使用一次性技術(shù)單克隆抗體生產(chǎn)設(shè)施VicePresidentVP副總裁417

1、CHINA ANNUAL CONFERENCE 16th 17th April 2012, BeijingMAb Single Use Technology Facilities使用一次性技術(shù)的單克隆抗體生產(chǎn)設(shè)施Niels GuldagerSenior Technology Partner, Biopharmaceuticals 資深生物制藥專家Niels Ulrik HaxthausenVice President (VP) 副總裁NNE Pharmaplan 恩宜琺瑪1Outline 概要Biotech - trends and challenges 生物技術(shù) - 趨勢和挑戰(zhàn)The MAb

2、 case 單克隆抗體案例 Facility of the Future based on the ISPE guideline 未來的生產(chǎn)設(shè)施 基于ISPE準(zhǔn)則3 Manufaturing Operations and Activities 生產(chǎn)運營和活動4 Process and Equipment 工藝和設(shè)備5 Process support and utilities 工藝支持和公用工程6 Facility design 廠房設(shè)計7 Process controls + Quality by Design & ASTM E2500 工藝控制+質(zhì)量源于設(shè)計 & ASTM E2500 Ho

3、w far can we standardize ? 我們什么時候能達(dá)到標(biāo)準(zhǔn)化？2Niels GuldagerNiels is a senior consult for bioprocess and technology at NNE Pharmaplan. He has 16 years of experience with operation and design of biopharmaceutical processes. Niels has spearheaded the implementation and development of new concepts within si

4、ngle use technology and within the application of Quality by Design and ASTM E2500. Niels 是恩宜琺瑪公司生物工藝和技術(shù)領(lǐng)域的高級顧問。他在生物制藥工藝的設(shè)計和運營領(lǐng)域有16年經(jīng)驗。他是實施和開發(fā)一次性使用技術(shù)，質(zhì)量源于設(shè)計和ASTM E2500應(yīng)用的先驅(qū)。Niels is currently engaged in collaborative writing efforts for task force and baseline guide groups. He holds the Certified Ph

5、armaceutical Industry Professional certification from ISPE.目前他負(fù)責(zé)專案組和基準(zhǔn)指南小組的協(xié)同寫作工作。 他持有ISPE認(rèn)證的“制藥行業(yè)專家”證書。3Biotechnology - challenges 生物技術(shù)-挑戰(zhàn)Modern production technologies and new facility design philosophies have the potential to revolutionize the business case for Biopharmaceutical development, laun

6、ch and production facilities. 現(xiàn)代生產(chǎn)技術(shù)和新建生產(chǎn)設(shè)施設(shè)計理念具有改革生物制藥開發(fā)，上市和生產(chǎn)設(shè) 施的潛能。Bringing Biopharmaceutical products from development to production introduces considerations about the long tem facility life cycle and how a pragmatic future oriented perspective can ensure project success.生物制藥產(chǎn)品從開發(fā)到生產(chǎn)要考慮生產(chǎn)設(shè)施的長期生

7、命周期和實際著眼于未來的能保證項目成功的因素。The challenge is not only process and technology driven factors like quality system, analytical program, technology transfer and organizational competences are also part of the synthesis necessary for successful bridging from development to commercial production. 所面臨的挑戰(zhàn)不僅是工藝和技

8、術(shù)為導(dǎo)向 - 質(zhì)量體系，分析程序，技術(shù)轉(zhuǎn)讓和組織能力等因 素也是成功的從開發(fā)到商業(yè)化生產(chǎn)的綜合必要因素。4Monoclonal Antibodies單克隆抗體Facility of the FutureContinued growth in Mab but:The paradigms will shiftThe market will be much more fragmented單克隆抗體技術(shù)生產(chǎn)設(shè)施在未來的發(fā)展-但是模式將變化市場將會變得更加散亂無序5Solid tumours實體腫瘤: 12Head/neck cancer頭頸癌: 3Leukemia白血病: 17Lung cancer肺

9、癌: 15Pancretic cancer胰腺癌: 9 Colorectal cancer腸癌: 10 Kidney cancer腎癌: 5Prostate cancer前列腺癌: 5Sarcoma惡性毒瘤: 4Cancer/chemotherapy癌癥/化療related conditions相關(guān)情況: 2Unspecified cancers未定義的癌癥: 5*Drugs that have potential for one or more of the mentioned cancers*表示有可能治療上述提到的一種或者幾種癌癥的藥物MAbs for cancer treatment

10、- many products, smaller volumes單克隆抗體用于癌癥治療-多種產(chǎn)品,小劑量Brain cancer 腦癌: 8 Breast cancer 乳腺癌: 10Ovarian cancer卵巢癌 : 7Liver cancer肝癌: 4Bladder cancer膀胱癌: 1Stomach cancer胃癌: 4Other cancers其他癌癥: 10Multiple myeloma多發(fā)性骨髓瘤: 7Lymphoma淋巴瘤: 22Skin cancer皮膚癌: 3Source: Nearly 900 Medicines and Vaccines in Testing

11、Offer Hope in the figh Against Cancer, 2011 report from Americas biopharmaceutical research companies)887 new cancer treatment products are currently in development - approximately 200 of these are monoclonal antibodies:目前正在研發(fā)的治療癌癥的新藥有887種-其中大約200種是單克隆抗體6創(chuàng)新的生物制藥可以治療那些致命的或是十年前嚴(yán)重降低生活質(zhì)量的疾病。但是，現(xiàn)實是并不是所有人

12、都能擁有這些創(chuàng)新藥。7Continued Growth - Patent Expiries 持續(xù)增長-專利到期Source: ) Top 10 pharmaceutials 2011 and their patent expiries 2011年前十位制藥企業(yè)以及他們專利到期的時間MAbs indicated in grey灰色表示單克隆抗體8Mabs: Yield Increases Changes Perspectives 單克隆抗體:提高產(chǎn)量改變前景 Case: Crucell PER.C6: 案例: Crucell PER.C6- Human origin cell line, hum

13、an-glycosylation pattern 人原代細(xì)胞系,人糖基化模式- Protein production platform: Therapeutic protein, MAbs, virus 蛋白質(zhì)生產(chǎn)平臺：治療型蛋白質(zhì),單克隆抗體,病毒- 6-8 g/liter fed batch 6-8克/升一組- Extreme Density process: 15 - 27 g/liter at harvest 高密度工藝:收獲15-27克/升New cell lines 新細(xì)胞生產(chǎn)線Media optimization and process understanding 培養(yǎng)基優(yōu)化和對

14、工藝的理解MAbs: From mgs/liter to 5 - 10 - 15 - 25 g/liter reported 單克隆抗體:從毫克/升至5-10-15-25克/升的報告Case: LONZA GS expression system:案例：LONZA 谷氨酰胺合成酶表達(dá)系統(tǒng)：- More than 100 X increase over 1990s cell line yields細(xì)胞株系的產(chǎn)量比20世紀(jì)90年代增長了100倍9Converging force field 趨同的領(lǐng)域 1Many new products will compete on same market,

15、so smaller volumes needed許多新產(chǎn)品在同一市場競爭，因而需要小劑量產(chǎn)品200+ new MAb based products in development超過200種單克隆抗體產(chǎn)品正在研發(fā)中Bio-similar legislation in development or approved from EU, JP, US, WHO生物仿制藥的法規(guī)正在完善中或者已經(jīng)獲得歐盟,日本,美國和世衛(wèi)組織批準(zhǔn)Local production capacity may be required for entry to some markets為了進(jìn)入一些市場可能需要增強(qiáng)本地生產(chǎn)能力I

16、nvestors in emerging market see a huge opportunity for “quick” entry in biotech新興市場的投資者在快速進(jìn)入生物科技行業(yè)中發(fā)現(xiàn)了巨大的機(jī)會Bioreactor yield increases生物反應(yīng)器產(chǎn)量增加Single use technology and increased yields reduce the investment levels drastically一次性使用技術(shù)和增加的產(chǎn)量導(dǎo)致投資水平急劇下降Single use technology gives flexibility to cover var

17、iations in platform processes一次性技術(shù)為平臺工藝的多樣化提供了靈活性10A New Paradigm 新的模式From Megafacilities to Small, Single Use Technology Units:從大規(guī)模設(shè)施到小規(guī)模,一次性使用技術(shù)單元Due to yield increases, there is a huge overcapacity in the market so no volume growth in the existing facilities in EU/US.由于產(chǎn)量增加，市場上產(chǎn)能過剩-所以歐盟和美國的現(xiàn)有設(shè)施沒有

18、增長的空間The existing facilities are designed for low yields ( 1g/l) and stainless steel. They are very capital intensive and現(xiàn)有生產(chǎn)設(shè)施的設(shè)計僅限于低產(chǎn)量 (3g/l)幾乎所有的新設(shè)施都追求一次性使用技術(shù)-追求更高的產(chǎn)量(3g/l)The shift to bio-similar, and to more or less protectionist emerging markets creates a big diversification向仿制藥的轉(zhuǎn)換，而且對新興市場或多或少

19、的貿(mào)易保護(hù)造成了市場巨大的多元化Result: A number of smaller units.結(jié)果:一系列更小規(guī)模的單元6 years. 1 Bill $1-2 years 50 mill $11Tomorrow is today明天源于今天Single Use MAb 次性技術(shù)單克隆抗體Other single use Biotech其他一次性使用生物技術(shù)122 Facility of the Future未來的生產(chǎn)設(shè)施Impact of single use technology 一次性使用技術(shù)的影響13ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六

20、卷Biopharmaceutical Manufacturing Facilities生物制藥生產(chǎn)設(shè)施June 2004 1st edition. Scheduled for update soon. 2004年6月第一版，預(yù)計會在近期更新Joint effort between industry and regulators 行業(yè)和監(jiān)管機(jī)構(gòu)之間的共同努力Updated 2nd edition will much more on closed systems, single use technology更新的第二版將更多關(guān)注封閉系統(tǒng)和一次性使用技術(shù)Contents 內(nèi)容3 Manufaturi

21、ng Operations and Activities 生產(chǎn)運營和活動4 Process and Equipment 工藝和設(shè)備5 Process support and utilities 工藝支持和公用工程6 Facility design 生產(chǎn)設(shè)施設(shè)計7 Process controls 工藝控制is not a list of final answers, but input for: 這不是最終答案，但是是為了Careful, risk based approach 謹(jǐn)慎，基于風(fēng)險的方法Regulatory and quality concerns 關(guān)注的法規(guī)和質(zhì)量Safety r

22、equirements 安全要求Points to consider 需要考慮的要點Regional differences in requirements 要求的區(qū)域差異14Facility of the Future (1) 未來的設(shè)施(1)Standard標(biāo)準(zhǔn)Process core is standard - support functions are adaptable for local conditions工藝核心是標(biāo)準(zhǔn)-支持功能要能適用本地條件Equipment, documentation and procedures based on platform process 設(shè)備

23、,文件記錄和規(guī)程都基于平臺工藝Fast 快速Ready for PQ within 12-18 months from approved concept基于批準(zhǔn)的概念，12-18個月內(nèi)可完成性能確認(rèn)之前的所有工作Single use technology reduces validation and installation一次性使用技術(shù)減少了驗證和安裝工作Flexible 靈活Flexibility and adaptability inherent in single use technologies靈活性和適應(yīng)性依賴于一次性技術(shù)15Standard facility output 標(biāo)準(zhǔn)設(shè)

24、施產(chǎn)量Annual output (bulk API) 年產(chǎn)量Up to 200 kg MAb in standard mode 使用標(biāo)準(zhǔn)模式生產(chǎn)的單克隆抗體產(chǎn)量達(dá)到200公斤Up to 400 kg MAb in upgraded mode使用升級后的模式達(dá)到400公斤(at titer 3 g/L, 70% overall yield, 90% facility utilization)(滴定量3 g/L,總產(chǎn)率70%,設(shè)施利用率90%）Sufficient to meet annual demand for all but biggest selling products today 現(xiàn)

25、在除了大規(guī)模銷售的藥品，足夠滿足每年的需求16Capacity 產(chǎn)能Installed capacity 安裝能力Initial 初始階段2 SUB Bioreactor groups of: 1x50L + 1x200L + 2x1000L2個一次性生物反應(yīng)器組： 1x50L + 1x200L + 2x1000LTotal production capacity: 4x1000L SUBs全部產(chǎn)能： 4x1000L 一次性生物返應(yīng)器Upgrade 升級Upgradeable to 4x2000L SUBs by substition可通過替換升級到4x2000L 的一次性生物反應(yīng)器(20L-

26、100L- 500L-2x2000L)1718ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六卷3 Manufacturing Operations and Activities生產(chǎn)運營和活動Concerns 擔(dān)憂：Process design is tied to facility design工藝設(shè)計與設(shè)施設(shè)計緊密結(jié)合Open processing places more focus on processes and people 開放式操作區(qū)更多關(guān)注工藝和人員Huge difference between single product and multip

27、roduct facility 單一產(chǎn)品和多產(chǎn)品生產(chǎn)設(shè)施之間的巨大差異Viral clearance病毒清除19Single Use technology design impact一次性使用技術(shù)設(shè)計影響Factors different from traditional technology不同于傳統(tǒng)技術(shù)的要素Operators come close to process equipment, touch connections 操作人員接近工藝設(shè)備，直接接觸設(shè)備Manual operations to install, make connections and disassemble 安裝

28、，鏈接和卸載的手動操作Transparency visual contact desirable (not critical) 透明度 優(yōu)良的虛擬式接觸（不是關(guān)鍵因素）Limitations in pressures, flows, mass and heat transfer 壓力，流量，數(shù)量和傳熱的限制Transport volumes and distances become critical 傳輸數(shù)量和距離成為關(guān)鍵Area for transport and maneuvering around - pipeless plant (for process) 傳輸區(qū)域和周圍機(jī)動-無管式設(shè)

29、施（工藝）Solid waste increased 固態(tài)廢棄增加Consumables storage space increased 消耗品存儲空間增加20Flexibility靈活性Single use technology decouples the process from the building 一次性技術(shù)分離工藝與建筑This means that flexibility mainly takes the form of low classification floor space! 這意味著靈活性主要采用低分類樓面空間的形式No complex distribution ma

30、trices as connections are flexible 簡單式分布矩陣作為鏈接是靈活的Media and buffer supply is configured to the given process 培養(yǎng)基和緩沖液供應(yīng)被設(shè)置為特定工藝Can start with only eg. 500L bioreactor train and expand rapidly 能夠從只有500L的生物反應(yīng)器開始培養(yǎng)和快速擴(kuò)張2000L footprint is not drastically larger than 500L footprint 2000L占地面積不大于500L的占地面積A

31、lot of production power in a simple facility 在簡單的生產(chǎn)設(shè)施里包含大量生產(chǎn)能力21ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六卷4 Process and Equipment 工藝和設(shè)備Concerns 擔(dān)憂Specific equipment design considerations 特定設(shè)備的設(shè)計考慮Controlling critical process parameters 關(guān)鍵工藝參數(shù)控制Equipment cleanability 設(shè)備清潔性Equipment shared use 設(shè)備共享使用Ma

32、intenance operations impacting production 維護(hù)操作影響生產(chǎn)22Niels Guldager, MAb single use technology facilities, Chinapharm 201123Design factors: 設(shè)計要素Trend: HTST media treatment趨勢：HTST培養(yǎng)基處理Media towers 培養(yǎng)基存儲器Shelf life 存儲期限23Niels Guldager, MAb single use technology facilities, Chinapharm 201124Design fact

33、ors: 設(shè)計要素Transport for harvest bag收獲袋的傳輸Depth filters dismantled深度過濾器的拆除Consider including proA step考慮包括proA步驟24ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六卷6 Facility design 設(shè)施設(shè)計Concerns 擔(dān)憂Segregation and flow patterns 隔離和流向模式Layout principles 布局原則Area classifications 區(qū)域分類Horizontal and vertical arrang

34、ements橫向和縱向安排25Niels Guldager, MAb single use technology facilities, Chinapharm 201126Media towers 培養(yǎng)基存儲器Bioreactors 生物反應(yīng)器Buffer towers 緩沖液存儲器Chrom skids 色譜板Waste control 廢棄物控制Side view media/buffer prep process interface 側(cè)視圖 培養(yǎng)基/緩沖液準(zhǔn)備 工藝接口Facility designFloor space for inspection, cleaning, transpo

35、rtHandling solid waste in controlled mannerExtra floor space is flexibility (just add more bags)Daylight for intensive operationsProcess flow unidirectional 26Niels Guldager, MAb single use technology facilities, Chinapharm 201127SolutionsProcessMaterialsSupportOverall Resulting Philosophy 總體結(jié)果模式Pro

36、cess support and utilities/Facility design Quality: Flow from dirty (powders) to cleaner (end product)Ergonomics: Flow from big to small volumes/loads27ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六卷5 Process support and utilities 工藝支持和公用工程Concerns 擔(dān)憂WFI or purified water? 注射用水或是純凈水？Risk of contamination

37、from shared systems 來自共享系統(tǒng)的污染風(fēng)險Design considerations for clean utility systems清潔公用工程系統(tǒng)的設(shè)計考慮Biowaste handling生物廢料的處理28Local conditions當(dāng)?shù)貤l件Classification approach: conservative or aggressive潔凈模式:保守還是激進(jìn)Media and water available as preproduced可用的作為預(yù)生產(chǎn)的培養(yǎng)基和水Fill-finish y/n:灌裝Warehouse:倉庫On site y/n:現(xiàn)場Bla

38、ck utilities非潔凈公用工程QC-laboratoryQC實驗室R&D laboratoryR&D 實驗室PD pilot plantPD中試廠Clinical pilot plant臨床中試廠Administration, reception行政，前臺Standard is adaptable: Site interfaces, building levels 標(biāo)準(zhǔn)化是具有靈活性的：現(xiàn)場接口，建筑層數(shù)Process support and UtiltitiesSimplify supply infrastructure by placing big users togetherSe

39、parate dispensing for good housekeepingProvide structured warehouse arrangement Sufficient local storage for SU consumables29ISPE Baseline Guide volume 6: ISPE基準(zhǔn)指南第六卷7 Process Controls - QbD and ASTM E2500工藝控制 質(zhì)量源于設(shè)計和ASTM E2500 Concerns 擔(dān)憂Identify the critical parameters based on science & risk確定關(guān)鍵參

40、數(shù) - 基于科學(xué)和風(fēng)險Know your product specifics but leverage the commonalities (starting point: the A-Mab study)知道你的產(chǎn)品細(xì)節(jié) - 但是要利用共性（起點：一個單抗案例研究）What needs to be qualified in the facility and what is consumables & operations生產(chǎn)設(shè)施里需要配備什么 - 什么是消耗品及營運Leachables & extractibles 浸出和提取30Raw Materials & Disposables Sou

41、rcing原材料&廢棄原料Operational know how 操作技能Market Knowledge市場知識Regulatory filing 依法申報Product & Process development 產(chǎn)品/工藝研發(fā)Clinical Material 臨床材料Quality Systems質(zhì)量系統(tǒng)GMP & QbD GMP&質(zhì)量源于設(shè)計Training培訓(xùn)Facility Approval 設(shè)施批準(zhǔn)Facility Design生產(chǎn)設(shè)施設(shè)計Construction施工Validation驗證The Road to Compliant production符合生產(chǎn)之路31Sta

42、ndard? YES & NO. 是否要標(biāo)準(zhǔn)化？A standard facility for Mab production can be defined but:可以定義單克隆產(chǎn)品的標(biāo)準(zhǔn)生產(chǎn)設(shè)施，但是A number of factors will drive differentiation in increasing impact order:許多因素將導(dǎo)致差異 - 以下因素按影響遞增排序Size matters 尺寸因素Specific processes & specific yields matters 具體工藝&具體產(chǎn)量因素Country matters: 國家因素Local re

43、gulations & practices 當(dāng)?shù)胤ㄒ?guī)Level of regulatory acceptance 監(jiān)管機(jī)構(gòu)認(rèn)可的水平Supply chain 供應(yīng)鏈Site matters 現(xiàn)場因素Available faciltites clean & black utilities, canteens, . 可用的生產(chǎn)設(shè)施 潔凈和非潔凈公用工程，食堂Existing functions QC, quality systems, maintenance,.現(xiàn)有的功能 QC, 質(zhì)量體系，維修Company Matters VERY MUCH 公司因素 很多Start-up or global

44、deployment 公司啟動或是全球發(fā)展Existing company knowhow and practice 現(xiàn)有的公司專有技術(shù)Internal regulations and procedures 內(nèi)部規(guī)范和流程Conservatism or risk&change preparedness 做好保守主義或是冒險變革的準(zhǔn)備So what stays standard? 那什么要保持標(biāo)準(zhǔn)化？32Biotech on Demand按需設(shè)計的生物科技設(shè)施Fast, affordable standard facilities 快速經(jīng)濟(jì)的標(biāo)準(zhǔn)設(shè)施High predictabality in price, time and quality 價格,時間和質(zhì)量的可預(yù)測性Configurable to meet local demands, site conditions and resou