【正文】 ter 建筑和設(shè)施 Design and Construction 人員衛(wèi)生 Consultants 產(chǎn)品質(zhì)量審核 范圍DIRECTION OF GMP (GOOD MANUFACTURING PRACTICE )OF RAW MATERIALS BY FDA美國(guó)FDA原料藥生產(chǎn)質(zhì)量管理規(guī)范（ 目錄1. INTRODUCTION簡(jiǎn)介 Objective .質(zhì)量管理 Principles 質(zhì)量部門(mén)的責(zé)任 Responsibility for Production Activities 人員 Personnel Qualifications 顧問(wèn) 設(shè)計(jì)和結(jié)構(gòu) Utilities 照明 Sewage and Refuse 工藝設(shè)備 Design and Construction 設(shè)備保養(yǎng)和清潔 Calibration. 校驗(yàn) Computerized Systems 中間體或原料藥的混批 Contamination Control10. STORAGE AND Warehousing Procedures 入庫(kù)程序 Distribution Procedures 分發(fā)程序 實(shí)驗(yàn)室控制 General Controls 分析方法的驗(yàn)證 Certificates of Analysis分析報(bào)告單 Stability Monitoring of APIs 原料藥的穩(wěn)定性監(jiān)測(cè) Expiry and Retest Dating 留樣 工藝驗(yàn)證的方法 Process Validation Program16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)協(xié)議生產(chǎn)商（包括實(shí)驗(yàn)室） 細(xì)胞庫(kù)的維護(hù)和記錄的保存 Cell Culture/Fermentation 細(xì)胞繁殖/發(fā)酵 Harvesting, Isolation and Purification 病毒的去除/滅活步驟 總則 Quality 驗(yàn)證 Changes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(chēng)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。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 remendations that, when followed, will ensure pliance 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。本指南未規(guī)定注冊(cè)/歸檔的要求、或修改藥典的要求。在世界范圍內(nèi)對(duì)原料藥的法定定義是各不相同的。 Scope本文件適用于人用藥品（醫(yī)療用品）所含原料藥的生產(chǎn)。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)。“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。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。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。本文件的指南通常適用于表1中的灰色步驟。 2．質(zhì)量管理 Principles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)。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。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)。 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. 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)。 The persons authorized to release intermediates and APIs should be specified. Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (., qualityrelated plaints, recalls, and regulatory actions). 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。 Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing pany2. Approving all specifications and master production instructions6. Approving changes that potentially affect intermediate or API quality10. Making sure that qualityrelated plaints are investigated and resolved12. Making sure that materials are appropriately tested and the results are reported14. Performing product quality reviews (as defined in Section ) 在供銷(xiāo)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. 確保進(jìn)行內(nèi)部審計(jì)（自檢）；8. 審核并批準(zhǔn)驗(yàn)證方案和報(bào)告；11. 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. Producing APIs and, when appropriate, intermediates according to preapproved instructions3. Making sure that the necessary calibrations are performed and records kept7. 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. 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. 確保驗(yàn)證方案和報(bào)告的審核與批準(zhǔn)；9. Internal Audits (Self Inspection) （自檢） To verify pliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. 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)。獲準(zhǔn)的整改措施應(yīng)當(dāng)及時(shí)、有效地完成。 關(guān)鍵工藝控制以及原料藥關(guān)鍵測(cè)試結(jié)果的審核； 所有關(guān)鍵的偏差或違規(guī)行為及有關(guān)調(diào)查的審核； 穩(wěn)定性監(jiān)測(cè)的審核； 整改措施的適當(dāng)性的審核。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)。3. PERSONNEL 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. The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing. 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. 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。 Personnel should avoid direct contact with intermediates and APIs. 4. 建筑和設(shè)施 Design and Construction設(shè)施的設(shè)計(jì)應(yīng)盡量減少潛在的污染。 Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mixups and contamination. 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(hù)外放置。 There should be defined areas or other control systems for the following activities:盥洗室應(yīng)當(dāng)與生產(chǎn)區(qū)隔離，但要便于達(dá)到。 Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for inprocess 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. 實(shí)驗(yàn)室區(qū)域/操作通常應(yīng)當(dāng)與生產(chǎn)區(qū)隔離。 Utilities應(yīng)當(dāng)有這些公用設(shè)施的系統(tǒng)圖。 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)。 Permanently installed pipework should be appropriately identified. This can be acplis