美國FDA原料藥生產(chǎn)質(zhì)量管理規(guī)范( 中英文)

1、DIRECTION OF GMP (GOOD MANUFACTURING PRACTICE )OF RAW MATERIALS BY FDA美國FDA原料藥生產(chǎn)質(zhì)量管理規(guī)范（ 中英文） Table of Contents   目錄1. INTRODUCTION    簡介1.1 Objective  目的1.2 Regulatory Applicability法規(guī)的適用性1.3 Scope       范圍   &#

2、160;  2. QUALITY MANAGEMENT    .質(zhì)量管理2.1 Principles  總則2.2 Responsibilities of the Quality Unit(s)    質(zhì)量部門的責任2.3 Responsibility for Production Activities  生產(chǎn)作業(yè)的職責2.4 Internal Audits (Self Inspection)     內(nèi)部審計（自檢）2.5 Product Quality

3、 Review   產(chǎn)品質(zhì)量審核      3. PERSONNEL    人員3.1 Personnel Qualifications  人員的資質(zhì)3.2 Personnel Hygiene   人員衛(wèi)生3.3 Consultants      顧問      4. BUILDINGS AND FACILITIES  

4、0;   建筑和設(shè)施4.1 Design and Construction  設(shè)計和結(jié)構(gòu)4.2 Utilities    公用設(shè)施4.3 Water       水4.4 Containment     限制4.5 Lighting    照明4.6 Sewage and Refuse  排污和垃圾4.7 Sanitation and Maintenance   &#

5、160; 衛(wèi)生和保養(yǎng)      5. PROCESS EQUIPMENT  工藝設(shè)備5.1 Design and Construction  設(shè)計和結(jié)構(gòu)5.2 Equipment Maintenance and Cleaning    設(shè)備保養(yǎng)和清潔5.3 Calibration. 校驗5.4 Computerized Systems    計算機控制系統(tǒng)      6. DOCUMENTATIO

6、N AND RECORDS 文件和記錄6.1 Documentation System and Specifications     文件系統(tǒng)和質(zhì)量標準6.2 Equipment cleaning and Use Record      設(shè)備的清潔和使用記錄6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 原料、中間體、原料藥的標簽和包裝材料的記錄6.4 Master Product

7、ion Instructions (Master Production and Control Records)   生產(chǎn)工藝規(guī)程（主生產(chǎn)和控制記錄）6.5 Batch Production Records (Batch Production and Control Records)     批生產(chǎn)記錄（批生產(chǎn)和控制記錄）6.6 Laboratory Control Records    實驗室控制記錄6.7 Batch Production Record Review &#

8、160;  批生產(chǎn)記錄審核      7. MATERIALS MANAGEMENT       物料管理7.1 General Controls      控制通則7.2 Receipt and Quarantine    接收和待驗7.3 Sampling and Testing of Incoming Production Materials 進廠物料的取樣與測試7.4 Stora

9、ge     儲存7.5 Re-evaluation   復(fù)驗      8. PRODUCTION AND IN-PROCESS CONTROLS   生產(chǎn)和過程控制8.1 Production Operations     生產(chǎn)操作8.2 Time Limits     時限8.3 In-process Sampling and Controls   工

10、序取樣和控制8.4 Blending Batches of Intermediates or APIs    中間體或原料藥的混批8.5 Contamination Control    污染控制      9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES     原料藥和中間體的包裝和貼簽9.1 General  

11、0;  總則9.2 Packaging Materials 包裝材料9.3 Label Issuance and Control     標簽發(fā)放與控制9.4 Packaging and Labeling Operations 包裝和貼簽操作      10. STORAGE AND DISTRIBUTION.儲存和分發(fā)10.1 Warehousing Procedures 入庫程序10.2 Distribution Procedures 分發(fā)程序   &

12、#160;  11. LABORATORY CONTROLS   實驗室控制11.1 General Controls    控制通則11.2 Testing of Intermediates and APIs 中間體和原料藥的測試11.3 Validation of Analytical Procedures      分析方法的驗證11.4 Certificates of Analysis分析報告單11.5 Stability Monitoring of APIs 原料藥

13、的穩(wěn)定性監(jiān)測11.6 Expiry and Retest Dating      有效期和復(fù)驗期11.7 Reserve/Retention Samples    留樣      12. VALIDATION  .驗證12.1 Validation Policy    驗證方針12.2 Validation Documentation     驗證文件12.3 Qualific

14、ation  確認12.4 Approaches to Process Validation  工藝驗證的方法12.5 Process Validation Program   工藝驗證的程序12.6 Periodic Review of Validated Systems  驗證系統(tǒng)的定期審核12.7 Cleaning Validation       清洗驗證12.8 Validation of Analytical Methods 分析方法的驗證   

15、;   13. CHANGE CONTROL     變更的控制      14. REJECTION AND RE-USE OF MATERIALS.拒收和物料的再利用14.1 Rejection 拒收14.2 Reprocessing  返工14.3 Reworking     重新加工14.4 Recovery of Materials and Solvents    &

16、#160; 物料與溶劑的回收14.5 Returns   退貨      15. COMPLAINTS AND RECALLS    投訴與召回      16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)協(xié)議生產(chǎn)商（包括實驗室）      17. AGENTS, BROKERS, TRADERS, DISTRIBU

17、TORS, REPACKERS, AND RELABELLERS  代理商、經(jīng)紀人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者17.1 Applicability   適用性17.2 Traceability of Distributed APIs and Intermediates已分發(fā)的原料藥和中間體的可追溯性17.3 Quality Management     質(zhì)量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates原料藥和中間體的重新

18、包裝、重新貼簽和待檢17.5 Stability  穩(wěn)定性17.6 Transfer of Information 信息的傳達17.7 Handling of Complaints and Recalls     投訴和召回的處理17.8 Handling of Returns      退貨的處理      18. Specific Guidance for APIs Manufactured by Cell Culture/Ferm

19、entation    用細胞繁殖/發(fā)酵生產(chǎn)的原料藥的特殊指南18.1 General   總則18.2 Cell Bank Maintenance and Record Keeping       細胞庫的維護和記錄的保存18.3 Cell Culture/Fermentation     細胞繁殖/發(fā)酵18.4 Harvesting, Isolation and Purification   收取、分離和精制18.5 Vi

20、ral Removal/Inactivation steps   病毒的去除/滅活步驟      19. APIs for Use in Clinical Trials 用于臨床研究的原料藥19.1 General   總則19.2 Quality   質(zhì)量19.3 Equipment and Facilities設(shè)備和設(shè)施19.4 Control of Raw Materials 原料的控制19.5 Production     生產(chǎn)

21、19.6 Validation       驗證19.7 Changes  變更19.8 Laboratory Controls      實驗室控制19.9 Documentation      文件20. Glossary   術(shù)語 1. INTRODUCTION     1. 簡介1.1 Objective  1.1目的This docume

22、nt is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purpor

23、t, or are represented, to possess.     本文件旨在為在合適的質(zhì)量管理體系下制造活性藥用成分（以下稱原料藥）提供有關(guān)優(yōu)良藥品生產(chǎn)管理規(guī)范（GMP）提供指南。它也著眼于幫助確保原料藥符合其旨在達到或表明擁有的質(zhì)量與純度要求。      In this guidance, the term manufacturing is defined to include all operations of receipt of materials, product

24、ion, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such app

25、roach satisfies the requirements of the applicable statues. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.本指南中所指的“制造”包括物料接收、生產(chǎn)、包裝、重新包裝、貼簽、重新貼簽、質(zhì)量控制、放行、原料藥的儲存和分發(fā)及其相關(guān)控制的所有操作。本指南中，“應(yīng)當”一詞表示希望采用的建議，除非證明其不適用或者可用一種已證明有同等或更高

26、質(zhì)量保證水平的供選物來替代。本指南中的“現(xiàn)行優(yōu)良生產(chǎn)管理規(guī)范（cGMP）”和“優(yōu)良生產(chǎn)管理規(guī)范（GMP）”是等同的。      The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of the manuf

27、acturer and are governed by national laws. 本指南在總體上未涉及生產(chǎn)人員的安全問題，亦不包括環(huán)保方面的內(nèi)容。這方面的管理是生產(chǎn)者固有的責任，也是國家法律規(guī)定的。      This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the abili

28、ty of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met.      本指南未規(guī)定注冊

29、/歸檔的要求、或修改藥典的要求。本指南不影響負責藥政審理部門在原料藥上市/制造授權(quán)或藥品申請方面建立特定注冊/歸檔要求的能力。注冊/歸檔的所有承諾必須做到。      1.2 Regulatory Applicability  1.2法規(guī)的適用性Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the regi

30、on or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.  在世界范圍內(nèi)對原料藥的法定定義是各不相同的。當某種物料在其制造或用于藥品的地區(qū)或國家被稱為原料藥，就應(yīng)該按照本指南進行生產(chǎn)。      1.3 Scope       1.3范圍This guidance app

31、lies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should b

32、e performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.      本文件適用于人用藥品（醫(yī)療用品）所含原料藥的生產(chǎn)。它適用于無菌原料藥在滅菌前的步驟。本指南不包括無菌原料藥的消毒和滅菌工藝，但是，應(yīng)當符合地方當局所規(guī)定的藥品（醫(yī)療用品）生產(chǎn)的GMP指南。      This guidance covers APIs t

33、hat are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18.本文件適用于通過化學合成、提取、細胞培養(yǎng)/發(fā)酵，通過從自然資源回收，或通過這些工藝的結(jié)合而得到的原料藥

34、。通過細胞培養(yǎng)/發(fā)酵生產(chǎn)的原料藥的特殊指南則在第18章論述。      This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materia

35、ls. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-packaged drug (medici

36、nal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals.    本指南不包括所有疫苗、完整細胞、全血和血漿、全血和血漿的衍生物（血漿成分）和基因治療的原料藥。但是卻包括以血或血漿為原材料生產(chǎn)的原料藥。值得注意的是細胞培養(yǎng)基（哺乳動物、植物、昆蟲或微生物的細胞、組織或動物源包括轉(zhuǎn)基因動物）和前期生產(chǎn)可能應(yīng)遵循GMP規(guī)范，但不包括在本指南之內(nèi)。另外，本指南不適用于醫(yī)用氣體、散裝的制劑藥（例如，散裝的片劑和膠囊）和放射性藥物的生產(chǎn)。 &

37、#160;    Section 19 contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products).第19章的指南只適用于用在藥品（醫(yī)療用品）生產(chǎn)中的原料藥制造，特別是臨床實驗用藥（研究用醫(yī)療產(chǎn)品）的原料藥制造。   &

38、#160;  An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased f

39、rom one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.  “原料藥的起始物料”是指一種原料、中間體或原料藥，用來生產(chǎn)一種原料藥，或者以主要結(jié)構(gòu)單元的形式被結(jié)合進原料藥結(jié)構(gòu)中。原料藥的起始物料可能是在市場上有售、能夠通過合同或商業(yè)協(xié)議從一個或多個供應(yīng)商處購得，或由生產(chǎn)廠家自制。原料藥的起始物料一般來說

40、有特定的化學特性和結(jié)構(gòu)。      The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fe

41、rmentation, extraction, purification), this rationale should be established on a case-by-case basis. Table 1 gives guidance on the point at which the API starting material is normally introduced into the process.生產(chǎn)廠商要指定并用書面文件說明原料藥的生產(chǎn)從何處開始的理論依據(jù)。對于合成工藝而言，就是“原料藥的起始物料”進入工藝的那一點。對其他工藝（如：發(fā)酵，提取，純化等）可能需要具體問題

42、具體對待。表1給出了原料藥的起始物料從哪一點引入工藝過程的指導(dǎo)原則。      From this point on, appropriate GMP as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality o

43、f the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that steps as critical.   從這步開始，本指南中的有關(guān)GMP規(guī)范應(yīng)當應(yīng)用在這些中間體和/或原料藥的制造中。這包括對原料藥質(zhì)量有影響的關(guān)鍵工藝步驟的驗證。但是，值得注意的是廠商選擇某一步驟進行驗證，并不一定將該步驟定為關(guān)鍵步驟。     

44、; The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Ph

45、ysical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, micronizing) should be conducted according to this guidance.     本文件的指南通常適用于表1中的灰色步驟。但在表中體現(xiàn)的所有步驟并不是將應(yīng)用GMP管理的所有步驟全部體現(xiàn)出來了。原料藥生產(chǎn)中的GMP要求應(yīng)當隨著工藝的進行，從原料藥的前幾步到最后幾步，精制和包裝

46、，越來越嚴格。原料藥的物理加工，如制粒、包衣或顆粒度的物理處理（例如制粉、微粉化）應(yīng)當按本指南的標準進行。      This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.本GMP指南不適用于引入定義了的“原料藥的起始物料”以前的步驟。  2. QUALITY MANAGEMENT    2質(zhì)量管理2.1 Principles

47、60; 2.1總則2.10 Quality should be the responsibilities of all persons involved in manufacturing.       參與原料藥生產(chǎn)的每一個人都應(yīng)當對質(zhì)量負責。      2.11 Each manufacturer should establish, document, and implement an effective system for managing quality t

48、hat involves the active participation of management and appropriate manufacturing personnel.     每一個生產(chǎn)商都應(yīng)當建立并執(zhí)行一套有管理人員和有關(guān)員工積極參與的有效的質(zhì)量管理體系，并使其文件化。      2.12 The system for managing quality should encompass the organizational structure, procedures

49、, process and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.     質(zhì)量管理體系應(yīng)當包括組織機構(gòu)、規(guī)程、工藝和資源，以及確保原料藥會符合其預(yù)期的質(zhì)量與純度要求所必需的活動。所有涉及質(zhì)量管理的活動

50、都應(yīng)當明確規(guī)定，并使其文件化。      2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual

51、or group, depending upon the size and structure of the organization.    2.13 應(yīng)當設(shè)立一個獨立于生產(chǎn)部門的質(zhì)量部門，同時履行質(zhì)量保證(QA)和質(zhì)量控制 (QC)的職責。依照組織機構(gòu)的大小，可以是分開的QA和QC部門，或者只是一個人或小組。      2.14 The persons authorized to release intermediates and APIs should be specified. 

52、; 2.14 應(yīng)當指定授權(quán)發(fā)放中間體和原料藥的人員。      2.15 All quality-related activities should be recorded at the time they are performed.      2.15 所有有關(guān)質(zhì)量的活動應(yīng)當在其執(zhí)行時就記錄。      2.16 Any deviation from established procedures sho

53、uld be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.2.16 任何偏離既定規(guī)程的情況都應(yīng)當有文字記錄并加以解釋。對于關(guān)鍵性偏差應(yīng)當進行調(diào)查，并記錄調(diào)查經(jīng)過及其結(jié)果。      2.17 No materials should be released or used before the satisfactory

54、 completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in Section 10 or the use of raw materials or intermediates pending completion of evaluation).   2.17 在質(zhì)量部門對物料完成滿意的評價之前，任何物料

55、都不應(yīng)當發(fā)放或使用，除非有合適的系統(tǒng)允許此類使用（如10.20條款所述的待檢情況下的使用，或是原料或中間體在等待評價結(jié)束時的使用）。      2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related c

56、omplaints, recalls, and regulatory actions).2.18 應(yīng)當有規(guī)程能確保公司的責任管理部門能及時得到有關(guān)藥政檢查、嚴重的GMP缺陷、產(chǎn)品缺陷及其相關(guān)活動（如質(zhì)量投訴，召回，藥政活動等）的通知。      2.2 Responsibilities of the Quality Unit(s)    2.2質(zhì)量部門的責任2.20 The quality unit(s) should be involved in all quality-related matters.

57、 2.20 質(zhì)量部門應(yīng)當參與所有與質(zhì)量有關(guān)的事物。      2.21 The quality unit(s) should review and approve all appropriate quality-related documents.2.21 所有與質(zhì)量有關(guān)的文件應(yīng)當由質(zhì)量部門審核批準。      2.22 The main responsibilities of the independent quality unit(s) should not b

58、e delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to:1.    Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company2.    Establishin

59、g a system to release or reject raw materials, intermediates, packaging, and labeling materials3.    Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution4.    Making sure that critical d

60、eviations are investigated and resolved5.    Approving all specifications and master production instructions6.    Approving all procedures affecting the quality of intermediates or APIs7.    Making sure that internal audits (self-inspections) are performe

61、d8.    Approving intermediate and API contract manufacturers9.    Approving changes that potentially affect intermediate or API quality10.   Reviewing and approving validation protocols and reports11.   Making sure that quality-related complaints are

62、 investigated and resolved12.   Making sure that effective systems are used for maintaining and calibrating critical equipment13.   Making sure that materials are appropriately tested and the results are reported14.   Making sure that there is stability data to support

63、retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate15.   Performing product quality reviews (as defined in Section 2.5) 2.22 獨立的質(zhì)量部門的主要職責不應(yīng)當委派給他人。這些責任應(yīng)當以文字形式加以說明，而且應(yīng)當包括，但不限于：1.    所有原料藥的放行與否。用于生產(chǎn)商控制范圍以外的中間體的放行與否；2.  &#

64、160; 建立一個放行與拒收原材料、中間體、包裝材料和標簽的系統(tǒng)；3.    在供銷售的原料藥放行前，審核已完成的關(guān)鍵步驟的批生產(chǎn)記錄和實驗室檢驗記錄；4.    確保已對重大偏差進行了調(diào)查并已解決；5.    批準所有的規(guī)格標準和主生產(chǎn)指令；6.    批準所有可能影響原料藥和中間體質(zhì)量的規(guī)程；7.    確保進行內(nèi)部審計（自檢）；8.    批準中間體或原料藥的委托生產(chǎn)商；9.   

65、 批準可能影響到中間體或原料藥質(zhì)量的變更；10.   審核并批準驗證方案和報告；11.   確保調(diào)查并解決質(zhì)量問題的投訴；12.   確保用有效的體系來維護和校驗關(guān)鍵設(shè)備；13.   確保物料都經(jīng)過了適當?shù)臋z驗并報告結(jié)果；14.   確保有穩(wěn)定性數(shù)據(jù)支持中間體或原料藥的復(fù)驗期或有效期和儲存條件；15.   開展產(chǎn)品質(zhì)量審核（詳見2.5節(jié)）。      2.3 Responsibility for Production

66、 Activities  2.3生產(chǎn)作業(yè)的職責The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:1.    Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according

67、to written procedures2.    Producing APIs and, when appropriate, intermediates according to pre-approved instructions3.    Reviewing all production batch records and ensuring that these are completed and signed4.    Making sure that all production deviati

68、ons are reported and evaluated and that critical deviations are investigated and the conclusions are recorded5.    Making sure that production facilities are clean and, when appropriate, disinfected6.    Making sure that the necessary calibrations are performed and reco

69、rds kept7.    Making sure that the premises and equipment are maintained and records kept8.    Making sure that validation protocols and reports are reviewed and approved9.    Evaluating proposed changes in product, process or equipment10.   Mak

70、ing sure that new and, when appropriate, modified facilities and equipment are qualified  生產(chǎn)作業(yè)的職責應(yīng)當以文字形式加以說明，并應(yīng)當包括，但不限于以下內(nèi)容：1.    按書面程序起草、審核、批準和分發(fā)中間體或原料藥的生產(chǎn)指令；2.    按照已批準的指令生產(chǎn)原料藥或者中間體；3.    審核所有的批生產(chǎn)記錄確保其完整并有簽名；4.    確保所有的生產(chǎn)偏差都已報告、評價，對關(guān)

71、鍵的偏差已做了調(diào)查，并記錄結(jié)論；5.    確保生產(chǎn)設(shè)施的清潔，必要時要消毒；6.    確保進行必要的校驗，并有記錄；7.    確保對廠房和設(shè)備進行保養(yǎng)，并有記錄；8.    確保驗證方案和報告的審核與批準；9.    對產(chǎn)品、工藝或設(shè)備擬作的變更進行評估；10.   確保新的或已改進的生產(chǎn)設(shè)施和設(shè)備經(jīng)過了確認。      2.4 Internal Audits (Self Inspection)     2.4內(nèi)部審計（自檢）2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be perform