原料藥生產(chǎn)質(zhì)量管理辦法

1、文件內(nèi)容：INDEX：1、質(zhì)量方針 .4 Quality Policy.42、質(zhì)量治理原則.4 Principles for Quality Assurance.43、定義.6Definitions.64、人員治理.10Personnel and Organization.105、培訓(xùn).15Training.156、廠房.16Premises.167、消毒與衛(wèi)生.21Sanitation and Hygiene.218、物料供應(yīng).27Materials Supply.279、生產(chǎn)文件與記錄.30Manufacturing - Documentation and Records.3010、原料藥

2、生產(chǎn).39Manufacture Of API.3911、質(zhì)量文件與記錄.52Q.A. Documentation and Records.5212、質(zhì)控處文件與記錄.63Quality Control.6313、檢驗報告單.84Certificate of Analysis.8414、有效期和復(fù)檢期.84Expiry and Retest Dating.8415、留樣.85Reserve / Retention Samples. 8516、倉儲. .86Warehousing and Distribution. 8617、托付生產(chǎn)/托付檢驗. 96Contract Manufacture a

3、nd Analysis. . 9618、驗證. .99Validations. 9919、客戶投訴與召回. .106Customer Complaints and Recalls. 10620、自檢. 108Self Inspection. . 10821、產(chǎn)品質(zhì)量回憶. .109Product Quality Review. 10922、變更操縱. 110Change Control. 110發(fā)放范圍：全廠文件復(fù)審：復(fù) 審 人復(fù)審日期復(fù)審意見編審批過程：起草人審核人批準(zhǔn)人部 門質(zhì)保處質(zhì)保處質(zhì)量部總工程師簽 名日 期質(zhì)量方針Quality Policy：“質(zhì)量” 的定義是指為符合預(yù)定用途所具有

4、的一系列固有特性的程度。質(zhì)量體系是基于一定的設(shè)備、人員基礎(chǔ)上通過設(shè)計、文件化、執(zhí)行及操縱來實現(xiàn)預(yù)期質(zhì)量、純度、安全性及穩(wěn)定性等目標(biāo)的系統(tǒng)。依照質(zhì)量系統(tǒng)分工，各部門包括研發(fā)、生產(chǎn)、技術(shù)、倉儲、銷售、質(zhì)量和質(zhì)檢等部門分工合作，共同實現(xiàn)質(zhì)量方針。質(zhì)量治理體系要緊包括驗證、GMP、文件、內(nèi)審、培訓(xùn)及客戶投訴。質(zhì)量目標(biāo)的最終實現(xiàn)是基于全員范圍質(zhì)量方針、質(zhì)量通則貫徹落實基礎(chǔ)上實現(xiàn)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.質(zhì)量治理原則PRINCIPLES

7、FOR QUALITY ASSURANCE2.1我公司保證產(chǎn)品質(zhì)量安全可靠，我廠質(zhì)量治理能夠?qū)崿F(xiàn)質(zhì)量目標(biāo)。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質(zhì)量目標(biāo)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）客戶的需求The needs of our customers（2）相關(guān)法規(guī)要求The relevant legal requirements（3）工藝要求The state of the art（4）內(nèi)控質(zhì)量標(biāo)準(zhǔn)。The inhouse standards2.3產(chǎn)品質(zhì)量的保證是研發(fā)、供應(yīng)、生產(chǎn)、倉儲、銷售等部門必須各自制定并完成相應(yīng)質(zhì)量目標(biāo)從而實現(xiàn)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質(zhì)量部的職責(zé)：The Quality Assurance Departments Duty：（1）質(zhì)量標(biāo)準(zhǔn)的建立及更新；Ensures that appropriate quality

10、 standards are set, maintained and kept upto date.（2）生產(chǎn)過程質(zhì)量監(jiān)督治理；Supervises the implementation of all necessary measures through the line / manufacturing functions.（3）提高全員質(zhì)量意識。Plays a leading role in promoting quality awareness throughout the company.2.5質(zhì)量部的工作：The tasks of the Quality Assurance Depar

11、tment include:（1）生產(chǎn)及托付生產(chǎn)生產(chǎn)過程監(jiān)督指導(dǎo)；Technical guidance and supervision to different manufacturing units owned by the company and third parties.（2）協(xié)調(diào)相關(guān)部門建立各項標(biāo)準(zhǔn)；Setting standards in co-operation with all departments concerned.（3）生產(chǎn)儲存及發(fā)運的全過程實施質(zhì)量治理；Implementing quality assurance measures at all levels of m

12、anufacture, storage and distribution.（4）組織應(yīng)對突發(fā)事件及產(chǎn)品召回；Organizing emergency and recall procedures.2.6質(zhì)量部長直接向廠長匯報工作，獨立于銷售、生產(chǎn)、供應(yīng)及研發(fā)部門。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遵守有關(guān)部門各項法律法規(guī)要求。Promise to observe all the relevant authorities on quality assurance matters. 3、定義DEFINITIONS3.1批Batch使用一定數(shù)量的物料通過一步或多步生產(chǎn)操作，生產(chǎn)出均質(zhì)的、符合質(zhì)量標(biāo)準(zhǔn)的產(chǎn)品的量。在連續(xù)生產(chǎn)中，批量能夠定義為一定數(shù)量或一段時刻內(nèi)生產(chǎn)的產(chǎn)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批號Batch Number一組唯一對應(yīng)、用于區(qū)分不同產(chǎn)品或物料從進廠到交付出廠過程，便于追溯生產(chǎn)全過程的

15、數(shù)字、字母和/或符號的組合。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批生產(chǎn)和操縱記錄Batch production and control record基于技術(shù)轉(zhuǎn)移文件依照生產(chǎn)工藝流程編寫的、用于描述給定批次產(chǎn)品其原料及生產(chǎn)過程的文件。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批包裝記錄Batch Packaging Record基于技術(shù)轉(zhuǎn)移文件并按照包裝操作過程編寫的用于描述指定批次成品、包材及包裝過程的文件。如需分步驟包裝，每步分不記錄。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校驗Calibration體現(xiàn)儀器設(shè)備經(jīng)檢定符合相關(guān)標(biāo)準(zhǔn)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操縱程序Control Procedure規(guī)定原料、包裝材料、過程產(chǎn)品、成品質(zhì)量標(biāo)準(zhǔn)和檢測方法的文件。A document giving specifications and test procedures for starting materials, packaging materials, In process, finished products.3.7原料藥Active pharmaceutical ingredient(Drug substance)用于藥品生產(chǎn)，作為活性中間體提供藥理活性或直接阻礙藥物在疾病的診斷、治愈、緩解、治療、預(yù)防，阻礙機體的結(jié)構(gòu)與功能的物質(zhì)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藥品生產(chǎn)質(zhì)量治理規(guī)范 Good Manufacture Practice（GMP）藥品生產(chǎn)質(zhì)量治理規(guī)范（GMP）是定義并有效組織生產(chǎn)操作以確保持續(xù)穩(wěn)定地生產(chǎn)出符合預(yù)定用途和注冊要求的藥品的操作規(guī)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過程操縱In-process Control在生產(chǎn)過程中監(jiān)管并調(diào)整工藝以確保原料藥符合質(zhì)量標(biāo)準(zhǔn)的行為。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主生產(chǎn)和治理記錄Master production and control record描述藥品生產(chǎn)的起始物料及其數(shù)量、生產(chǎn)操作過程操縱細(xì)節(jié)（一般除包裝外）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主包裝指令Master Packaging Instruction用于描述物料包裝過程使用的包材、包裝方式、包裝過程操縱細(xì)節(jié)的文件。包括貼標(biāo)簽或嘜頭等的操作。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包裝材料Packaging Material用于產(chǎn)品包裝的物料，一般不包括苫布、集裝箱等。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. 包材分類：The Classification for packing material：直接接觸產(chǎn)品的包裝材料，即內(nèi)包材；Packaging materials which come in contact with the product (often called Primary Packaging Material

27、s)中級包裝材料，外包材；Secondary packaging materials（3） 其他包裝材料。Other packaging materials3.13確認(rèn)Qualification驗證設(shè)備或輔助設(shè)施正確安裝、正常運轉(zhuǎn)、能夠?qū)崿F(xiàn)預(yù)期效果的操作。確認(rèn)是驗證的一部分，但僅有確認(rèn)驗證并不是完整的工藝驗證。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質(zhì)量保證Quality Assurance質(zhì)量保證是以保證產(chǎn)品質(zhì)量達(dá)到預(yù)期要求為目的，組織和治理活動的總和。質(zhì)量保證協(xié)調(diào)GMP與其他外在因素如原始設(shè)計和實際進展等的資源配置。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隔離Quarantine在未決定物料批準(zhǔn)或拒收之前，物料應(yīng)單獨存放或其他有效措施隔離的狀態(tài)。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完成所有生產(chǎn)步驟預(yù)備包裝產(chǎn)品（即散裝產(chǎn)品）A product, which has completed all stages of production, and is ready for packaging (Also known as bulk product).3.17標(biāo)準(zhǔn)操作規(guī)

31、程Standard Operating Procedure (SOP)經(jīng)審批、可作為批生產(chǎn)文件補充規(guī)定的通用操作標(biāo)準(zhǔn)（如設(shè)備操作、維護與清潔、區(qū)域清潔、環(huán)境操縱、取樣和檢驗等）。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除包材外用于生產(chǎn)藥物的原料、輔料、中間體等物料。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驗證Validation有效保證某一工藝、方法或系統(tǒng)可持續(xù)產(chǎn)生符合既定標(biāo)準(zhǔn)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、人員治理PERSONNEL ORGANISATION4.1通則General Requirements4.1.1人事處應(yīng)為各部門配備足夠數(shù)量的勝任相應(yīng)工作能力、培訓(xùn)、經(jīng)驗、專業(yè)技術(shù)資格和治理技能方面要求的職員。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建立組織機構(gòu)圖，明確各負(fù)責(zé)人職責(zé)權(quán)限。質(zhì)量相關(guān)的工作職責(zé)不應(yīng)存在空缺或重疊。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負(fù)責(zé)生產(chǎn)、質(zhì)保、銷售、產(chǎn)品出廠環(huán)節(jié)的工作人員為關(guān)鍵人員。負(fù)責(zé)生產(chǎn)和質(zhì)保的人員不能兼任，但均有責(zé)任實現(xiàn)質(zhì)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負(fù)責(zé)監(jiān)督生產(chǎn)和質(zhì)量的關(guān)鍵人員應(yīng)具備化學(xué)、藥劑學(xué)、化學(xué)工藝、微生物等學(xué)科工藝培訓(xùn)經(jīng)歷及法規(guī)要求的操作經(jīng)驗等資質(zhì)。從事新工作項時應(yīng)遵循專業(yè)人員指導(dǎo)。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上述關(guān)鍵人員除生產(chǎn)關(guān)系外禁止利益往來或沖突以便執(zhí)行指定的職責(zé)。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兼職人員或顧問禁止從事關(guān)鍵崗位操作。Persons engaged part-time or in consultative capacity should not be appointed to key positions.4.1.7關(guān)鍵崗位職能能夠托付，

41、然而職責(zé)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要緊職責(zé)Key Responsibilities4.2.1明確定義關(guān)鍵人員職責(zé)并依據(jù)指導(dǎo)方針和相關(guān)法律法規(guī)進行委派。Responsibilities of key personnel should be clearly defined and allocat

42、ed in accordance with these guidelines and national legislation.4.2.2生產(chǎn)部門職責(zé)：The production department has the following responsibilities:依照書面程序起草、審核、批準(zhǔn)并下發(fā)原料藥生產(chǎn)指令單，依照預(yù)先批準(zhǔn)的指令生產(chǎn)原料藥或中間體。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.審核所有批次產(chǎn)品記錄，確保已完成并簽字。Reviewing all production batch records and ensuring that these are completed and signed.確保產(chǎn)品偏差的及時上報及評估，調(diào)查關(guān)鍵偏差并記錄結(jié)論。Making sure that all production deviations are reported and evaluat

44、ed and that critical deviations are investigated and the conclusions are recorded.確保生產(chǎn)設(shè)施清潔和定期消毒。Making sure that production facilities are clean and when appropriate disinfected.確保校驗的執(zhí)行及記錄存檔。Making sure that the necessary calibrations are performed and records kept.確保廠房和設(shè)備的維護保養(yǎng)及相關(guān)記錄存檔。Making sure th

45、at the premises and equipment are maintained and records kept.確保驗證方案及報告經(jīng)審核并獲得批準(zhǔn)。Making sure that validation protocols and reports are reviewed and approved.提出產(chǎn)品、工藝或設(shè)備變更。Evaluating proposed changes in product, process or equipment.確保設(shè)備設(shè)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.其他職責(zé)見本手冊相關(guān)章節(jié)要求。Other duties are given in the relevant section of this manual.4.2.3質(zhì)量部門有權(quán)參與質(zhì)量相關(guān)全部事宜，其要緊職責(zé)不予委派且包括但不僅限以下項：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原料藥放行或拒收。Releasing or rejecting all APIs.建立原料、中間體、包材及標(biāo)簽的放行或拒收系統(tǒng)。Establishing a system to release or reject raw materials, intermediates, packaging and all labeling materials.（3）原料藥放行

48、前審核完成的批產(chǎn)品生產(chǎn)和關(guān)鍵步驟檢測記錄。Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution.（4）確保重大偏差的調(diào)查及關(guān)閉。Making sure that critical deviations are investigated and resolved. （5）審批質(zhì)量標(biāo)準(zhǔn)和生產(chǎn)指令。Approving all specifications and production

49、 instructions.（6）審批阻礙原料藥質(zhì)量的流程，執(zhí)行相關(guān)監(jiān)管流程。包括內(nèi)審（自檢）、托付生產(chǎn)、變更。Approving all procedures impacting the quality of APIs.Include making sure that Self-inspections、internal audits、contract manufacturers、changes are performed. （7）審核和批準(zhǔn)驗證方案及報告。Reviewing and approving validation protocols and reports.（8）確保質(zhì)量相關(guān)投訴經(jīng)

50、調(diào)查解決。Making sure that quality related complaints are investigated and resolved.確保關(guān)鍵設(shè)備維護、校正有效運行。Making sure that effective systems are used for maintaining and calibrating critical equipment.確保原輔料正確檢測并出具報告。Making sure that materials are appropriately tested and the results are reported.確保原料藥有效期和倉儲條件有

51、穩(wěn)定性數(shù)據(jù)支持。Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs where appropriate, and執(zhí)行產(chǎn)品質(zhì)量回憶。Performing product quality reviews.其他職責(zé)參見本手冊相關(guān)章節(jié)。Other duties are given in the relevant sections of this Manual.4.2.4廠長同樣對質(zhì)量負(fù)責(zé)，在遵守相關(guān)法規(guī)要求條件下具備下列職責(zé)：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準(zhǔn)。The authorization of written procedures and other documents including amendments（2）生產(chǎn)環(huán)境的監(jiān)督和操縱。The monitoring and control of the manufacturing

53、 environment廠區(qū)衛(wèi)生Plant hygiene工藝驗證Process validation培訓(xùn)Training物料供應(yīng)商、托付生產(chǎn)的批準(zhǔn)和監(jiān)管。The approval and monitoring of suppliers of materialsThe approval and monitoring of contract manufacturers監(jiān)管物料和成品的貯存條件。The monitoring of storage conditions for materials and productsGMP執(zhí)行情況監(jiān)管。The monitoring of compliance w

54、ith the requirements of GMP記錄保存。The retention of records（9）通過巡視、調(diào)查及取樣監(jiān)控可能阻礙產(chǎn)品質(zhì)量的因素。The inspection, investigation and taking samples in order to monitor factors which may affect product quality5、培訓(xùn)TRAINING5.1應(yīng)依照培訓(xùn)打算對生產(chǎn)、儲存、檢測相關(guān)人員進行培訓(xùn)（包括工藝員、機修人員、保潔人員）。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應(yīng)定期培訓(xùn)GMP相關(guān)知識并對培訓(xùn)效果進行評估。Training on Good Manufacturing Practices should be repeated periodically and its practical effe

56、ctiveness should be assessed.5.3應(yīng)對新進職員進行適應(yīng)崗位要求的崗前培訓(xùn)。經(jīng)評估崗位技能合格后方予以獨立上崗操作。評估記錄應(yīng)存檔。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高風(fēng)險操作區(qū)（如：高活性、高毒性、傳染性、高致敏性物料的生產(chǎn)區(qū)）的工作人員應(yīng)同意專門培訓(xùn)。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質(zhì)量保證的理念和質(zhì)量過程操縱方法應(yīng)全員重點培訓(xùn)以提高質(zhì)量治理工作理解和執(zhí)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培訓(xùn)治理制度由質(zhì)量部長和總工程師審核批準(zhǔn)后，執(zhí)行相關(guān)培訓(xùn)記錄存檔。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定期評估培訓(xùn)效果。At definite intervals, assessment of training programmes effectiveness should be done.6、廠房PREMISES6.1一般要求General Requirements6.1.1廠房選址、設(shè)計、布局、建筑、改造和維護必須符

60、合藥品生產(chǎn)需求，應(yīng)當(dāng)能夠最大限度幸免阻礙產(chǎn)品質(zhì)量的污染和混淆，便于清潔、操作和維護。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,