DIRECTION OF GMP (GOOD MANUFACTURING PRACTICE )OF RAW MATERIALS BY FDA

　　Table of Contents 目錄

　　1. INTRODUCTION

　　1.1 Objective 目的

　　1.2 Regulatory Applicability法規(guī)的適用性

　　1.3 Scope 范圍

　　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(mén)的責(zé)任

　　2.3 Responsibility for Production Activities 生產(chǎn)作業(yè)的職責(zé)

　　2.4 Internal Audits (Self Inspection) 內(nèi)部審計(jì)(自檢)

　　2.5 Product Quality 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(wèn)

　　4. BUILDINGS AND FACILITIES 建筑和設(shè)施

　　4.1 Design and Construction 設(shè)計(jì)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 衛(wèi)生和保養(yǎng)

　　5. PROCESS EQUIPMENT 工藝設(shè)備

　　5.1 Design and Construction 設(shè)計(jì)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(yàn)

　　5.4 Computerized Systems 計(jì)算機(jī)控制系統(tǒng)

　　6. DOCUMENTATION AND RECORDS 文件和記錄

　　6.1 Documentation System and Specifications 文件系統(tǒng)和質(zhì)量標(biāo)準(zhǔn)

　　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(biāo)簽和包裝材料的記錄

　　6.4 Master Production 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(shí)驗(yàn)室控制記錄

　　6.7 Batch Production Record Review 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(yàn)

　　7.3 Sampling and Testing of Incoming Production Materials 進(jìn)廠物料的取樣與測(cè)試

　　7.4 Storage 儲(chǔ)存

　　7.5 Re-evaluation 復(fù)驗(yàn)

　　8. PRODUCTION AND IN-PROCESS CONTROLS 生產(chǎn)和過(guò)程控制

　　8.1 Production Operations 生產(chǎn)操作

　　8.2 Time Limits 時(shí)限

　　8.3 In-process Sampling and Controls 工序取樣和控制

　　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 總則

　　9.2 Packaging Materials 包裝材料

　　9.3 Label Issuance and Control 標(biāo)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(chǔ)存和分發(fā)

　　10.1 Warehousing Procedures 入庫(kù)程序

　　10.2 Distribution Procedures 分發(fā)程序

　　11. LABORATORY CONTROLS 實(shí)驗(yàn)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(cè)試

　　11.3 Validation of Analytical Procedures 分析方法的驗(yàn)證

　　11.4 Certificates of Analysis分析報(bào)告單

　　11.5 Stability Monitoring of APIs 原料藥的穩(wěn)定性監(jiān)測(cè)

　　11.6 Expiry and Retest Dating 有效期和復(fù)驗(yàn)期

　　11.7 Reserve/Retention Samples 留樣

　　12. VALIDATION .驗(yàn)證

　　12.1 Validation Policy 驗(yàn)證方針

　　12.2 Validation Documentation 驗(yàn)證文件

　　12.3 Qualification 確認(rèn)

　　12.4 Approaches to Process Validation 工藝驗(yàn)證的方法

　　12.5 Process Validation Program 工藝驗(yàn)證的程序

　　12.6 Periodic Review of Validated Systems 驗(yàn)證系統(tǒng)的定期審核

　　12.7 Cleaning Validation 清洗驗(yàn)證

　　12.8 Validation of Analytical Methods 分析方法的驗(yàn)證

　　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 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(shí)驗(yàn)室)

　　17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 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 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(dá)

　　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/Fermentation

　　用細(xì)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(xì)胞庫(kù)的維護(hù)和記錄的保存

　　18.3 Cell Culture/Fermentation 細(xì)胞繁殖/發(fā)酵

　　18.4 Harvesting, Isolation and Purification 收取、分離和精制

　　18.5 Viral 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)

　　19.6 Validation 驗(yàn)證

　　19.7 Changes 變更

　　19.8 Laboratory Controls 實(shí)驗(yàn)室控制

　　19.9 Documentation 文件

　　20. Glossary 術(shù)語(yǔ)

　　1. INTRODUCTION 1. 簡(jiǎn)介

　　1.1 Objective 1.1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 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 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 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(chǔ)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(lái)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 manufacturer 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(wèn)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(guó)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 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(cè)/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(mén)在原料藥上市/制造授權(quán)或藥品申請(qǐng)方面建立特定注冊(cè)/歸檔要求的能力。注冊(cè)/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 region 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(duì)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(guó)家被稱為原料藥，就應(yīng)該按照本指南進(jìn)行生產(chǎn)。

　　1.3 Scope 1.3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 sterilization 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(wú)菌原料藥在滅菌前的步驟。本指南不包括無(wú)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 guidance 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(guò)化學(xué)合成、提取、細(xì)胞培養(yǎng)/發(fā)酵，通過(guò)從自然資源回收，或通過(guò)這些工藝的結(jié)合而得到的原料藥。通過(guò)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 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 (medicinal) products (e.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(dòng)物、植物、昆蟲(chóng)或微生物的細(xì)胞、組織或動(dòng)物源包括轉(zhuǎn)基因動(dòng)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 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(shí)驗(yàn)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 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 from 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(lái)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(chǎng)上有售、能夠通過(guò)合同或商業(yè)協(xié)議從一個(gè)或多個(gè)供應(yīng)商處購(gòu)得，或由生產(chǎn)廠家自制。原料藥的起始物料一般來(lái)說(shuō)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 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 starting material is normally introduced into the process.

　　生產(chǎn)廠商要指定并用書(shū)面文件說(shuō)明原料藥的生產(chǎn)從何處開(kāi)始的理論依據(jù)。對(duì)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(diǎn)。對(duì)其他工藝(如：發(fā)酵，提取，純化等)可能需要具體問(wèn)題具體對(duì)待。表1給出了原料藥的起始物料從哪一點(diǎn)引入工藝過(guò)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 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(kāi)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。這包括對(duì)原料藥質(zhì)量有影響的關(guān)鍵工藝步驟的驗(yàn)證。但是，值得注意的是廠商選擇某一步驟進(jìn)行驗(yàn)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 steps 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(lái)了。原料藥生產(chǎn)中的GMP要求應(yīng)當(dāng)隨著工藝的進(jìn)行，從原料藥的前幾步到最后幾步，精制和包裝，越來(lái)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。

　　2. QUALITY MANAGEMENT 2.質(zhì)量管理

　　2.1 Principles 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(gè)人都應(yīng)當(dāng)對(duì)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 participation of management and appropriate manufacturing personnel.

　　每一個(gè)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 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(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(huì)符合其預(yù)期的質(zhì)量與純度要求所必需的活動(dòng)。所有涉及質(zhì)量管理的活動(dòng)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 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(gè)獨(dú)立于生產(chǎn)部門(mén)的質(zhì)量部門(mén)，同時(shí)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(kāi)的QA和QC部門(mén)，或者只是一個(gè)人或小組。

　　2.14 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(dòng)應(yīng)當(dāng)在其執(zhí)行時(shí)就記錄。

　　2.16 Any deviation from established procedures should 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(dāng)有文字記錄并加以解釋。對(duì)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(guò)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 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(mén)對(duì)物料完成滿意的評(píng)價(jià)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(píng)價(jià)結(jié)束時(shí)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 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(mén)能及時(shí)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(dòng)(如質(zhì)量投訴，召回，藥政活動(dòng)等)的通知。

　　2.2 Responsibilities of the Quality Unit(s) 2.2質(zhì)量部門(mén)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(mén)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(mén)審核批準(zhǔn)。

　　2.22 The main responsibilities of the 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 company

　　2. Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials

　　3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution

　　4. Making sure that critical deviations are investigated and resolved

　　5. Approving all specifications and master production instructions

　　6. Approving all procedures affecting the quality of intermediates or APIs

　　7. Making sure that internal audits (self-inspections) are performed

　　8. Approving intermediate and API contract manufacturers

　　9. Approving changes that potentially affect intermediate or API quality

　　10. Reviewing and approving validation protocols and reports

　　11. Making sure that quality-related complaints are investigated and resolved

　　12. Making sure that effective systems are used for maintaining and calibrating critical equipment

　　13. Making sure that materials are appropriately tested and the results are reported

　　14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate

　　15. Performing product quality reviews (as defined in Section 2.5)

　　2.22 獨(dú)立的質(zhì)量部門(mén)的主要職責(zé)不應(yīng)當(dāng)委派給他人。這些責(zé)任應(yīng)當(dāng)以文字形式加以說(shuō)明，而且應(yīng)當(dāng)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. 建立一個(gè)放行與拒收原材料、中間體、包裝材料和標(biāo)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(shí)驗(yàn)室檢驗(yàn)記錄;

　　4. 確保已對(duì)重大偏差進(jìn)行了調(diào)查并已解決;

　　5. 批準(zhǔn)所有的規(guī)格標(biāo)準(zhǔn)和主生產(chǎn)指令;

　　6. 批準(zhǔn)所有可能影響原料藥和中間體質(zhì)量的規(guī)程;

　　7. 確保進(jìn)行內(nèi)部審計(jì)(自檢);

　　8. 批準(zhǔn)中間體或原料藥的委托生產(chǎn)商;

　　9. 批準(zhǔn)可能影響到中間體或原料藥質(zhì)量的變更;

　　10. 審核并批準(zhǔn)驗(yàn)證方案和報(bào)告;

　　11. 確保調(diào)查并解決質(zhì)量問(wèn)題的投訴;

　　12. 確保用有效的體系來(lái)維護(hù)和校驗(yàn)關(guān)鍵設(shè)備;

　　13. 確保物料都經(jīng)過(guò)了適當(dāng)?shù)臋z驗(yàn)并報(bào)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(yàn)期或有效期和儲(chǔ)存條件;

　　15. 開(kāi)展產(chǎn)品質(zhì)量審核(詳見(jiàn)2.5節(jié))。

　　2.3 Responsibility for Production Activities 2.3生產(chǎn)作業(yè)的職責(zé)

　　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 to written procedures

　　2. Producing APIs and, when appropriate, intermediates according to pre-approved instructions

　　3. Reviewing all production batch records and ensuring that these are completed and signed

　　4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded

　　5. Making sure that production facilities are clean and, when appropriate, disinfected

　　6. Making sure that the necessary calibrations are performed and records kept

　　7. Making sure that the premises and equipment are maintained and records kept

　　8. Making sure that validation protocols and reports are reviewed and approved

　　9. Evaluating proposed changes in product, process or equipment

　　10. Making sure that new and, when appropriate, modified facilities and equipment are qualified 生產(chǎn)作業(yè)的職責(zé)應(yīng)當(dāng)以文字形式加以說(shuō)明，并應(yīng)當(dāng)包括，但不限于以下內(nèi)容：

　　1. 按書(shū)面程序起草、審核、批準(zhǔn)和分發(fā)中間體或原料藥的生產(chǎn)指令;

　　2. 按照已批準(zhǔn)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(bào)告、評(píng)價(jià)，對(duì)關(guān)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(shí)要消毒;

　　6. 確保進(jìn)行必要的校驗(yàn)，并有記錄;

　　7. 確保對(duì)廠房和設(shè)備進(jìn)行保養(yǎng)，并有記錄;

　　8. 確保驗(yàn)證方案和報(bào)告的審核與批準(zhǔn);

　　9. 對(duì)產(chǎn)品、工藝或設(shè)備擬作的變更進(jìn)行評(píng)估;

　　10. 確保新的或已改進(jìn)的生產(chǎn)設(shè)施和設(shè)備經(jīng)過(guò)了確認(rèn)。

　　2.4 Internal Audits (Self Inspection) 2.4內(nèi)部審計(jì)(自檢)

　　2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.

　　2.40 為確實(shí)符合原料藥GMP原則，應(yīng)當(dāng)按照批準(zhǔn)的計(jì)劃進(jìn)行定期的內(nèi)部審計(jì)。

　　2.41 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.

　　2.41 審計(jì)結(jié)果及整改措施應(yīng)當(dāng)形成文件，并引起公司責(zé)任管理人員的重視。獲準(zhǔn)的整改措施應(yīng)當(dāng)及時(shí)、有效地完成。

　　2.5 Product Quality Review 2.5產(chǎn)品質(zhì)量審核

　　2.50 Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:

　　A review of critical in-process control and critical API test results

　　A review of all batches that failed to meet established specification(s)

　　A review of all critical deviations or nonconformances and related investigations

　　A review of any changes carried out to the processes or analytical methods

　　A review of results of the stability monitoring program

　　A review of all quality-related returns, complaints and recalls

　　A review of adequacy of corrective actions

　　2.50 原料藥的定期質(zhì)量審核應(yīng)當(dāng)以證實(shí)工藝的一致性為目的來(lái)進(jìn)行。此種審核通常應(yīng)當(dāng)每年進(jìn)行一次，并記錄，內(nèi)容至少應(yīng)當(dāng)包括：

　　關(guān)鍵工藝控制以及原料藥關(guān)鍵測(cè)試結(jié)果的審核;

　　所有不符合既定質(zhì)量標(biāo)準(zhǔn)的產(chǎn)品批號(hào)的審核;

　　所有關(guān)鍵的偏差或違規(guī)行為及有關(guān)調(diào)查的審核;

　　任何工藝或分析方法變動(dòng)的審核;

　　穩(wěn)定性監(jiān)測(cè)的審核;

　　所有與質(zhì)量有關(guān)的退貨、投訴和召回的審核;

　　整改措施的適當(dāng)性的審核。

　　2.51 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.

　　應(yīng)當(dāng)對(duì)質(zhì)量審核結(jié)果進(jìn)行評(píng)估，并做出是否需要整改或做任何再驗(yàn)證的評(píng)價(jià)。此類整改措施的理由應(yīng)當(dāng)文件化。獲準(zhǔn)的整改措施應(yīng)當(dāng)及時(shí)、有效地完成。

　　3. PERSONNEL 3. 人員

　　3.1 Personnel Qualifications 3.1員工的資質(zhì)

　　3.10 There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.

　　3.10 應(yīng)當(dāng)有足夠數(shù)量的員工具備從事和監(jiān)管原料藥和中間體生產(chǎn)的教育、培訓(xùn)和/或經(jīng)歷等資格。

　　3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

　　3.11 參與原料藥和中間體生產(chǎn)的所有人員的職責(zé)應(yīng)當(dāng)書(shū)面規(guī)定。

　　3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee’s functions. Records of training should be maintained. Training should be periodically assessed.

　　3.12 應(yīng)當(dāng)由有資格的人員定期進(jìn)行培訓(xùn)，內(nèi)容至少應(yīng)當(dāng)包括員工所從事的特定操作和與其職能有關(guān)的GMP。培訓(xùn)記錄應(yīng)當(dāng)保存，并應(yīng)當(dāng)定期對(duì)培訓(xùn)進(jìn)行評(píng)估。

　　3.2 Personnel Hygiene 3.2 員工的衛(wèi)生

　　3.20 Personnel should practice good sanitation and health habits.

　　3.20 員工應(yīng)當(dāng)養(yǎng)成良好的衛(wèi)生和健康習(xí)慣。

　　3.21 Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.

　　3.21 員工應(yīng)當(dāng)穿著適合其所從事生產(chǎn)操作的干凈服裝，必要時(shí)應(yīng)當(dāng)更換。其它保護(hù)性用品如頭、臉、手和臂等遮護(hù)用品必要時(shí)也應(yīng)當(dāng)佩帶，以免原料藥和中間體受到污染。

　　3.22 Personnel should avoid direct contact with intermediates and APIs.

　　3.22 員工應(yīng)當(dāng)避免與中間體或原料藥的直接接觸。

　　3.23 Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.

　　3.23 吸煙、吃、喝、咀嚼及存放食品僅限于與生產(chǎn)區(qū)隔開(kāi)的指定區(qū)域。

　　3.24 Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person’s inclusion would not jeopardize the safety or quality of the APIs.

　　3.24 患傳染性疾病或身體表面有開(kāi)放性創(chuàng)傷的員工不應(yīng)當(dāng)從事危及原料藥質(zhì)量的生產(chǎn)活動(dòng)。在任何時(shí)候(經(jīng)醫(yī)學(xué)檢驗(yàn)或監(jiān)控檢查)任何患有危及到原料藥質(zhì)量的疾病或創(chuàng)傷的人員都不應(yīng)當(dāng)參與作業(yè)，直到健康狀況已恢復(fù)，或者有資格的醫(yī)學(xué)人員確認(rèn)該員工不會(huì)危及到原料藥的安全性和質(zhì)量。

　　3.3 Consultants 3.3 顧問(wèn)

　　3.30 Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

　　3.30 中間體或原料藥生產(chǎn)和控制的顧問(wèn)應(yīng)當(dāng)有足夠的學(xué)歷，受訓(xùn)和經(jīng)驗(yàn)，能勝任所承擔(dān)的工作。

　　3.31 Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

　　3.31 顧問(wèn)的姓名、地址、資格和提供服務(wù)的類型都應(yīng)當(dāng)有文字記錄。

　　4. BUILDINGS AND FACILITIES 4. 建筑和設(shè)施

　　4.1 Design and Construction 4.1 設(shè)計(jì)和結(jié)構(gòu)

　　4.10 Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants, as appropriate.

　　4.10 用于中間體和原料藥生產(chǎn)的廠房和設(shè)施的選址、設(shè)計(jì)和建造應(yīng)當(dāng)便于清潔，維護(hù)和適應(yīng)一定類型和階段的生產(chǎn)操作。設(shè)施的設(shè)計(jì)應(yīng)盡量減少潛在的污染。如果中間體或原料藥的生產(chǎn)有微生物限度要求，那么設(shè)施設(shè)計(jì)應(yīng)相應(yīng)的限制有害微生物的污染。

　　4.11 Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.

　　4.11 廠房和設(shè)施應(yīng)有足夠空間，以便有秩序地放置設(shè)備和物料，防止混淆和污染。

　　4.12 Where the equipment itself (e.g., closed or contained system) provides adequate protection of the material, such equipment can be located outdoors.

　　4.12 自身能對(duì)物料提供足夠保護(hù)的設(shè)備(如關(guān)閉的或封閉的系統(tǒng))，可以在戶外放置。

　　4.13 The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups and contamination.

　　4.13 通過(guò)廠房和設(shè)施的物流和人流的設(shè)計(jì)應(yīng)當(dāng)能防止混雜和污染。

　　4.14 There should be defined areas or other control systems for the following activities:

　　以下活動(dòng)應(yīng)當(dāng)有指定區(qū)域或其它控制系統(tǒng)：

　　4.15 Adequate and clean washing and toilet facilities should be provided for personnel. These facilities should be equipped with hot and cold water, as appropriate, soap or detergent, air dryers, or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.

　　4.15 應(yīng)當(dāng)為員工提供足夠和清潔的盥洗設(shè)施。這些盥洗設(shè)施應(yīng)當(dāng)裝有冷熱水(視情況而定)、肥皂或洗滌劑，干手機(jī)和一次性毛巾。盥洗室應(yīng)當(dāng)與生產(chǎn)區(qū)隔離，但要便于達(dá)到。應(yīng)當(dāng)根據(jù)情況提供足夠的淋浴和/或更衣設(shè)施。

　　4.16 Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process, intermediate, or API.

　　4.16 實(shí)驗(yàn)室區(qū)域/操作通常應(yīng)當(dāng)與生產(chǎn)區(qū)隔離。有些實(shí)驗(yàn)室區(qū)域，特別是用于中間控制的，可以位于生產(chǎn)區(qū)內(nèi)，只要生產(chǎn)工藝操作對(duì)實(shí)驗(yàn)室測(cè)量的準(zhǔn)確性沒(méi)有負(fù)面影響，而且，實(shí)驗(yàn)室及其操作對(duì)生產(chǎn)過(guò)程，或中間體，或原料藥也沒(méi)有負(fù)面影響。

　　4.2 Utilities 4.2 公用設(shè)施

　　4.20 All utilities that could affect product quality (e.g., steam, gas, compressed air, heating, ventilation, and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.4.20 對(duì)產(chǎn)品質(zhì)量會(huì)有影響的所有公用設(shè)施(如蒸汽，氣體，壓縮空氣和加熱，通風(fēng)及空調(diào))都應(yīng)當(dāng)確認(rèn)合格，并進(jìn)行適當(dāng)監(jiān)控，在超出限度時(shí)應(yīng)當(dāng)采取相應(yīng)措施。應(yīng)當(dāng)有這些公用設(shè)施的系統(tǒng)圖。

　　4.21 Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimize risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be giving to areas where APIs are exposed to the environment.

　　4.21 應(yīng)當(dāng)根據(jù)情況，提供足夠的通風(fēng)、空氣過(guò)濾和排氣系統(tǒng)。這些系統(tǒng)應(yīng)當(dāng)根據(jù)相應(yīng)的生產(chǎn)階段，設(shè)計(jì)和建造成將污染和交叉污染降至最低限度，并包括控制氣壓、微生物(如果適用)、灰塵、濕度和溫度的設(shè)備。特別值得注意的是原料藥暴露的區(qū)域。

　　4.22 If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.

　　4.22 如果空氣再循環(huán)到生產(chǎn)區(qū)域，應(yīng)當(dāng)采取適當(dāng)?shù)目刂莆廴竞徒徊嫖廴镜娘L(fēng)險(xiǎn)。

　　4.23 Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control system, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or ApI.

　　4.23 永久性安裝的管道應(yīng)當(dāng)有適宜的標(biāo)識(shí)。這可以通過(guò)標(biāo)識(shí)每根管道、提供證明文件、計(jì)算機(jī)控制系統(tǒng)，或其它替代方法來(lái)達(dá)到。管道的安裝處應(yīng)當(dāng)防止污染中間體或原料藥。

　　4.24 Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.

　　4.24 排水溝應(yīng)當(dāng)有足夠的尺寸，而且應(yīng)當(dāng)根據(jù)情況裝有空斷器或適當(dāng)?shù)难b置，防止倒虹吸。

　　4.3 Water 4.3 水

　　4.30 Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.

　　4.30 原料藥生產(chǎn)中使用的水應(yīng)當(dāng)證明適合于其預(yù)定的用途。

　　4.31 Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (portable) water quality.

　　除非有其它理由，工藝用水最低限度應(yīng)當(dāng)符合世界衛(wèi)生組織(WHO)的飲用水質(zhì)量指南。

　　4.32 If drinking (portable) water is insufficient to ensure API quality and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms, and/or endotoxins should be established.

　　4.32 如果飲用水不足以確保原料的質(zhì)量，并要求更為嚴(yán)格的化學(xué)和/或微生物水質(zhì)規(guī)格標(biāo)準(zhǔn)，應(yīng)當(dāng)指定合適的物理/化學(xué)特性、微生物總數(shù)、控制菌和/或內(nèi)毒素的規(guī)格標(biāo)準(zhǔn)。

　　4.33 Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

　　4.33 在工藝用水為達(dá)到規(guī)定質(zhì)量由制造商進(jìn)行處理時(shí)，處理工藝應(yīng)當(dāng)經(jīng)過(guò)驗(yàn)證，并用合適的處置限度來(lái)監(jiān)測(cè)。

　　4.34 Where the manufacturer of a nonsterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

　　4.34 當(dāng)非無(wú)菌原料藥的制造商打算或者聲稱該原料藥適用于進(jìn)一步加工生產(chǎn)無(wú)菌藥品(醫(yī)療用品)時(shí)，最終分離和精制階段的用水應(yīng)當(dāng)進(jìn)行微生物總數(shù)、致病菌和內(nèi)毒素方面的監(jiān)測(cè)和控制。