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A Tech Transfer Case Study From a CDMO Sigma S. Mostafa Director, Process Development KBI Biopharma 10-03-2015.

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Presentation on theme: "A Tech Transfer Case Study From a CDMO Sigma S. Mostafa Director, Process Development KBI Biopharma 10-03-2015."— Presentation transcript:

1 A Tech Transfer Case Study From a CDMO Sigma S. Mostafa Director, Process Development KBI Biopharma

2 Overview Introduction – CDMO – KBI Tech Transfer in a CDMO – Unique constrains – KBI’s work paradigm Case Study

3 What is a CDMO? Confidential 3 | Contract Development & Manufacturing Organization Responsible for clinical trial material (CTM) development and manufacturing –Process development & manufacturing of Bulk Drug Substance (BDS) –Formulation and manufacturing of dosage forms, i.e. Drug Product (DP) –Analytical support for BDS and DP A large portion of CTM development & manufacturing expenditure is outsourced to CDMOs

4 a customer and science-focused contract development & manufacturing organization DURHAM SITE

5 KBI Locations Confidential 5 | KBI RTP Cell Culture Process Development Downstream Process Development Microbial Process Development Analytical Development KBI Boulder Microbial Process Development Microbial cGMP Manufacturing Analytical Development KBI Durham Analytical and Formulation Dev. Cell Line Development Cell Culture cGMP Manufacturing Microbial cGMP Manufacturing

6 About KBI – Our Services Confidential 6 | Cell line Development Analytical Method Development Preformulation and Formulation Development Process Development API Manufacturing -Microbial -Mammalian Release testing and stability studies

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 year – KBI has >10 tech transfers per year from PD to manufacturing Each cell type, molecule, and process are different; opportunities to leverage platform is limited Timeline for tech transfer is short and overlaps with development work – PD scale-up run and first manufacturing run are 1 -2 months apart – Short timeframe necessitates staggered tech transfer approach

9 Process Development Work Flow Process Development - Kick-off meeting - Shake flask study - ambr, 3L, & 15L bioreactor study - Harvest study Tech Transfer to Manufacturing - Facility Fit - Risk Assessment - BOM - PFD - Process Description Scale-up Run - 200L Disposable Reactor - MCB vial - Representative seed train - Final Process

10 Tools of Tech Transfer Development Report, Demo Report, Process Description Process Flow DiagramsBill of Material Risk Assessment Raw Data Process Control Trends

11 Technology Transfer – Key Contributors Confidential 11 | Process: well characterized for scale up & Mfg Facility cGMP compliant Facility fit Program management: System for information transfer People: experienced & dedicated 30+ with advanced scientific and technical degrees in Proc Dev 30+ manufacturing staff with significant operations experience with small and large biotech/biopharma 30+ with advanced scientific and technical degrees in Proc Dev 30+ manufacturing staff with significant operations experience with small and large biotech/biopharma

12 KBI’s Business Process for Tech Transfer Confidential 12 | PD AFS MFG QA Client Develop upstream and downstream Perform Confirmation and Demo runs Prepare process overview, facility fit, process description, solution and buffer recipes, sampling plan w/AD Review batch records, person in plant for key steps for 1 st run Facility Fit Draft batch records and solution records Finalize BOM, order raw materials, ensure solutions and buffers specifications Execute Eng and GMP runs, close deviations Campaign Summary Review and approve MBRs, solutions records, sampling plans Deviation closure and Batch release Review process overview, facility fit and process descriptions Approve process descriptions, BRs, BOM, solutions records, person in plant as decided Method Development Method Qualifications Formulation Development Sampling and Testing plans, Specifications IP and release Stability

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 Confidential 14 | Medium and Supplement Screening ambr TM Bioreactors3L Bioreactors Shake Flasks Process Parameter Screening Process Optimization and Robustness 3L Bioreactors15L Bioreactors Demonstration Run 200L Bioreactor

15 Data from mixing studies used to set agitation rate, aeration strategy, process control strategy Mixing Characteristics in Bioreactors

16 Viable Cell Density VCD data matches across scale Comparability Across Scale – 3L, 15L, 200L, and 2000L Gottschalk, U., Shukla, A. Single-use disposable technologies for biopharmaceutical manufacturing, Trends in Biotechnology, 31(3), , Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing, Bioprocess International, 10(6), , 2012.

17 Titer data matches across scale Titer Comparability Across Scale – 3L, 15L, 200L, and 2000L

18 Comparison across scales for the production of a recombinant glycoprotein in a recombinant CHO cell line –The process decisions and results from ambr TM were reproducible to other scales Scale-up studies Cell GrowthTitersProduct Quality Attributes Rameez, 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 mAb Data from client on shake flask batch study CHO 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 September Face to Face Kick-off meeting in mid September Tech Transfer into KBI – A shake flask study and a 3 x 3L bioreactor study completed by mid October A 200L Disposable Bioreactor Supply Run completed by mid October Studies at ambr, 3L and 15L bioreactor scaled conducted November through January PD Demonstration Run at 200L Disposable Bioreactor done in Feb Vial thaw for cGMP run in KBI manufacturing facility in March Start of project to manufacturing vial thaw in 7 months for a full development mAb project. Tech Transfer to KBI (Shake flask and 3L bioreactor scale) Process Optimization (Ambr Study) Process Confirmation (15 L bioreactor-scale) Process Optimization (3 L bioreactor-scale) Demo Run (200 L-scale) cGMP Run (2000 L-scale) Material Supply Run (15 L Scale) Material Supply Run (200 L Scale) Sep 2013 Oct 2013 Nov 2013 Dec 2013 Jan 2014 Feb 2014 Mar 2014 Tech Transfer

21 Case Study – Tech Transfer into KBI Client transferred shake flask batch process In Tech Transfer Run, client’s process was carried out in shake flask and 3L reactors In parallel one feed was tested in preparation for 200L material supply run Cell growth improved in the fed-batch culture

22 Case Study – Tech Transfer into KBI At 3L bioreactor scale productivity with the KBI fed-batch process was 2.2x higher than the original batch process

23 Case Study – 200L Material Supply Run An initial 200L Material Supply Run was carried out following the 3L Tech Transfer Run This 200L run was done prior to initiation of Process development Initial cell growth and peak cell density in the 200L run was slightly higher than the 3L scale Viability drop was faster in the 200L scale Compared to the 3L fed-batch culture

24 Case Study – 200L Material Supply Run Titer in the 200L scale did not match the 3L fed-batch data A significant amount of base addition occurred in the run Maintaining pH within deadband (0.05 pH) Was difficult

25 Case Study – 200L Material Supply Run Glucose uptake was somewhat higher in the 200L scale compared to the 3L fed-batch culture Final 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 Project required expedited process development Shake flask study focused on feed and supplement evaluation ambr study focused on pH set-point and feed impact on lactate & titer Titer Lactate Comparison ambr Shake flasks

27 Case Study – 3L Bioreactor Study A fractional factorial DOE was carried out in the 3L scale Multiple feeds, temperature scheme, and pH set point were tried pH dead band was expanded Feeds with lower lactate level and higher productivity were identified

28 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale Vesper - Confidential Cell growth and viability compared well among 3L, 200L, and 2000L scales

29 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale Vesper - Confidential Lactate profile was much improved compared to the 200L material supply run Maximum lactate level in the 2000L was 4 g/L, less than half of the level observed in the material supply run

30 cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale Vesper - Confidential Titer was comparable across 3L, 200L, and 2000L scales 4.5X increase in titer compared to the 200L material supply run.

31 Conclusions Understanding of cell line characteristics and process parameter impact on cell line is imperative for successful tech transfer Use of high throughput systems such as ambr micro-bioreactors provide significant advantage during expedited process development For 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 activities Testing of scalability early in process development allows identification of cell line specific scalability challenges; therefore, using material supply runs as scale-up tests is advisable.

32 Acknowledgements Process Development -Niket Bubna -Lynwel Cunanan -Brian Baker -Ronnie Nichols Tech Transfer -Sam Pallerla - Manufacturing -Les Smith -Michael Huerta -Joaquin Lopez Analytical -Michael Pollock -James Smedley Executive Management -Abhinav Shukla -Prathima Acharya -Joe McMahon


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