Presentation on theme: "A Tech Transfer Case Study From a CDMO"— Presentation transcript:
1 A Tech Transfer Case Study From a CDMO
Sigma S. MostafaDirector, Process Development KBI Biopharma
2 Overview Introduction Tech Transfer in a CDMO Case Study CDMO KBI
Unique constrainsKBI’s work paradigmCase Study
3 What is a CDMO? Contract Development & Manufacturing Organization
Responsible for clinical trial material (CTM) development and manufacturingProcess development & manufacturing of Bulk Drug Substance (BDS)Formulation and manufacturing of dosage forms, i.e. Drug Product (DP)Analytical support for BDS and DPA large portion of CTM development & manufacturing expenditure is outsourced to CDMOsConfidential
4 Durham Site
5 KBI Locations KBI Durham Analytical and Formulation Dev.
Cell Line DevelopmentCell Culture cGMP ManufacturingMicrobial cGMP ManufacturingKBI BoulderMicrobial Process DevelopmentMicrobial cGMP ManufacturingAnalytical DevelopmentKBI RTPCell Culture Process DevelopmentDownstream Process DevelopmentMicrobial Process DevelopmentAnalytical DevelopmentConfidential
6 About KBI – Our Services
Cell line DevelopmentAnalytical Method DevelopmentPreformulation and Formulation DevelopmentProcess DevelopmentAPI Manufacturing-Microbial-MammalianRelease testing and stability studiesConfidential
7 Types of Projects in Process Development
Process TransferFull Process DevelopmentMaterial SupplyProcess CharacterizationProcess Optimization
8 Tech Transfer Aspects in a CDMO
Large number of tech transfers per yearKBI has >10 tech transfers per year from PD to manufacturingEach cell type, molecule, and process are different; opportunities to leverage platform is limitedTimeline for tech transfer is short and overlaps with development workPD scale-up run and first manufacturing run are 1 -2 months apartShort timeframe necessitates staggered tech transfer approach
9 Process Development Work Flow
- Kick-off meeting- Shake flask study- ambr, 3L, & 15L bioreactor study- Harvest studyTech Transfer to Manufacturing- Facility Fit- Risk Assessment- BOM- PFD- Process DescriptionScale-up Run- 200L Disposable Reactor- MCB vial- Representative seed train- Final Process
10 Tools of Tech TransferDevelopment Report, Demo Report, Process DescriptionRaw DataProcess Control TrendsProcess Flow DiagramsBill of MaterialRisk Assessment
11 Technology Transfer – Key Contributors
30+ with advanced scientific and technical degrees in Proc Dev30+ manufacturing staff with significant operations experience with small and large biotech/biopharmaPeople:experienced &dedicatedProcess: well characterized for scale up & MfgFacilitycGMP compliantFacility fitProgram management: System for informationtransferConfidential
12 KBI’s Business Process for Tech Transfer
PDAFSMFGQAClientDevelop upstream and downstreamPerform Confirmation and Demo runsPrepare process overview, facility fit, process description, solution and buffer recipes, sampling plan w/ADReview batch records, person in plant for key steps for 1st runMethod DevelopmentMethod QualificationsFormulation DevelopmentSampling and Testing plans,SpecificationsIP and releaseStabilityFacility FitDraft batch records and solution recordsFinalize BOM, order raw materials, ensure solutions and buffers specificationsExecute Eng and GMP runs, close deviationsCampaign SummaryReview and approve MBRs, solutions records, sampling plansDeviation closure and Batch releaseReview process overview, facility fit and process descriptionsApprove process descriptions, BRs, BOM, solutions records, person in plant as decidedConfidential
13 Single use disposable technologies
Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing,Bioprocess International, 10(6), 34-47, 2012.
14 KBI’s Cell Culture Platform Process
Shake FlasksambrTM Bioreactors3L BioreactorsMedium and Supplement ScreeningProcess Parameter Screening200L Bioreactor3L Bioreactors15L BioreactorsProcess Optimization and RobustnessDemonstration RunConfidential
15 Mixing Characteristics in Bioreactors
Data from mixing studies used to set agitation rate,aeration strategy, process control strategy
16 Comparability Across Scale – 3L, 15L, 200L, and 2000L
Viable Cell DensityVCD data matches across scale Gottschalk, U., Shukla, A. Single-use disposable technologies for biopharmaceutical manufacturing, Trends in Biotechnology, 31(3), , 2013.Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing, Bioprocess International, 10(6), 34-47, 2012.
17 Comparability Across Scale – 3L, 15L, 200L, and 2000L
TiterTiter data matches across scale
18 Scale-up studiesComparison across scales for the production of a recombinant glycoprotein in a recombinant CHO cell lineThe process decisions and results from ambrTM were reproducible to other scalesCell GrowthTitersProduct Quality AttributesRameez, S., Mostafa, S., Miller, C., Shukla, A. High-throughput miniaturized bioreactors for cell culture process development – reproducibility, scalability and control,Biotechnology Progress, 30(3), , 2014.
19 Case Study – Project Start-up
Expedited Process Development for a novel mAbData from client on shake flask batch studyCHO DG44 cell line from client (prepared by a third party)Client expressed need for 200L scale material delivery before process development started
20 Case Study – Project Scope of Work
Contract Signed in early SeptemberFace to Face Kick-off meeting in mid SeptemberTech Transfer into KBI – A shake flask study and a 3 x 3L bioreactor study completed by mid OctoberA 200L Disposable Bioreactor Supply Run completed by mid OctoberStudies at ambr, 3L and 15L bioreactor scaled conducted November through JanuaryPD Demonstration Run at 200L Disposable Bioreactor done in FebVial thaw for cGMP run in KBI manufacturing facility in MarchStart of project to manufacturing vial thaw in 7 months for a full development mAb project.Sep 2013Tech Transfer to KBI (Shake flask and 3L bioreactor scale)Material Supply Run(200 L Scale)Oct 2013Process Optimization(Ambr Study)Nov 2013Material Supply Run(15 L Scale)Process Optimization (3 L bioreactor-scale)Dec 2013Process Confirmation (15 L bioreactor-scale)Jan 2014Tech TransferDemo Run(200 L-scale)Feb 2014cGMP Run(2000 L-scale)Mar 2014
21 Case Study – Tech Transfer into KBI
Client transferred shake flask batch processIn Tech Transfer Run, client’s process wascarried out in shake flask and 3L reactorsIn parallel one feed was tested in preparationfor 200L material supply runCell growth improved in the fed-batchculture
22 Case Study – Tech Transfer into KBI
At 3L bioreactor scale productivity with theKBI fed-batch process was 2.2x higher than theoriginal batch process
23 Case Study – 200L Material Supply Run
An initial 200L Material Supply Runwas carried out following the 3L Tech Transfer RunThis 200L run was done prior to initiation ofProcess developmentInitial cell growth and peak cell density in the200L run was slightly higher than the 3L scaleViability drop was faster in the 200L scaleCompared to the 3L fed-batch culture
24 Case Study – 200L Material Supply Run
Titer in the 200L scale did not match the3L fed-batch dataA significant amount of base additionoccurred in the runMaintaining pH within deadband (0.05 pH)Was difficult
25 Case Study – 200L Material Supply Run
Glucose uptake was somewhat higher in the 200Lscale compared to the 3L fed-batch cultureFinal lactate level was around 10 g/L in the 200L scale(compared to 7 g/L in 3L fed-batch reactor)
26 Case Study – Shake Flask & ambr Studies
TiterLactate ComparisonShake flasksambrProject required expedited process developmentShake flask study focused on feed and supplement evaluationambr study focused on pH set-point and feed impact on lactate & titer
27 Case Study – 3L Bioreactor Study
A fractional factorial DOE was carried out in the 3L scaleMultiple feeds, temperature scheme, and pH set point were triedpH dead band was expandedFeeds with lower lactate level and higher productivity were identified
28 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
Cell growth and viability compared well among 3L, 200L, and 2000L scalesVesper - Confidential
29 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
Lactate profile was much improved comparedto the 200L material supply runMaximum lactate level in the 2000L was4 g/L, less than half of the level observed in thematerial supply runVesper - Confidential
30 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
Titer was comparable across 3L,200L, and 2000L scales4.5X increase in titer compared tothe 200L material supply run.Vesper - Confidential
31 ConclusionsUnderstanding of cell line characteristics and process parameter impact on cell line is imperative for successful tech transferUse of high throughput systems such as ambr micro-bioreactors providesignificant advantage during expedited process developmentFor an expedited manufacturing plan, a phased approach to tech transfer is needed; identifying and ordering the long lead items and determining facility fit are often the most rate limiting activitiesTesting of scalability early in process development allows identification ofcell line specific scalability challenges; therefore, using material supplyruns as scale-up tests is advisable.
32 Acknowledgements Analytical Executive Management Tech Transfer
Process DevelopmentNiket BubnaLynwel CunananBrian BakerRonnie NicholsTech TransferSam PallerlaManufacturingLes SmithMichael HuertaJoaquin LopezAnalyticalMichael PollockJames SmedleyExecutive ManagementAbhinav ShuklaPrathima AcharyaJoe McMahon
Presentation on theme: "International Technology Transfer Case Study Dec. 15 2008."— Presentation transcript:
1 International Technology Transfer Case Study Dec. 15 2008
2 Definition and Channels International technology transfer (ITT) is a comprehensive term covering mechanisms for shifting information across borders and its effective diffusion into recipient economies. it refers to numerous complex processes, ranging from innovation and international marketing of technology to its absorption and imitation. Included in these processes are technology, trade, and investment policies that can affect the terms of access to knowledge. Channels – One major channel is trade in goods, especially capital goods and technological inputs. – A second is foreign direct investment (FDI) – A third is technology licensing – non-market channels of ITT: the process of imitation through product inspection, reverse engineering – temporary migration of students, scientists, and managerial and technical personnel
3 Policies impacting ITT Host country policies – Absorption of ITT and its translation into greater competition depend on having an adequate supply of engineering and management skills. – Backward spillovers from ITT appear to be strongest in countries where multinational firms are capable of working with competitive suppliers in order to increase their productivity and standards. Reducing entry barriers in supplier industries can assist ITT. – Important factors include, among others, an effective infrastructure, transparency and stability in government, and a reasonably open trade and investment regime. – Governments may reduce the "technological distance" between their firms and foreign firms in order to encourage ITT. – attention should be paid to selecting IP standards that recognize the rights of inventors but encourage dynamic competition.
4 Policies (cont) Source country policies – Governments in developed countries could increase their technical and financial assistance for improving the ability of poor countries to absorb technology and trade. – Governments could agree to offer identical fiscal benefits to firms transferring technologies to developing countries as to developing home regions. – Developed countries could offer the same tax advantages for R&D performed abroad as for R&D done at home. – Governments could ensure that tax deductions are available for contributions of technology to non-profit entities engaged in ITT. – Fiscal incentives could be offered to encourage enterprises to employ, at least – temporarily, recent scientific and engineering and management graduates from developing countries. – Universities could be encouraged to recruit and train students from LDCs in science, technology, and management.
5 Case: Auto Industry in Chinese Economy 1.6 million Chinese were directly employed by this industry as of 2003 (not counting the employees of industries that supply the auto industry (i.e. steel, rubber), which are estimated at approximately 36.4 million workers). Auto industry is 3 percent of total manufacturing employment. The value added by the Chinese auto industry represented 6.3% of the total value added of manufacturing in China in 2003, a tripling of this percentage from its level in 1990 (CATARC 2004).
6 History of Chinese Auto Industry Little to no manufacturing experience prior to WWII Tech transfer from Soviets before Sino-Soviet split in 1960 After Cultural Revolution, no technological capabilities in this sector Decision to “make or buy” – forced to buy because of weak technological capabilities Formation of many joint ventures with foreign firms and licensing of technology from them as well, but without formal industrial policy 1994 Auto Industry Policy – intention to create national industry Consolidation of industry, but currently 118 manufacturers; all the major ones have formed joint ventures with foreign auto companies Joining WTO in 2001 effectively reversed many previous policies, but increased competition 2004 Auto Industry Policy – auto industry as “pillar” industry; create better technological capabilities and consolidate industry
7 Chinese Automakers Currently 116 automakers in China Vast majority of output comes from the firms that have formed joint ventures with foreign companies (quasi-exceptions are Chery and Geely) High profitability Skills in manufacturing, parts and components, and business development Weak design and innovation capabilities, especially for advanced engines and system integration
8 Terms of WTO for Chinese Auto Industry Import tariffs for complete vehicles are to be reduced from the current 80 to 100 percent to 25 percent by July 1, 2006 Import tariffs for parts and components are to be reduced from 35 percent to 10 percent by the same date Import quotas on vehicles will be decreased 15 percent per year until they are cancelled in 2005 Import licenses will also be phased out by 2005. Majority ownership limits on foreign manufacturers for engines will also be eliminated Also, provincial governments will be given the authority to approve foreign direct investment projects up to $150 million by 2005 (used to be $30 million) All of the Chinese government’s requirements regarding technology transfer, maintaining a foreign exchange balance, maintaining a trade balance, and meeting localization standards were eliminated upon China’s entry to the WTO in 2001.
9 2004 Auto Industry Policy 10-year update to 1994 policy Emphasizes need for consolidation of industry (i.e. FAW-Tianjin-Toyota) Urges more capacity-building and innovation First articulation of concern about environment and oil imports More emphasis on (and incentives for) exports
10 11 th 5-Year Plan for Auto Industry 依托现有基础加快产业自主发展。 – Speed up autonomous development based on the current conditions (Chinese branding) 依靠技术进步推动产业可持续发展。 – Promote sustainable development by using advanced technologies 利用市场机制促进产业结构优化升级。 – Optimize and upgrade the industrial structure using market mechanisms
11 Background Data
12 Comparisons United StatesChina Total Oil Consumption, 2005 20 million bbls/day6.5 million bbls/day Percent Oil Consumed by Motor Vehicles 50 percent40 percent Percent Oil Imported, 2005 60 percent (12 million bbls/day) 43 percent (3 million bbls/day) Total Number of Passenger Cars 228 million (approx.)20 million (approx.)
14 Production Mix is Changing Source: CATARC, 2006
15 Vehicles Per Capita
17 BP Statistical Review of World Energy, 2004
18 The Sino-U.S. Joint Ventures
19 Shanghai Auto Industry Corp. First Auto Works Tianjin Auto Works Guangzhou Auto Works Dongfeng Auto Works (former SAW) Beijing Auto Industry Holding Co. General Motors VW Toyota DaimlerChrysler Hyundai Nissan Honda Geely Chery Chang’An Ford Citroen Suzuki Foreign Investment in China’s Auto Industry: A Complicated Network ? Shenyang Brilliance BMW Kia
20 Comparative Analysis Beijing JeepShanghai GMChang’An Ford Technology or R&D Center? Internal, but no joint work (all Chinese engineers) Yes (PATAC)Internal, but very small for product adaptation Capability level of Chinese partner accord. to US firm product adaptation, localization Too new to characterize U.S. firm funds other research in Chinese univ. or institutes? NoYesYes – In coordination with National Science Foundation of China Number of Chinese vs. U.S. engineers 200 Chinese 1 U.S. 400 Chinese >20 U.S. n/a Management of Tech Centers 1 Chinese, 1 U.S. 7 of 11 dept’s managed by U.S. engineers n/a Funding30,000 RMB per year ($3,600) For PATAC, GM put $25 million in cash and SAIC put $22 million (“in kind”) n/a
21 Seven Main Findings U.S. FDI did not substantially contribute to improving Chinese vehicle technological capabilities because little knowledge was transferred along with the product. Chinese government failed to design and implement an aggressive, consistent strategy for the acquisition of technological capabilities from foreigners in the automobile industry. U.S. companies in JV’s are purely profit-motivated – Chinese also seek profits in short term, but most want skills for long term.
22 Findings (cont.) Chinese firms have acquired good manufacturing skills and also acquired some product adaptation capabilities. Parts suppliers appear to have more advanced capabilities due to local content requirements. Technologies that were transferred by U.S. firms in the period studied were rarely, if ever, updated once a model was in production, with the emerging exception of SGM. This is now changing due to competitiveness. Even though technology transfer was purely product, the FDI has contributed to the growth of the industry, which has benefited the Chinese economy in terms of jobs and spillovers. U.S. firms did not transfer pollution-control technology until required to do so by the Chinese government.