ICH-Q7(中英文對照)

1、Q7a（中英文對照）FDA原料藥GMP指南Table of Contents目錄1. INTRODUCTION1. 簡介1.1 Objective1.1目的1.2 Regulatory Applicability1.2法規(guī)的適用性1.3 Scope1.3范圍2. QUALITY MANAGEMENT2.質(zhì)量管理2.1 Principles2.1總則2.2 Responsibilities of the Quality Unit(s)2.2質(zhì)量部門的責(zé)任2.3 Responsibility for Production Activities2.3生產(chǎn)作業(yè)的職責(zé)2.4 Internal Audit

2、s (Self Inspection)2.4內(nèi)部審計（自檢）2.5 Product Quality Review2.5產(chǎn)品質(zhì)量審核3. PERSONNEL3. 人員3.1 Personnel Qualifications3.人員的資質(zhì)3.2 Personnel Hygiene3.2 人員衛(wèi)生3.3 Consultants3.3 顧問4. BUILDINGS AND FACILITIES4. 建筑和設(shè)施4.1 Design and Construction4.1 設(shè)計和結(jié)構(gòu)4.2 Utilities4.2 公用設(shè)施4.3 Water4.3 水4.4 Containment4.4 限制4.5 Li

3、ghting4.5 照明4.6 Sewage and Refuse4.6 排污和垃圾4.7 Sanitation and Maintenance4.7 衛(wèi)生和保養(yǎng)5. PROCESS EQUIPMENT5. 工藝設(shè)備5.1 Design and Construction5.1 設(shè)計和結(jié)構(gòu)5.2 Equipment Maintenance and Cleaning5.2 設(shè)備保養(yǎng)和清潔5.3 Calibration5.3 校驗5.4 Computerized Systems5.4 計算機(jī)控制系統(tǒng)6. DOCUMENTATION AND RECORDS6. 文件和記錄6.1 Documentati

4、on System and Specifications6.1 文件系統(tǒng)和質(zhì)量標(biāo)準(zhǔn)6.2 Equipment cleaning and Use Record6.2 設(shè)備的清潔和使用記錄6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials6.3 原料、中間體、原料藥的標(biāo)簽和包裝材料的記錄6.4 Master Production Instructions (Master Production and Control Records)6.4 生產(chǎn)工藝規(guī)程（主生產(chǎn)和控制記錄）6.5 Batc

5、h Production Records (Batch Production and Control Records)6.5 批生產(chǎn)記錄（批生產(chǎn)和控制記錄）6.6 Laboratory Control Records6.6 實驗室控制記錄6.7 Batch Production Record Review6.7批生產(chǎn)記錄審核7. MATERIALS MANAGEMENT7. 物料管理7.1 General Controls7.1 控制通則7.2 Receipt and Quarantine7.2接收和待驗7.3 Sampling and Testing of Incoming Producti

6、on Materials7.3 進(jìn)廠物料的取樣與測試 7.4 Storage7.4儲存7.5 Re-evaluation7.5復(fù)驗8. PRODUCTION AND IN-PROCESS CONTROLS8. 生產(chǎn)和過程控制8.1 Production Operations8.1 生產(chǎn)操作8.2 Time Limits8.2 時限8.3 In-process Sampling and Controls8.3 工序取樣和控制8.4 Blending Batches of Intermediates or APIs8.4 中間體或原料藥的混批8.5 Contamination Control8.5

7、 污染控制9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES9. 原料藥和中間體的包裝和貼簽9.1 General9.1 總則9.2 Packaging Materials9.2 包裝材料9.3 Label Issuance and Control9.3 標(biāo)簽發(fā)放與控制9.4 Packaging and Labeling Operations9.4 包裝和貼簽操作10. STORAGE AND DISTRIBUTION10.儲存和分發(fā)10.1 Warehousing Procedures10.1 入庫程序10.2

8、 Distribution Procedures10.2 分發(fā)程序11. LABORATORY CONTROLS11.實驗室控制11.1 General Controls11.1 控制通則11.2 Testing of Intermediates and APIs11.2 中間體和原料藥的測試11.3 Validation of Analytical Procedures11.3 分析方法的驗證11.4 Certificates of Analysis11.4 分析報告單11.5 Stability Monitoring of APIs11.5 原料藥的穩(wěn)定性監(jiān)測11.6 Expiry and

9、 Retest Dating11.6 有效期和復(fù)驗期11.7 Reserve/Retention Samples11.7 留樣12. VALIDATION12.驗證12.1 Validation Policy12.1 驗證方針12.2 Validation Documentation12.2 驗證文件12.3 Qualification12.3 確認(rèn)12.4 Approaches to Process Validation12.4 工藝驗證的方法12.5 Process Validation Program12.5 工藝驗證的程序12.6 Periodic Review of Validate

10、d Systems12.6驗證系統(tǒng)的定期審核12.7 Cleaning Validation12.7 清洗驗證12.8 Validation of Analytical Methods12.8 分析方法的驗證13. CHANGE CONTROL13.變更的控制14. REJECTION AND RE-USE OF MATERIALS14.拒收和物料的再利用14.1 Rejection14.1 拒收14.2 Reprocessing14.2 返工14.3 Reworking14.3 重新加工14.4 Recovery of Materials and Solvents14.4 物料與溶劑的回收1

11、4.5 Returns14.5 退貨15. COMPLAINTS AND RECALLS15.投訴與召回16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)16.協(xié)議生產(chǎn)商（包括實驗室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS17.代理商、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者17.1 Applicability17.1適用性17.2 Traceability of Distributed APIs and Intermediates17

12、.2已分發(fā)的原料藥和中間體的可追溯性17.3 Quality Management17.3質(zhì)量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates17.4原料藥和中間體的重新包裝、重新貼簽和待檢17.5 Stability17.5穩(wěn)定性17.6 Transfer of Information17.6 信息的傳達(dá)17.7 Handling of Complaints and Recalls17.7 投訴和召回的處理17.8 Handling of Returns17.8 退貨的處理18. Specific Gu

13、idance for APIs Manufactured by Cell Culture/Fermentation18. 用細(xì)胞繁殖/發(fā)酵生產(chǎn)的原料藥的特殊指南18.1 General18.1 總則18.2 Cell Bank Maintenance and Record Keeping18.2細(xì)胞庫的維護(hù)和記錄的保存18.3 Cell Culture/Fermentation18.3細(xì)胞繁殖/發(fā)酵18.4 Harvesting, Isolation and Purification18.4收取、分離和精制18.5 Viral Removal/Inactivation steps18.5 病毒

14、的去除/滅活步驟19. APIs for Use in Clinical Trials19. 用于臨床研究的原料藥19.1 General19.1 總則19.2 Quality19.2 質(zhì)量19.3 Equipment and Facilities19.3 設(shè)備和設(shè)施19.4 Control of Raw Materials19.4 原料的控制19.5 Production19.5 生產(chǎn)19.6 Validation19.6 驗證19.7 Changes19.7 變更19.8 Laboratory Controls19.8 實驗室控制19.9 Documentation19.9 文件20. G

15、lossary20. 術(shù)語Q7a GMP Guidance for APIsQ7a原料藥的GMP指南1. INTRODUCTION1. 簡介1.1 Objective1.1目的This document 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

16、also intended to help ensure that APIs meet the quality and purity characteristics that they purport, 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(dá)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

17、 of receipt of materials, production, 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

18、 approach may be used if such approach 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(dāng)”一詞

19、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 manufact

20、urer 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(zé)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 ability of the responsible regulatory agency to es

21、tablish 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/歸檔的要求、或修改藥典的要求。本指南不影響負(fù)責(zé)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

22、 Regulatory Applicability1.2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 region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.在世

23、界范圍內(nèi)對原料藥的法定定義是各不相同的。當(dāng)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(jìn)行生產(chǎn)。1.3 Scope1.3范圍This guidance applies 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 steriliz

24、ation and aseptic processing of sterile APIs are not covered by this guidance, but should be 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(dāng)符合地方當(dāng)局所規(guī)定的藥品（醫(yī)療用品）生產(chǎn)的GMP指南。This gui

25、dance covers APIs that 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(xué)合成、提取、細(xì)胞培養(yǎng)/發(fā)酵，通過從自然資源回

26、收，或通過這些工藝的結(jié)合而得到的原料藥。通過細(xì)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 materials. Note that cel

27、l 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 (medicinal) products (e.

28、g., tablets or capsules in bulk containers), or radiopharmaceuticals.本指南不包括所有疫苗、完整細(xì)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(xì)胞培養(yǎng)基（哺乳動物、植物、昆蟲或微生物的細(xì)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)。 Section 19 contains guidance that only applies

29、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。An API starting material is a raw material, an intermediate, or an API that is used in the prod

30、uction 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 from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials n

31、ormally 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(jìn)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有特定的化學(xué)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

32、 synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction, purification), this rationale should be established on a case-by-case basis. Table 1 gives guidance on the point at which the API starti

33、ng 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(jìn)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 manufacturi

34、ng steps. This would include the validation of critical process steps determined to impact the quality of 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(dāng)應(yīng)用在這些中間體和/或原料藥的制造中。這包括

35、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(jìn)行驗證，并不一定將該步驟定為關(guān)鍵步驟。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 ste

36、ps to final steps, purification, and packaging. Physical 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(dāng)隨著工藝的進(jìn)行

37、，從原料藥的前幾步到最后幾步，精制和包裝，越來越嚴(yán)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(dāng)按本指南的標(biāo)準(zhǔn)進(jìn)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。Table 1: Application of this Guidance to API ManufacturingType of ManufacturingApplication

38、 of this guidance to steps (shown in gray) used in this type of manufacturingChemical manufacturingProduction of the API Starting materialIntroduction of the API starting material into processProduction of Intermediate(s)Isolation and purificationPhysical processing, and packagingAPI derived from an

39、imal sourcesCollection of organ, fluid, or tissueCutting, mixing, and/or initial processingIntroduction of the API starting material into processIsolation and purificationPhysical processing, and packagingAPI extracted from plant sourcesCollection of plantCutting and initial extraction(s)Introductio

40、n of the API starting material into processIsolation and purificationPhysical processing, and packagingHerbal extracts used as APICollection of plantsCutting and initial extractionFurther extractionPhysical processing, and packagingAPI consisting of comminuted or powdered herbsCollection of plants a

41、nd/or cultivation and harvestingCutting/comminutingPhysical processing, and packagingBiotechnology: fermentation/cell cultureEstablishment of master cell bank and working cell bankMaintenance of working cell bankCell culture and/or fermentationIsolation and purificationPhysical processing, and packa

42、ging“Classical” fermentation to produce an APIEstablishment of cell bankMaintenance of the cell bankIntroduction of the cells into fermentationIsolation and purificationPhysical processing, and packagingIncreasing GMP requirements表 1: 本指南在原料藥生產(chǎn)中的應(yīng)用生產(chǎn)類型本指南在用于各類生產(chǎn)的工藝步驟（灰色背景）中的應(yīng)用化學(xué)品的生產(chǎn)原料藥起始物料的生產(chǎn)原料藥起始物料

43、引入工藝過程中間體的生產(chǎn)分離和純化物理加工和包裝動物源原料藥器官、分泌物或組織的收集切割、混合和/或初步加工原料藥起始物料引入工藝過程分離和純化物理加工和包裝從植物源提取的原料藥植物的收集切割和初步提取原料藥起始物料引入工藝過程分離和純化物理加工和包裝草藥提取物用作原料藥植物的收集切割和初步提取進(jìn)一步提取物理加工和包裝由粉碎的或粉末狀草藥組成的原料藥植物的收集和/或培養(yǎng)和收獲切割/粉碎物理加工和包裝生物技術(shù)：發(fā)酵/細(xì)胞培養(yǎng)主細(xì)胞庫和工作細(xì)胞庫的建立工作細(xì)胞庫的維護(hù)細(xì)胞培養(yǎng)和/或發(fā)酵分離和純化物理加工和包裝“經(jīng)典” 發(fā)酵生產(chǎn)原料藥細(xì)胞庫的建立細(xì)胞庫的維護(hù)細(xì)胞引入發(fā)酵分離和純化物理加工和包裝GMP

44、的要求增加2. QUALITY MANAGEMENT2質(zhì)量管理2.1 Principles2.1總則2.10 Quality should be the responsibilities of all persons involved in manufacturing.2.10 參與原料藥生產(chǎn)的每一個人都應(yīng)當(dāng)對質(zhì)量負(fù)責(zé)。2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active particip

45、ation of management and appropriate manufacturing personnel.2.11 每一個生產(chǎn)商都應(yīng)當(dāng)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, process and resources, as well as activities to ensure confidence that the API will meet it

46、s intended specifications for quality and purity. All quality-related activities should be defined and documented.2.12 質(zhì)量管理體系應(yīng)當(dāng)包括組織機(jī)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)量管理的活動都應(yīng)當(dāng)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

47、 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 or group, depending upon the size and structure of the organization.2.13 應(yīng)當(dāng)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(zé)。依照組織機(jī)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

48、.14 The persons authorized to release intermediates and APIs should be specified.2.14 應(yīng)當(dāng)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(dāng)在其執(zhí)行時就記錄。2.16 Any deviation from established procedures should be documented and explained. C

49、ritical 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(dāng)有文字記錄并加以解釋。對于關(guān)鍵性偏差應(yīng)當(dāng)進(jìn)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 completion of evaluation by the quality unit(s) unless there are appr

50、opriate 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，任何物料都不應(yīng)當(dāng)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

51、 exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).2.18 應(yīng)當(dāng)有規(guī)程能確保公司的責(zé)任管理部門能及時得到有關(guān)藥政檢查、嚴(yán)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 Res

52、ponsibilities of the Quality Unit(s)2.2質(zhì)量部門的責(zé)任2.20 The quality unit(s) should be involved in all quality-related matters.2.20 質(zhì)量部門應(yīng)當(dāng)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(dāng)由質(zhì)量部門審核批準(zhǔn)。2.22 The main responsibilities of t

53、he independent quality unit(s) should not be 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. Esta

54、blishing 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 deviations are investigated an

55、d 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 performed8. Approving intermediate and API contract manufacturers9. Approving changes that

56、potentially affect intermediate or API quality10. Reviewing and approving validation protocols and reports11. Making sure that quality-related complaints are 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 retest or expiry dates and storage conditions o