Transcript Document

A Tech Transfer Case
Study From a CDMO
Sigma S. Mostafa
Director, Process Development
KBI Biopharma
10-03-2015
Overview
• Introduction
– CDMO
– KBI
• Tech Transfer in a CDMO
– Unique constrains
– KBI’s work paradigm
• Case Study
What is a CDMO?
• 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
3 |
Confidential
DURHAM SITE
a customer and science-focused
contract development & manufacturing organization
KBI Locations
KBI Durham
•
Analytical and Formulation Dev.
•
Cell Line Development
•
Cell Culture cGMP Manufacturing
•
Microbial cGMP Manufacturing
KBI Boulder
•
Microbial Process Development
•
Microbial cGMP Manufacturing
•
Analytical Development
KBI RTP
•
Cell Culture Process Development
•
Downstream Process Development
•
Microbial Process Development
•
Analytical Development
5 |
Confidential
About KBI – Our Services
Cell line
Development
6 |
Process
Development
Analytical
Method
Development
Preformulation
and Formulation
Development
Confidential
API Manufacturing
-Microbial
-Mammalian
Release testing
and stability
studies
Types of Projects in Process Development
Process Transfer
Full Process Development
Material Supply
Process Characterization
Process Optimization
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
Process Development Work Flow
Process Development
Tech Transfer to Manufacturing
- Kick-off meeting
Scale-up Run
- Shake flask study
- Facility Fit
- ambr, 3L, & 15L
bioreactor study
- Risk Assessment
- Harvest study
- PFD
- BOM
- Process Description
- 200L Disposable
Reactor
- MCB vial
- Representative
seed train
- Final Process
Tools of Tech Transfer
Development Report, Demo Report, Process Description
Process Flow Diagrams
Raw Data
Bill of Material
Process Control Trends
Risk Assessment
Technology Transfer – Key Contributors
•
•
People:
experienced &
dedicated
Process: well
characterized
for scale up &
Mfg
Facility
cGMP compliant
Facility fit
Program
management: System
for information
transfer
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30+ with advanced scientific and
technical degrees in Proc Dev
30+ manufacturing staff with
significant operations experience
with small and large
biotech/biopharma
Confidential
KBI’s Business Process for Tech Transfer
PD
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
AFS
Method
Development
Method
Qualifications
Formulation Development
Sampling and
Testing plans,
Specifications
IP and release
Stability
MFG
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
QA
Client
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Review and approve
MBRs, solutions
records, sampling plans
Review process overview,
facility fit and process
descriptions
Confidential
Deviation closure and
Batch release
Approve process descriptions,
BRs, BOM, solutions records,
person in plant as decided
Single use disposable technologies
Media and Feed preparation utilizing disposable
mixing, filtration and storage systems
Aseptic
connection
MCB or
WCB vial
Disposable shake flasks or
disposable spinner flasks
Hold vessel
(bag)
Disposable expansion
reactor
Disposable fluid path
purification system
Disposable
mixing tank
Disposable
seed bioreactor
0,2 µm
filter
Hold vessel
(bag)
Disposable production
bioreactor
Disposable fluid path
purification system
Disposable fluid path
centrifuge
Disposable
mixing tank
0,2 µm
filter
Hold vessel
(bag)
Hold vessels
(Bags)
0,2 µm
filter
Disposable depth
filtration system
Virus
filter
Hold vessel
(bag)
Retentate
BPC
Permeate
BPC
BPC
BPC
PD
Hold vessel
(bag)
Disposable fluid path
UF/DF system
0,2 µm
filter
Hold vessel
(bag)
0,2 µm
filter
Sterile bulk fill and
sampling bags
Buffer preparation utilizing disposable mixing,
filtration and storage systems
Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing,
Bioprocess International, 10(6), 34-47, 2012.
KBI’s Cell Culture Platform Process
Shake Flasks
ambrTM Bioreactors
Medium and Supplement Screening
Process Parameter Screening
200L Bioreactor
3L Bioreactors
15L Bioreactors
Process Optimization and Robustness
Demonstration Run
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3L Bioreactors
Confidential
Mixing Characteristics in Bioreactors
Data from mixing studies used to set agitation rate,
aeration strategy, process control strategy
Comparability Across Scale – 3L, 15L, 200L,
and 2000L
Viable Cell Density
• VCD data matches across scale
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), 3447, 2012.
Comparability Across Scale – 3L, 15L, 200L,
and 2000L
Titer
• Titer data matches across scale
Scale-up studies
Cell Growth
•
Titers
Product Quality Attributes
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
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.
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
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
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Material Supply Run
(200 L Scale)
Oct 2013
Process Optimization
(Ambr Study)
Nov 2013
Process Optimization
(3 L bioreactor-scale)
Dec 2013
Process Confirmation
(15 L bioreactor-scale)
Jan 2014
Demo Run
(200 L-scale)
Feb 2014
Material Supply Run
(15 L Scale)
Tech Transfer
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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.
Sep 2013
Tech Transfer to KBI
(Shake flask and 3L
bioreactor scale)
cGMP Run
(2000 L-scale)
Mar 2014
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
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
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
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
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)
Case Study – Shake Flask & ambr Studies
re
CS1 - Control (pH 7.0)
CS2 - Control (pH 7.0)
Cell Boost 6 - pH 6.90
Feed C - pH 6.90
ambr
Lactate Comparison
2.00
Lactate (g/L)
0.47
Titer
Harvest Titer (Day 12 or Day 14)
2.50
Shake
flasks
0.56
0.38
1.50
1.00
0.29
0.50
0.00
0.2
4
Feed A+B
Feed (A+B)
Feed C
Cell Boost 6
5
6
7
8
9
10
11
12
Time (Days)
• Project required expedited process development
A:Feed
• Shake flask study focused on feed and supplement evaluation
• ambr study focused on pH set-point and feed impact on lactate & titer
13
14
Case Study – 3L Bioreactor Study
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•
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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
cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
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120.0
100.0
12
Cell Viability (%)
VCD (1 x 10^6 cells/mL)
14
10
8
6
2000 L GMP Run #1
2000 L GMP Run #2
200 L-scale PD Demo Run
3 L-scale Final Process
4
2
80.0
60.0
40.0
2000 L GMP Run #1
2000 L GMP Run #2
200 L-scale PD Demo Run
3 L-scale Final Process
20.0
0
0.0
0
2
4
6
8
Time (Days)
•
10
12
14
16
0
2
4
6
8
10
12
14
Time (Days)
Cell growth and viability compared well among 3L, 200L, and 2000L scales
Vesper - Confidential
16
cGMP Manufacturing (2000 L-scale) Comparison w/ Small-scale
• 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
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 to
the 200L material supply run.
Vesper - Confidential
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.
Acknowledgements
Process Development
Analytical
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Niket Bubna
Lynwel Cunanan
Brian Baker
Ronnie Nichols
Michael Pollock
James Smedley
Executive Management
Tech Transfer
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Sam Pallerla
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Manufacturing
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Les Smith
Michael Huerta
Joaquin Lopez
Abhinav Shukla
Prathima Acharya
Joe McMahon