should not be gaps or unexplained overlaps in the responsibilities of personnel concerned with GMP applications.4.1.3负责生产、质保、销售、产品出厂环节的工作人员为关键人员。负责生产和质保的人员不能兼任，但均有责任实现质量要求。Key personnel include person respon

37、sible for production, person responsible for quality assurance and person responsible for sales/distribution. Different persons should be responsible for production and quality assurance, neither of who should be responsible for other, but who both have a responsibility for achieving the requisite q

38、uality.4.1.4负责监督生产和质量的关键人员应具备化学、药剂学、化学工艺、微生物等学科工艺培训经历及法规要求的操作经验等资质。从事新工作项时应遵循专业人员指导。The key personnel responsible for supervising the production and quality assurance should possess the qualification of scientific education and practical experience required for national legislation. This includes st

39、udy of Chemistry, Pharmacy, Chemical Technology, Microbiology or other related sciences.While gaining the practical experience, they should exercise their duties under professional guidance.4.1.5上述关键人员除生产关系外禁止利益往来或冲突以便执行指定的职责。Such key personnel should not have, preferably, any interests outside the

40、manufacturers organization so as to prevent or restrict their devoting the necessary time to their assigned duties and/or result into conflict of financial interest. 4.1.6兼职人员或顾问禁止从事关键岗位操作。Persons engaged part-time or in consultative capacity should not be appointed to key positions.4.1.7关键岗位职能能够托付，

41、然而职责不能托付。The duties of the key personnel may be delegated to the designated deputies with a satisfactory qualification. However, the responsibility cannot be delegated.4.2要紧职责Key Responsibilities4.2.1明确定义关键人员职责并依据指导方针和相关法律法规进行委派。Responsibilities of key personnel should be clearly defined and allocat

42、ed in accordance with these guidelines and national legislation.4.2.2生产部门职责：The production department has the following responsibilities:依照书面程序起草、审核、批准并下发原料药生产指令单，依照预先批准的指令生产原料药或中间体。Preparing, reviewing, approving and distributing the instructions for the production of APIs according to written proc

43、edures.Producing APIs and, when appropriate, intermediates according to pre-approved instructions.审核所有批次产品记录，确保已完成并签字。Reviewing all production batch records and ensuring that these are completed and signed.确保产品偏差的及时上报及评估，调查关键偏差并记录结论。Making sure that all production deviations are reported and evaluat

44、ed and that critical deviations are investigated and the conclusions are recorded.确保生产设施清洁和定期消毒。Making sure that production facilities are clean and when appropriate disinfected.确保校验的执行及记录存档。Making sure that the necessary calibrations are performed and records kept.确保厂房和设备的维护保养及相关记录存档。Making sure th

45、at the premises and equipment are maintained and records kept.确保验证方案及报告经审核并获得批准。Making sure that validation protocols and reports are reviewed and approved.提出产品、工艺或设备变更。Evaluating proposed changes in product, process or equipment.确保设备设施改造或新增符合要求。Making sure that new and, when appropriate, modified f

46、acilities and equipment are qualified.其他职责见本手册相关章节要求。Other duties are given in the relevant section of this manual.4.2.3质量部门有权参与质量相关全部事宜，其要紧职责不予委派且包括但不仅限以下项：The quality units should be involved in all quality related matters. The main responsibilities of the independent quality unit(s) should not be

47、 delegated. These responsibilities should be described in writing and should include but not necessarily be limited to原料药放行或拒收。Releasing or rejecting all APIs.建立原料、中间体、包材及标签的放行或拒收系统。Establishing a system to release or reject raw materials, intermediates, packaging and all labeling materials.（3）原料药放行

48、前审核完成的批产品生产和关键步骤检测记录。Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution.（4）确保重大偏差的调查及关闭。Making sure that critical deviations are investigated and resolved. （5）审批质量标准和生产指令。Approving all specifications and production

49、 instructions.（6）审批阻碍原料药质量的流程，执行相关监管流程。包括内审（自检）、托付生产、变更。Approving all procedures impacting the quality of APIs.Include making sure that Self-inspections、internal audits、contract manufacturers、changes are performed. （7）审核和批准验证方案及报告。Reviewing and approving validation protocols and reports.（8）确保质量相关投诉经

50、调查解决。Making sure that quality related complaints are investigated and resolved.确保关键设备维护、校正有效运行。Making sure that effective systems are used for maintaining and calibrating critical equipment.确保原辅料正确检测并出具报告。Making sure that materials are appropriately tested and the results are reported.确保原料药有效期和仓储条件有

51、稳定性数据支持。Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs where appropriate, and执行产品质量回忆。Performing product quality reviews.其他职责参见本手册相关章节。Other duties are given in the relevant sections of this Manual.4.2.4厂长同样对质量负责，在遵守相关法规要求条件下具备下列职责：The Heads

52、 of Plant and QA has some shared or jointly exercised responsibilities related to quality. These may include, with respect to national regulations; 文件及文件修正的批准。The authorization of written procedures and other documents including amendments（2）生产环境的监督和操纵。The monitoring and control of the manufacturing

53、 environment厂区卫生Plant hygiene工艺验证Process validation培训Training物料供应商、托付生产的批准和监管。The approval and monitoring of suppliers of materialsThe approval and monitoring of contract manufacturers监管物料和成品的贮存条件。The monitoring of storage conditions for materials and productsGMP执行情况监管。The monitoring of compliance w

54、ith the requirements of GMP记录保存。The retention of records（9）通过巡视、调查及取样监控可能阻碍产品质量的因素。The inspection, investigation and taking samples in order to monitor factors which may affect product quality5、培训TRAINING5.1应依照培训打算对生产、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 wr

55、itten 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 effe

56、ctiveness should be assessed.5.3应对新进职员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 inde

57、pendently. 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）的工作人员应同意专门培训。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 thes

58、e activities. 5.5质量保证的理念和质量过程操纵方法应全员重点培训以提高质量治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培训治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

59、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PREMISES6.1一般要求General Requirements6.1.1厂房选址、设计、布局、建筑、改造和维护必须符

60、合药品生产需求，应当能够最大限度幸免阻碍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,