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![Page 1: A Tech Transfer Case Study From a CDMO Sigma S. Mostafa Director, Process Development KBI Biopharma 10-03-2015.](https://reader030.fdocuments.in/reader030/viewer/2022032702/56649cb85503460f9497e0b2/html5/thumbnails/1.jpg)
A Tech Transfer Case Study From a CDMOSigma S. MostafaDirector, Process DevelopmentKBI Biopharma10-03-2015
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Overview• Introduction
– CDMO– KBI
• Tech Transfer in a CDMO– Unique constrains– KBI’s work paradigm
• Case Study
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What is a CDMO?
Confidential3 |
• 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
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a customer and science-focused contract development & manufacturing organization
DURHAM SITE
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KBI Locations
Confidential5 |
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
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About KBI – Our Services
Confidential6 |
Cell line Development
Analytical Method
Development
Preformulation and
Formulation Development
Process Development
Release testing and
stability studies
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Types of Projects in Process Development
Process Transfer
Full Process Development
Material Supply
Process Characterization
Process Optimization
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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
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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
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Tools of Tech Transfer
Development Report, Demo Report, Process Description
Process Flow Diagrams Bill of Material Risk Assessment
Raw Data Process Control Trends
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Technology Transfer – Key Contributors
Confidential11 |
Process: well characterized for scale up &
Mfg
FacilitycGMP 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
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KBI’s Business Process for Tech Transfer
Confidential12 |
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 1st run
Facility FitDraft 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 DevelopmentSampling and Testing plans,Specifications
IP and releaseStability
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Single use disposable technologies
Media and Feed preparation utilizing disposable mixing, filtration and storage systems
Disposable shake flasks or disposable spinner flasks
MCB or WCB vial
Disposable expansion reactor
Disposable seed bioreactor
Disposable production bioreactor
Disposable fluid path centrifuge
Disposable depth filtration system
0,2 µm filter
Hold vessels (Bags)
Hold vessel (bag)
Disposable fluid path purification system
Disposable mixing tank
0,2 µm filter
Retentate
Permeate
PD
Disposable fluid path purification system
Disposable mixing tank
0,2 µm filter
BPC
Virus filter
BPC
0,2 µm filter
BPCBPC
Sterile bulk fill and sampling bags
Buffer preparation utilizing disposable mixing, filtration and storage systems
0,2 µm filter
Disposable fluid path UF/DF system
Aseptic connection
Hold vessel (bag)
Hold vessel (bag)
Hold vessel (bag)
Hold vessel (bag)
Hold vessel (bag)
Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing, Bioprocess International, 10(6), 34-47, 2012.
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KBI’s Cell Culture Platform Process
Confidential14 |
Medium and Supplement Screening
ambrTM Bioreactors 3L Bioreactors
Shake Flasks
Process Parameter Screening
Process Optimization and Robustness
3L Bioreactors 15L Bioreactors
Demonstration Run
200L Bioreactor
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Data from mixing studies used to set agitation rate, aeration strategy, process control strategy
Mixing Characteristics in Bioreactors
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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), 147-154, 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.
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• Titer data matches across scale
Titer
Comparability Across Scale – 3L, 15L, 200L, and 2000L
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• Comparison across scales for the production of a recombinant glycoprotein in a recombinant CHO cell line
– The process decisions and results from ambrTM were reproducible to other scales
Scale-up studies
Cell Growth Titers Product 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), 718-727, 2014.
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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
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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
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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
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Case Study – Tech Transfer into KBI
• At 3L bioreactor scale productivity with theKBI fed-batch process was 2.2x higher than theoriginal batch process
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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 ofProcess development• Initial cell growth and peak cell density in the200L run was slightly higher than the 3L scale• Viability drop was faster in the 200L scaleCompared to the 3L fed-batch culture
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Case Study – 200L Material Supply Run
• Titer in the 200L scale did not match the3L fed-batch data
• A significant amount of base additionoccurred in the run
• Maintaining pH within deadband (0.05 pH)Was difficult
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Case Study – 200L Material Supply Run
• Glucose uptake was somewhat higher in the 200Lscale 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)
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Case Study – Shake Flask & ambr Studies
Design-Expert® Software
Correlation: 0.331Color points by level ofA:Feed
Feed A+BFeed (A+B)Feed CCell Boost 6
Ha
rve
st
Tit
er
(Da
y 1
2 o
r D
ay
14
)
Feed A+B Feed (A+B) Feed C Cell Boost 6
0.2
0.29
0.38
0.47
0.56
• 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
Tite
r
0.00
0.50
1.00
1.50
2.00
2.50
4 5 6 7 8 9 10 11 12 13 14
Lact
ate
(g/L
)
Time (Days)
CS1 - Control (pH 7.0)CS2 - Control (pH 7.0)Cell Boost 6 - pH 6.90Feed C - pH 6.90
Lactate Comparison ambrShake flasks
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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
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Vesper - Confidential
cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
• Cell growth and viability compared well among 3L, 200L, and 2000L scales
0
2
4
6
8
10
12
14
16
0 2 4 6 8 10 12 14 16
VCD
(1 x
10^
6 ce
lls/m
L)
Time (Days)
2000 L GMP Run #12000 L GMP Run #2200 L-scale PD Demo Run3 L-scale Final Process
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 2 4 6 8 10 12 14 16
Cell
Via
bilit
y (%
)Time (Days)
2000 L GMP Run #12000 L GMP Run #2200 L-scale PD Demo Run3 L-scale Final Process
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Vesper - Confidential
cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
• Lactate profile was much improved comparedto the 200L material supply run
• Maximum lactate level in the 2000L was4 g/L, less than half of the level observed in thematerial supply run
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Vesper - Confidential
cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
• Titer was comparable across 3L,200L, and 2000L scales
• 4.5X increase in titer compared tothe 200L material supply run.
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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.
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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