實驗室控制GMP實施指南

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目錄

目錄1 前言...............................................................................................................................................12 目的...............................................................................................................................................23 范圍...............................................................................................................................................34 指南內(nèi)容結(jié)構...............................................................................................................................45.質(zhì)量控制實驗室總體描述............................................................................................................55.1 職責....................................................................................................................................55.2 布局....................................................................................................................................55.2.1原則..........................................................................................................................55.2.2 要求.........................................................................................................................55.3 人員....................................................................................................................................65.3.1 組織架構.................................................................................................................65.3.2 資質(zhì)要求.................................................................................................................65.3.3 培訓.........................................................................................................................65.4 文件系統(tǒng)....................................................................................................................................75.4.1 分類.........................................................................................................................75.4.2 要求.........................................................................................................................76 取樣.............................................................................................................................................106.16.26.36.4

定義.........................................................................................................................11應用范圍.................................................................................................................12要求.........................................................................................................................126.3.1人員........................................................................................................................126.3.2取樣器具................................................................................................................126.3.3樣品容器................................................................................................................136.3.4取樣間....................................................................................................................13流程實施.................................................................................................................136.4.1取樣方案................................................................................................................136.4.2取樣........................................................................................................................146.4.3標識........................................................................................................................146.4.4取樣記錄................................................................................................................146.4.5取樣的異常處理....................................................................................................146.4.6留樣........................................................................................................................157 試劑及試液的管理.....................................................................................................................177.1 定義和應用范圍..............................................................................................................177.2 要求..................................................................................................................................177.2.1 采購接收和標識...................................................................................................177.2.2 儲存和使用...........................................................................................................187.2.3 試劑使用效期的管理...........................................................................................187.2.4 報廢.......................................................................................................................187.2.5 文件管理...............................................................................................................188 標準品/對照品............................................................................................................................198.1 定義..................................................................................................................................198.2 分類..................................................................................................................................198.3 應用范圍..........................................................................................................................208.4 要求..................................................................................................................................208.4.1 接收.......................................................................................................................208.4.2 標識.......................................................................................................................208.4.3 標準溶液的穩(wěn)定性研究.......................................................................................20i目錄

實驗室控制系統(tǒng)GMP實施指南8.4.4 標準品、對照品的使用、處置和貯存...............................................................218.4.5 文件管理...............................................................................................................219實驗室分析儀器的確認.............................................................................................................229.1 應用范圍..........................................................................................................................239.2 確認實施..........................................................................................................................249.2.1 驗證總計劃...........................................................................................................249.2.2 確認方案...............................................................................................................249.2.3 確認實施...............................................................................................................259.2.4 確認報告...............................................................................................................279.2.5 系統(tǒng)適用性試驗...................................................................................................279.2.6 實驗室儀器控制系統(tǒng)和數(shù)據(jù)處理系統(tǒng)的確認...................................................279.2.7 再確認...................................................................................................................2810 實驗室分析儀器的校準與維護...............................................................................................3210.1定義................................................................................................................................3310.2應用范圍........................................................................................................................3310.3要求................................................................................................................................3310.3.1 人員.....................................................................................................................3310.3.2 分類.....................................................................................................................3410.3.3 實施指導.............................................................................................................3410.3.4 文件.....................................................................................................................3611 分析方法的驗證和確認...........................................................................................................4511.1分析方法........................................................................................................................4611.2方法驗證........................................................................................................................4611.3方法確認........................................................................................................................4711.4適用范圍........................................................................................................................4711.5方法驗證的一般原則....................................................................................................4711.6需要驗證的檢驗項目....................................................................................................4711.7方法驗證內(nèi)容................................................................................................................4911.7.1 準確度.........................................................................................................................4911.7.2精密度..................................................................................................................5011.7.3 專屬性.................................................................................................................5211.7.4 檢測限（LOD）..................................................................................................5311.7.5 定量限（LOQ）..................................................................................................5311.7.6 線性.....................................................................................................................5411.7.7 范圍.....................................................................................................................5511.7.8 耐用性.................................................................................................................5511.8方法確認........................................................................................................................5911.9方法再驗證....................................................................................................................5911.10文件管理......................................................................................................................6012 穩(wěn)定性實驗...............................................................................................................................6412.1定義................................................................................................................................6612.2應用范圍........................................................................................................................6612.3原則................................................................................................................................6612.4穩(wěn)定性分類....................................................................................................................6612.5技術要點........................................................................................................................6712.5.1 基本要求.............................................................................................................6712.5.2 樣品儲存.............................................................................................................6712.5.3 樣品提取.............................................................................................................7312.5.4 分析.....................................................................................................................7312.5.5 簡化方案設計.....................................................................................................7812.5.6 上市產(chǎn)品的穩(wěn)定性試驗.....................................................................................79ii實驗室控制系統(tǒng)GMP實施指南

目錄12.5.7 評估.....................................................................................................................8012.5.8 數(shù)據(jù)匯總.............................................................................................................8212.5.9 統(tǒng)計分析的程序.................................................................................................8212.6文件................................................................................................................................8312.6.1 標準操作規(guī)程.....................................................................................................8312.6.2 穩(wěn)定性實驗草案.................................................................................................8312.6.3 計劃.....................................................................................................................8312.6.4 記錄.....................................................................................................................8312.6.5 報告.....................................................................................................................8412.6.6 年度趨勢分析與評估.........................................................................................8412.7穩(wěn)定性超標或超趨勢調(diào)查處理....................................................................................8412.7.1原則.....................................................................................................................8412.7.2 程序.....................................................................................................................8413 超出標準及超趨勢的實驗結(jié)果調(diào)查.......................................................................................8713.1定義................................................................................................................................8713.2重要性............................................................................................................................8713.3應用范圍........................................................................................................................8713.4實施................................................................................................................................8713.4.1 一般原則.............................................................................................................8713.4.2 流程.....................................................................................................................8813.4.3 文件.....................................................................................................................9313.7.2 職責的確定：.....................................................................................................9314 原始數(shù)據(jù)的管理.......................................................................................................................9814.1實驗室原始數(shù)據(jù)的范圍................................................................................................9914.1.1 實驗室記錄要求...............................................................................................10014.1.2 數(shù)據(jù)完整性.......................................................................................................10014.1.3 數(shù)據(jù)記錄形式...................................................................................................10014.2實驗室記錄的設計......................................................................................................10114.3實驗室記錄的填寫和復核..........................................................................................10114.3.1 實驗室記錄的填寫...........................................................................................10214.3.2 記錄的復核.......................................................................................................10214.3.3記錄更正要求...................................................................................................10314.4記錄的管理..................................................................................................................10315 物料及產(chǎn)品的檢驗.................................................................................................................10515.1質(zhì)量標準的管理..........................................................................................................10815.1.1 質(zhì)量標準的設計與制定...................................................................................10915.1.2 質(zhì)量標準的審核與批準...................................................................................11015.1.3 質(zhì)量標準的分發(fā)、撤銷、復制、銷毀...........................................................11015.2檢驗..............................................................................................................................11115.2.1 檢驗樣品：.......................................................................................................11115.3檢驗報告書的管理......................................................................................................11115.4委托檢驗......................................................................................................................11215.4.1 原則...................................................................................................................11515.4.2 應用范圍...........................................................................................................11516.4.3 職責...................................................................................................................11616.4.4 受托方的選定...................................................................................................11615.4.5 合同簽訂...........................................................................................................11715.4.6 合同實施...........................................................................................................11715.4.7 結(jié)果評估...........................................................................................................11715.4.8 實驗后樣品處理...............................................................................................11816 微生物檢驗.............................................................................................................................119iii目錄

實驗室控制系統(tǒng)GMP實施指南16.1應用范圍......................................................................................................................12016.2原則..............................................................................................................................12016.3人員資質(zhì)及培訓要求..................................................................................................12016.4設施..............................................................................................................................12016.4.1 無菌及微生物限度檢驗等實驗區(qū)域...............................................................12116.4.2 菌種處理、微生物鑒別和陽性對照室...........................................................12116.4.3 抗生素微生物檢定室.......................................................................................12116.4.4 培養(yǎng)室及其他功能間.......................................................................................12116.5設備..............................................................................................................................12216.5.1 無菌隔離器（如使用）...................................................................................12216.5.2 實驗室用層流臺...............................................................................................12316.5.3 培養(yǎng)箱...............................................................................................................12316.5.4 蒸汽滅菌柜.......................................................................................................12316.5.5 空調(diào)高效過濾器...............................................................................................12316.6滅菌消毒方式..............................................................................................................12316.7菌種的管理..................................................................................................................12416.8培養(yǎng)基..........................................................................................................................12516.8.1 培養(yǎng)基的制備...................................................................................................12516.8.2 培養(yǎng)基的貯藏...................................................................................................12616.8.3 培養(yǎng)基的質(zhì)量控制實驗...................................................................................12616.9實驗分類......................................................................................................................12716.9.1 總菌落數(shù)檢查...................................................................................................12716.9.2 控制菌檢查.......................................................................................................13216.9.3 非無菌產(chǎn)品的實驗頻率...................................................................................13416.9.4 無菌檢查法.......................................................................................................13516.9.5 內(nèi)毒素檢查.......................................................................................................138參考文獻.......................................................................................................................................141術語表...........................................................................................................................................142關鍵詞索引...................................................................................................................................144iv實驗室控制系統(tǒng)GMP實施指南

表格索引

表格索引表1-1指南邏輯關系圖...............................................................................................................1表9-1自動取樣溶出儀確認測試項目示例..............................................................................29表10-1 儀器使用日志示例.........................................................................................................36表10-2校準記錄示例...............................................................................................................37表10-3外部校準評估報告示例...............................................................................................38表10-4分析天平校準要求示例...............................................................................................40表10-5HPLC校準項目及周期示例.......................................................................................42表10-6HPLC年度預防性維護示例........................................................................................43表11-1檢驗項目和驗證內(nèi)容...................................................................................................48表11-2方法驗證對比表...........................................................................................................48表11-3 準確度方法驗證示例.....................................................................................................49表11-4精密度驗證方法...........................................................................................................51表11-5中間精密度的設計方案...............................................................................................51表11-5專屬性方法驗證............................................................................................................52表11-6雜質(zhì)測定檢測限驗證方法...........................................................................................53表11-7雜質(zhì)定量測定驗證方法...............................................................................................53表11-8 線性驗證和準確度驗證需涵蓋的最低濃度范圍..........................................................54表11-9方法耐用性影響因素示例...........................................................................................55表11-10HPLC含量方法耐用性考慮因素及變化范圍示例..................................................56表11-11 分析方法驗證接受標準示例.........................................................................................56表12-1四個氣候帶的分類表...................................................................................................67表12-2 標準貯藏條件表.............................................................................................................68表12-3溫度選擇性制劑的標準貯藏條件................................................................................69表12-4原料藥包裝分類（水蒸氣滲透性）............................................................................69表12-5 原料藥及制劑影響因素試驗條件..................................................................................71表12-6半滲透包裝標準貯藏條件...........................................................................................72表12-7密閉包裝貯藏條件.......................................................................................................72表12-8擬冷藏藥物的貯藏條件...............................................................................................72表12-9擬冷凍貯藏藥物標準貯藏條件....................................................................................72表12-10穩(wěn)定性試驗點時間表.................................................................................................74表12-11 原料藥及制劑穩(wěn)定性重點考察項目參考表................................................................74表12-12片劑中間產(chǎn)品放置時間研究示例..............................................................................77表12-13轉(zhuǎn)運運輸條件示例.....................................................................................................78表12-14括號法方案設計.........................................................................................................79表12-15矩陣法方案設計.........................................................................................................79表16-1非無菌制劑產(chǎn)品類型與檢驗頻次示例......................................................................134表16-2原料檢驗頻次及分類標準示例..............................................