【文章內容簡介】 blishment of master cell bank and working cell bankMaintenance of working cell bankCell culture and/or fermentationIsolation and purificationPhysical processing, and packaging“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中的應用生產類型本指南在用于各類生產的工藝步驟（灰色背景）中的應用化學品的生產原料藥起始物料的生產原料藥起始物料引入工藝過程中間體的生產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：發(fā)酵/細胞培養(yǎng)主細胞庫和工作細胞庫的建立工作細胞庫的維護細胞培養(yǎng)和/或發(fā)酵分離和純化物理加工和包裝“經(jīng)典” 發(fā)酵生產原料藥細胞庫的建立細胞庫的維護細胞引入發(fā)酵分離和純化物理加工和包裝GMP的要求增加2. QUALITY MANAGEMENT2．質量管理 Principles Quality should be the responsibilities of all persons involved in manufacturing. 參與原料藥生產的每一個人都應當對質量負責。 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. 每一個生產商都應當建立并執(zhí)行一套有管理人員和有關員工積極參與的有效的質量管理體系，并使其文件化。 The system for managing quality should enpass 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 qualityrelated activities should be defined and documented. 質量管理體系應當包括組織機構、規(guī)程、工藝和資源，以及確保原料藥會符合其預期的質量與純度要求所必需的活動。所有涉及質量管理的活動都應當明確規(guī)定，并使其文件化。 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. 應當設立一個獨立于生產部門的質量部門，同時履行質量保證(QA)和質量控制 (QC)的職責。依照組織機構的大小，可以是分開的QA和QC部門，或者只是一個人或小組。 The persons authorized to release intermediates and APIs should be specified. 應當指定授權發(fā)放中間體和原料藥的人員。 All qualityrelated activities should be recorded at the time they are performed. 所有有關質量的活動應當在其執(zhí)行時就記錄。 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. 任何偏離既定規(guī)程的情況都應當有文字記錄并加以解釋。對于關鍵性偏差應當進行調查，并記錄調查經(jīng)過及其結果。 No materials should be released or used before the satisfactory pletion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (., release under quarantine as described in Section 10 or the use of raw materials or intermediates pending pletion of evaluation). 在質量部門對物料完成滿意的評價之前，任何物料都不應當發(fā)放或使用，除非有合適的系統(tǒng)允許此類使用（，或是原料或中間體在等待評價結束時的使用）。 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). 應當有規(guī)程能確保公司的責任管理部門能及時得到有關藥政檢查、嚴重的GMP缺陷、產品缺陷及其相關活動（如質量投訴，召回，藥政活動等）的通知。 Responsibilities of the Quality Unit(s) The quality unit(s) should be involved in all qualityrelated matters. 質量部門應當參與所有與質量有關的事物。 The quality unit(s) should review and approve all appropriate qualityrelated documents. 所有與質量有關的文件應當由質量部門審核批準。 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 pany2. Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials3. Reviewing pleted batch production and laboratory control records of critical process steps before release of the API for distribution4. Making sure that critical deviations 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 (selfinspections) are performed8. 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 qualityrelated plaints 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 on APIs and/or intermediates, where appropriate15. Performing product quality reviews (as defined in Section ) 獨立的質量部門的主要職責不應當委派給他人。這些責任應當以文字形式加以說明，而且應當包括，但不限于：1. 所有原料藥的放行與否。用于生產商控制范圍以外的中間體的放行與否；2. 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，審核已完成的關鍵步驟的批生產記錄和實驗室檢驗記錄；4. 確保已對重大偏差進行了調查并已解決；5. 批準所有的規(guī)格標準和主生產指令；6. 批準所有可能影響原料藥和中間體質量的規(guī)程；7. 確保進行內部審計（自檢）；8. 批準中間體或原料藥的委托生產商；9. 批準可能影響到中間體或原料藥質量的變更；10. 審核并批準驗證方案和報告；11. 確保調查并解決質量問題的投訴；12. 確保用有效的體系來維護和校驗關鍵設備；13. 確保物料都經(jīng)過了適當?shù)臋z驗并報告結果；14. 確保有穩(wěn)定性數(shù)據(jù)支持中間體或原料藥的復驗期或有效期和儲存條件；15. 開展產品質量審核（）。 Responsibility for Production ActivitiesThe 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 procedures2. Producing APIs and, when appropriate, intermediates according to preapproved instructions3. Reviewing all production batch records and e