With intensification of upstream and downstream processes, several scenarios for mAb production become apparent. We will identify these scenarios with process modeling data to quantify the financial benefits and holistic value of these technologies.
The biopharmaceutical industry is adopting a more strategic view toward monoclonal antibody manufacturing. There is a drive to develop processes with higher productivity and improved economics without sacrificing robustness or quality. Initiatives to achieve these goals through unit operation intensification, connected processing, and continuous processing have been a major focus and this trend will only accelerate.
Opportunities for process intensification exist throughout the entire monoclonal antibody process. With the implementation of perfusion-based operations from seed train to production bioreactors, and downstream technologies such as intensified capture chromatography, in-line virus inactivation, and flow-through polishing, a variety of scenarios for Mab production trains become apparent. In this presentation, we will identify several of these production scenarios with process modeling data to quantify the financial benefits and holistic value derived from the integration and intensification of Mab processes.
In this webinar, you will learn:
- The technologies being evaluated for upstream and downstream process intensification.
- Options for integration of these technologies for Mab production.
- Process and cost modeling for several process scenarios using intensification, connected, and continuous operations.
5. BPOG Technology Road Map
A Major Shift in Business Drivers
Market Growth
Cost Pressure
Uncertainty
New Product
Classes
Business Drivers
Flexibility
Reduce product change-
over time by 90%
Speed
Reduce new facility build
times by 70%. Compress
production lead time by
80%
Cost
90% reduction in cost to
manufacture and CAPEX
Quality
10X transformation in mfg.
robustness and reliability
Process Analytics
5
Next Generation Processing
https://www.biophorum.com/category/resources/tech
nology-roadmapping-resources/introduction/
6. Market Research
Drivers for Adoption of Next Generation Processing Technologies
Cost Control /
CoGs Reduction
90%
Facility
Flexibility
93%
Multiple Molecule
Pipeline
77%
Multi-Use
Product Facilities
73%
6
7. Market Research
The Many Definitions of Next Generation Processing
Process
Intensification
for existing
bottleneck
Process
Compression
Continuous
Processing
New greenfield
facility
leveraging
single-use
Industry
definitions of
Next Generation
Processing
Light Asset
Facility
??
7
8. 8
Any technology, expendable, service, or system which
significantly changes the existing monoclonal
antibody manufacturing template to deliver:
Speed
Flexibility
Quality
Cost
Next Generation
Processing
10. 10
Factory of the Future
Evolutionary Journey Across Many Disciplines
Timeline
Today
Near-term
Mid-term
End state
Process
Batch
Intensified
Connected
Continuous
Format
Stainless
Hybrid
Single Use
SU/Closed
Controls
Process Monitoring
Unit operation
control
Integrated process
control
Holistic process
control
Analytics
QC
Manufacturing
At-line
In-line/real-time
Software
Unit Operation
Control
Systems
Connectivity
Paperless Facility
Process Simulation
11. Focus Areas:
(1) Cell Culture Media For Intensified Processes
(2) Integrated Perfusion Bioreactor
(3) Protein A for Intensified Capture
(4) In-Line Viral Inactivation
(5) Flow Through Polishing Toolbox
(6) Single-Pass UF/DF
2018
2018-2020+
11
14. MCB
200 vial
NN-1
or
x x
Seed TrainInoc. Train Production
MWCB
200 vial
BatchBatch
Intensified Seed Intensified Production
• Fed-batch
• Conventional
Perfusion
1. High Cell Density
Process Intermediates
2. Perfused Seed Train
1. High Seed Fed-Batch
2. Concentrated Fed-Batch
3. Ultra High VCD Fed-Batch
4. Steady State Perfusion
5. Dynamic Perfusion
Intensified Upstream
Several Opportunities for Intensified Upstream Processing
14
19. Intensified Upstream
Intensified Seed Train
Batch
x
1-2 mL
10 - 30 .106 VC/mL
N-1
or
x
Batch
MCB/MWCB Inoculum Train
Seed Train
Production
CRD
Perfusion
CRD
50-100 .106 VC/mL
or or
4.5mL 50-500 mL bag
CRD
CRD
N
CRD
(2) High Cell Density Process Intermediates
(1) Perfused Seed Train
19
20. Intensified Seed Train
Perfused Seed Train
14 days
10 days
Conventional
Fed-Batch
(~ 0.2 .106 VC/mL)
High Seed
Fed-Batch
(~ 5 .106 VC/mL)
Conventional
(Batch N-1)
3 days3 days3 days3 days
or
5 days
Compressed
Seed Train
High Seed
(N-1 only)
High Seed
(N-1 & N-2)
Compressed Seed Train: facility utilization and reduced footprint
High Seed: increased manufacturing capacity, facility utilization
8 days
or
3 days3 days3 days
10 days
or
3 days3 days3 days3 days
5 days8 days
or
3 days3 days3 days
20
21. Intensified Seed Train
High Cell Density Process Intermediate
Batch
x
1-2 mL
10 - 30 .106 VC/mL N-1
or
x
Batch
MCB/MWCB Inoculum Train
Seed Train
Production
50-100 .106 VC/mL
or or
4.5 mL 50-500 mL bagCRD
CRD
N
CRD
High Cell Density Process Intermediate
CRD
Perfusion
CRD
21
23. 23
What is Biosolve® Software?
• Excel-based process model from BioPharm Services
• Limited Calculates process economics
• Database of industry averages with the option for user-
specific information
Benefits of Process Modeling
1. Focus on the “holistic process”
2. Side-by-side evaluation of alternatives
3. Can run “what if”, sensitivity analyses
4. Clear communication of value
Unique Intensified Operation Modules of
Process Modeling
1. Perfusion seed train and production options
2. Continuous chromatography
3. Flow through polishing
4. Single-pass TFF
Biosolve® Software
The Benefits of Process Modeling (Value Modeling)
24. Upstream Value Modeling
Intensified (High) Seed Train
14 days
10 days
Conventional
Fed-Batch
(~ 0.2 .106 VC/mL)
High Seed
Fed-Batch
(~ 5 .106 VC/mL)
Conventional
(Batch N-1)
3 days3 days3 days3 days
or
5 days
High Seed
(N-1 Perfusion)
High Seed: increased manufacturing capacity, facility utilization
10 days
or
3 days3 days3 days3 days
60-300 mL 1-2 L 10 L 50-200 L
1600-
2000 L
24
25. Upstream Value Modeling
Assumptions
Conventional
Train
N-2
(Batch)
N-1
(Fed-Batch)
Production
(Fed-Batch)
Harvest Product
Titer
Reactor
Volume
200 L 500 L 2000 L 5 g/L
Duration 3 Days 5 Days 14 Days -
High Seed
Train
N-2
(Seed)
N-1
(Perfusion)
Production
(Fed-Batch)
Harvest Product
Titer
Reactor
Volume
50 L
Batch
200 L
(2 VVD)
2000 L
Fed-batch
5 g/L
Duration 3 Days 10 Days 10 Days -
• Value modeling focus on
upstream only (all other
processes held constant)
• Seed train bioreactor volumes
differ based on feed-in ratios
• High seed train scenario
duration 1 day longer than
base-case
• Production bioreactor run
is 4 days shorter
or
N-2 Seed N-1 Seed Production Centrifugation
Depth
Filtration
Full DSP
25
26. Upstream Value Modeling
Comparison with High Seed Train Scenario
11.5% COGS reduction with
High Seed Train Scenario
• N-2 reactor through depth filters
COGS Contribution
Lower COGS with High Seed Train despite higher media costs
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
26
27. Upstream Value Modeling
Impact on Plant Throughput
• High Seed Train Scenario provides:
• Shorter time in production
bioreactor
• Increased batches per year
• Additional production bioreactors
deliver further increase in capacity
High Seed: increased manufacturing capacity, facility utilization
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
27
30. Toolbox Approach
Flow Through Polishing
Leached
Protein A
Aggregates
Virus
Host Cell DNA
Host Cell Protein
Others?
(Fragments,
Charge Variants)
Chemistries Matrices Devices
30
31. 3
1
Flow Through Polishing
Existing Toolbox
▪ Eshmuno® CP-FT resin
Flow through aggregate removal at high
loading
5 – 10X buffer reduction
Easy implementation
▪ NatriFlo® HD-Q AEX membrane
Impurity clearance at high loading
High velocity operation (~1 sec RT)
▪ Millistak+® Pod CR depth filter
Activated carbon media
Binding: van der Waals interactions
Size-based selectivity
Impurity (MW) Capacity
Insulin 60 g/L
Methotrexate 75 g/L
Pluronic® F68
surfactant
75 g/L
Antifoam C > 16 g/L
31
32. Low pH
VI Pool
Virus
Filter
Pool
Carbon Depth Filter
+ FT-AEX
FT-CEX
+ Virus Filtration
In-line pH
Low pH
VI Pool
Depth
Filter
Pool
CEX
Pool
AEX
Pool
Virus
Filter
Pool
pH Adjust
& Dilution
Depth Filter Bind & Elute
CEX
FT-AEX Virus
Filtration
Traditional Batch Polishing
Flow Through Polishing
32
Batch vs. Integrated Implementation of Flow Through Technology
Robust Performance with Significant Footprint Reduction
Robust Purification across 8 Molecules
- High product yield (83 – 91%)
- Aggregates: < 1%
- Fragments: up to 1 LRV
- HCP clearance: < 10 ppm
Significant Facility Footprint Reduction
- Lower media and buffer requirements
- Eliminate intermediate hold tanks
- Single-skid operation
33. 33
Value Modeling
What Value Does FT Polishing Deliver?
Bioreactor Clarification Affinity
Chromatography
Virus
Inactivation
CEX Bind and
Elute
Flow Through AEX Viral
Clearance
Final
Filtration
Concentration &
Diafiltration
Traditional Batch
(Baseline)
Depth
Filtration
Four polishing steps run continuously without intermediate hold steps
• Lower buffer volume
• Higher loading on chromatography media and virus filter
• Smaller facility footprint for systems, columns, and tanks
Bioreactor Clarification Affinity
Chromatography
Virus
Inactivation
Final
Filtration
Concentration &
Diafiltration
Flow Through
Polishing
Activated Carbon Flow Through
CEX
Flow Through
AEX
Viral
Clearance
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
34. Assumption Activated
Carbon
AEX FT CEX FT Virus
Filtration
Technology Millistak+®
Carbon Filter
Eshmuno® Q
resin
Eshmuno®
CP-FT resin
Viresolve®
Pro filter
Yield 93% 95% 95% 98%
Capacity 1500 g/m2 3000 g/L 1000 g/L 5000 g/m2
# Re-uses Single use 150 150 Single use
# Buffers 1 5 4 0
Activated Carbon Flow Through
CEX
Flow Through
AEX
Viral
Clearance
Value Modeling
34
35. 35
Baseline Scenario vs. Flow Through Polishing
• Most significant savings capital, consumables, and labor
• Buffer reduction due primarily from switching CEX to flow through mode
10% COGS reduction
47% Buffer reduction
43% COGS reduction
87% Buffer reduction
Polishing alone… Total process…
Value Modeling Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
36. COGS Reduction with Varying Titers and Scales
Value Modeling
36
• Varying product titer and
bioreactor volume
• Comparison made between
batch and flow through
polishing processes
Benefits increase with
increasing titer &
independent of
bioreactor scale
37. 37
Value Modeling – Baseline vs. FT Polishing
Impact on buffer volumes & facility footprint
CEX Bind and
Elute
Flow Through AEX
Virus
Filter
Depth
Filtration
Activated
Carbon
Flow Through
CEX
Flow Through
AEX
Virus
Filter
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
38. 38
Value Modeling – Baseline vs. FT Polishing
Impact on buffer volumes & facility footprint
CEX Bind and
Elute
Flow Through AEX
Virus
Filter
Depth
Filtration
Activated
Carbon
Flow Through
CEX
Flow Through
AEX
Virus
Filter
X
X X X
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
39. 39
Process Time Decreases Can Drive Output
Value Modeling
Bioreactor: 2k L fed-batch
Titer: 5 g/L Mab
Time Savings
• 72% decrease in polishing
process time
• 24% decrease in overall DSP
process time
• Replace B/E CEX contributes
most to decrease
Decreased Process Time
More Batches / Year
12.4 hours
3.5 hours
42. Summary
Through the use of process
modeling significant improvements
identified with Flow Through
Polishing:
• COGS reduction 5-10%
• Footprint reduction through
reduced buffer volumes and
hold tanks
• 72% reduction in processing
time with flow through polishing
There is an evolution happening
in bioprocessing
• Step change in business drivers
• Intensification and Connection
• Increased Flexibility & Speed,
Decreased Risk & Cost
Perfusion operations in seed train
and production bioreactor can:
• Shorten overall process time
• Increase product titer
• Enable continuous processing
with constant harvest
42