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
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.