【正文】 Validation Plan驗(yàn)證計(jì)劃 498. Validation prerequisite驗(yàn)證先決條件 51 Personal Identification人員確認(rèn) 51 Process Documentation Verification 生產(chǎn)文件確認(rèn) 51 Training Verification 培訓(xùn)確認(rèn) 52 System and Equipment Instruments Calibration Verification 系統(tǒng)和設(shè)備儀表校驗(yàn)確認(rèn) 52 System and Equipment Instruments Calibration Verification 生產(chǎn)相關(guān)驗(yàn)證狀態(tài)確認(rèn) 53 Test Instruments Calibration Verification 測試儀器和儀表校驗(yàn)確認(rèn) 53 Testing Method Validation Verification檢驗(yàn)方法驗(yàn)證的確認(rèn) 54 Raw Material and Excipient Verification原輔料確認(rèn) 549. Sampling Plan and Evaluation Criteria取樣計(jì)劃及評估標(biāo)準(zhǔn) 5610. Sample Coding Method樣品編碼原則 7011. Process Validation Test Execution 工藝驗(yàn)證執(zhí)行 72 Liquid Preparation 液體配制 72 Cell Resurrection and Passage細(xì)胞復(fù)蘇及傳代 74 Harvest liquid test 收獲液檢測 81 Clarification Filtration Efficacy Test 澄清過濾效果檢測 83 UF Concentration 1 Efficacy Test超濾濃縮1效果檢測 83 Ammonium sulfate precipitation efficacy test 硫酸銨沉淀效果檢測 85 Potassium bromide extraction efficacy test 溴化鉀提取效果檢測 86 First density gradient centrifugation efficacy test 一次密度梯度離心效果檢測 87 Second density gradient centrifugation efficacy test 二次密度梯度離心效果檢測 88 UF Concentration 2 Efficacy Test 超濾濃縮2效果檢測 89 Chromatography purification product test 層析純化產(chǎn)物檢測 9012. Bulk Determination原液檢驗(yàn) 9213. Process Validation Summarization工藝驗(yàn)證總結(jié) 9314. PV Report工藝驗(yàn)證報(bào)告 94 Process Validation Report 工藝驗(yàn)證報(bào)告 94 Process Validation Analysis and Evaluation 工藝驗(yàn)證分析與評價(jià) 9415. Requirements on Execution Records 執(zhí)行記錄要求 9516. Deviation Handling 偏差處理 9517. Change Handling 變更處理 9518. Test Form測試表 96表格 1 縮略語 9表格 2原輔料質(zhì)量標(biāo)準(zhǔn)表 11表格 3物料消耗表1 21表格 4物料消耗表2 21表格 5所用液體配料表 22表格 6生產(chǎn)車間一覽表 26表格 7主要生產(chǎn)設(shè)備一覽表 29表格 8工藝風(fēng)險(xiǎn)分析表 33表格 9工藝時(shí)間表 49表格 10取樣計(jì)劃表 56表格 11樣品編碼原則 70表格 12配液取樣檢測信息表 72表格 13復(fù)蘇和傳代取樣表 74表格 14復(fù)蘇和傳代樣品編碼 80表格 15收獲液標(biāo)準(zhǔn) 82表格 16澄清過濾標(biāo)準(zhǔn) 83表格 17超濾濃縮1標(biāo)準(zhǔn) 84表格 18硫酸銨沉淀標(biāo)準(zhǔn) 85表格 19溴化鉀提取標(biāo)準(zhǔn) 86表格 20一次密度梯度離心標(biāo)準(zhǔn) 87表格 21二次密度梯度離心標(biāo)準(zhǔn) 88表格 22超濾濃縮2標(biāo)準(zhǔn) 89表格 23純化產(chǎn)物標(biāo)準(zhǔn) 90表格 24原液標(biāo)準(zhǔn) 92表格 25測試表列表 961. Purpose目的This purpose of this process validation is to provide documented evidence to show that the bination of the personnel, materials, equipment, methods, environmental conditions and the other related utilities XXX Co., LTD (XXX) can ensure the consistent production of products conforming to the enterprise internal standards and the national standards, and the processes are reliable and conforming to the GMP requirements. The process validation and the test results are to be documented based on this validation protocol.本工藝驗(yàn)證用于提供文件化的證據(jù)，證明XXX疫苗一室生產(chǎn)XXX原液的人員、材料、設(shè)備、方法、環(huán)境條件以及其它有關(guān)公用設(shè)施的組合可以始終如一的生產(chǎn)出符合企業(yè)內(nèi)控標(biāo)準(zhǔn)及國家法定標(biāo)準(zhǔn)的產(chǎn)品，工藝穩(wěn)定可靠，符合GMP要求，工藝驗(yàn)證的過程和檢查的結(jié)果將按照該驗(yàn)證方案進(jìn)行記錄。由于工作細(xì)胞庫制備的過程并非常規(guī)生產(chǎn)過程，因此，不在本次驗(yàn)證中進(jìn)行考察。3. Responsibility職責(zé) AAA responsibilities AAA的職責(zé) 252。 Guide Protocol execution, data collection/ Provide test data for review upon request by customer指導(dǎo)方案的實(shí)施，數(shù)據(jù)的收集/在客戶要求時(shí)提供測試數(shù)據(jù)供其審核252。 Review and approve protocol審核并批準(zhǔn)驗(yàn)證方案252。 Assure all the raw materials used for validation can be supplied timely and ply with domestic quality criteria of enterprise保證驗(yàn)證用原輔包裝材料能按時(shí)到貨，并符合企業(yè)內(nèi)控標(biāo)準(zhǔn)n Research and development department 研發(fā)部252。 Review and make assurance the pliance of raw material supplier with registered supplier審核原輔料供應(yīng)商和注冊資料的一致性252。 Coordination and implementation of this validation protocol協(xié)調(diào)、實(shí)施本驗(yàn)證方案252。 Collection, sorting and reviewing of validation data and drafting of validation reports (including the deviation report, if there are any deviations)收集、整理和審核驗(yàn)證數(shù)據(jù)，起草驗(yàn)證報(bào)告（如方案執(zhí)行有偏差，要完成偏差報(bào)告）。 Assistance in implementation of this validation protocol協(xié)助本驗(yàn)證方案的實(shí)施252。 Assure normal operation of the utility system保證公用系統(tǒng)的正常運(yùn)行252。 Determination of test methods used in this validation protocol負(fù)責(zé)確定本驗(yàn)證方案的檢驗(yàn)方法252。 The quality inspections on XXXXX Tablet involved in this validation protocol, and presenting full item certificates of analysis and quality inspection reports and records負(fù)責(zé)本驗(yàn)證方案涉及的重組乙型肝炎疫苗（CHO細(xì)胞）原液生產(chǎn)的質(zhì)量檢驗(yàn)，并出具全項(xiàng)檢驗(yàn)報(bào)告，提供質(zhì)量檢驗(yàn)報(bào)告書及檢驗(yàn)記錄252。 Coordinating the plant in the implementation of this validation protocol協(xié)同車間實(shí)施本驗(yàn)證方案252。 Supervision of validation process, review and approval of this protocol, and ensuring the implementation following this protocol負(fù)責(zé)驗(yàn)證過程監(jiān)督，方案的審核與批準(zhǔn)，確保按批準(zhǔn)的方案執(zhí)行252。 Coordination among different departments involved in the validation activities負(fù)責(zé)驗(yàn)證涉及到的各部門之間的協(xié)調(diào)252。 Identification, audit and assessment of suppliers供應(yīng)商的確認(rèn)、審計(jì)及評價(jià)252。 Final report Review 最終報(bào)告的審核4. Regulation and Guidance 法規(guī)和指南252。 Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice : Qualification and Validation , September 2001EudraLex 第四卷 藥品生產(chǎn)質(zhì)量管理規(guī)范，附錄15 驗(yàn)證與確認(rèn)，2001年9月252。 EMEA Annex II to note for guidance on process validation, January 2005歐洲藥品管理局 – 附錄II 工藝驗(yàn)證指南252。 FDA Process Validation: General Principles and Practices , January 2011FDA工藝驗(yàn)證：一般原則和實(shí)踐，2011年01月252。 PIC PIC/S Pharmaceutical Inspection Convention, Pharmaceutical Inspection Cooperation Scheme, “Remendations on Validation Master Plan, Installation and Operational Qualification, Nonsterile Process Validation, Cleaning Validation”, July 2004PIC/S藥品監(jiān)管公約，藥品監(jiān)管合作計(jì)劃，“有關(guān)驗(yàn)證主計(jì)劃、安裝和運(yùn)行確認(rèn)、非無菌工藝驗(yàn)證、清潔驗(yàn)證的建議”，2004年7月252。 Chinese Pharmacopoeia (CP) 2010 Edition 中國藥典（CP）2010年版252。 2005 by PDA)蛋白生產(chǎn)的工藝驗(yàn)證（技術(shù)報(bào)告42，PDA， 2005年版）5. Abbreviations縮略語The abbreviations which will be used in this protocol are listed in the following form.在下面的表格中規(guī)定了本方案中使用的縮略語。n Using this defined process validation shall be performed for three consecutive successful runs based on GMP requirements to demonstrate the process control reliability and the repeatability.鑒于XXX的生產(chǎn)已經(jīng)有近20年歷史，本次驗(yàn)證僅是對生產(chǎn)地址發(fā)生變更后且主要設(shè)備未發(fā)生變化的再驗(yàn)證，考慮到本產(chǎn)品生產(chǎn)周期長（總生產(chǎn)周期為158天）的原因，本方案實(shí)施的工藝驗(yàn)證將生產(chǎn)1批成功的產(chǎn)品以證明其可靠性。n The process recipe of Bulk of XXX (Registration batch No.: for 20μg: GUOYAOZHUNZI XXX, and for 10μg GUOYAOZHUNZI XXX) is briefly described in this protocol. The contents of the recipe are described and the process flow diagram is listed. The process procedure is conformed to the registration standard.本方案對XXX原液的工藝處方（注冊批號：20μg：國藥準(zhǔn)字 XXX、10μg：國藥準(zhǔn)字 XXX）進(jìn)行了簡介，對處方