Applying New Biologic
Manufacturing Technologies
Anthony Mire-Sluis
Vice President, North America, Singapore, Abingdon, Contract and
Product Quality
Investing in New Manufacturing Technologies is
Benefiting Production, Compliance and Our Ability to
Deliver and Supply Products More Efficiently
• Enable speed to market (R&D and Operations)
• Similar Scale and Platform Throughout Develop Cycle
• Reduce capital investment
• Smaller Facility, Reconfigurable and Modular Design requires
less capital investment and match of capacity to current need
• Enhance compliance through standardization
and application of technology
• Rapid and in-line testing provides more real time process data
and control
• New Manufacturing technologies provide robust controls
2
Advances in Manufacturing Have Enabled Quantum
Improvements in Operating Performance
Key Technical Advances
Operational Benefits
 Up to 15 fold greater protein output
per unit volume
 Enables smaller bioreactors for same
output (2,000 Liters vs. 20,000 Liters)
 Portable equipment and disposable
technology
 Eliminates infrastructure for cleaning
and sterilization and ~45 miles of pipes
 Standardized, modular, flexible
design
 Simplifies changeovers between
molecules (from one week to one day)
 Continuous downstream protein
processing steps
 Fewer intermediate steps, less
equipment, and faster cycle times
 Real-time quality control
 Real time detection and response ability
We believe we are the first major Biotech to integrate these features into a
single commercial facility
New Manufacturing Platform Delivers the
Same Productivity With 75% Less Size
Singapore
Facility
QC Lab
Utilities
Mechanical
Support
Warehouse
~75% size reduction
Manufacturing
Admin and
Amenities
Amgen Singapore
170k sq ft ~$200M
Amgen Rhode Island
750k sq ft ~$1,000M
4
Manufacturing Advances Have Dramatic
Environmental Sustainability Impact
• Site energy consumption and waste generation is
strongly affected by WFI usage
• Reducing cleaning surfaces by >95% reduces water for
cleaning
• More efficient processes use smaller vessels and require less
water
• Smaller, more efficient site with fewer staff uses less
resources overall
• Compared to traditional stainless steel facility of same
output:
• 4-5 fold reduction in carbon emissions
• 25 fold reduction in waste water generation
• >50% reduction in total solid waste generation (process + staff)
Our Newest Facility In Singapore is a
Reconfigurable Manufacturing Facility
• First commercial facility to employ new manufacturing
platform
• Reconfigurable Manufacturing System (RMS)
• Integration of multiple technology platforms
• One building for all site operations and support
•
•
•
•
•
Manufacturing
Controlled temperature warehouse
Administration
Quality control and microbiology laboratories
Clean utilities
• Facility was built in <18 months
Amgen’s Reconfigurable Manufacturing
System is Basis for Facility Design
• High productivity in smaller reactor vessels
• New cell lines highly productive
• New media addition equipment allows for high cell density
• Substantially reduced footprint
• High utilization of single-use equipment
• Single use bioreactors (SUBs)
• Solution preparation in single use mixers
• 95% of the product contact surface is single use
• Connected/continuous purification processing
• Process advances directly to subsequent step
• Elimination of pool vessels between unit operations
Transforming the Mammalian Network Accelerates
Commercialization and Reduces Product Approval Risk
Current
pilot plant
clinical plant
commercial plant
20KL
20KL
2KL
2KL
TT
TT
TT
TT
2KL
2KL
Commercial
Commercial
Process
Process
Development
Development
(CPD)
(CPD)
Early
FIH
FIH
PD
TOX
TOX
Clinical
Clinical
(Phase 1/2)
(Phase 1/2)
2KL
2KL
Clinical
Clinical
(Phase 3)
(Phase 3)
Commercial
Commercial
TT
commercial
plant
TT
pilot plant
2KL
2KL
MoF
Titer
g/L
5 g/L
<5
Titer <
>5
Bioreactors
>5 Bioreactors
TT
TT
Technology
Transfer
Technology Transfer
2KL
2KL
Titer
g/L
20 g/L
Titer 20
(Dmab)
(Dmab)
4-6
Bioreactors
4-6 Bioreactors
FIH
FIH
Clinical (Phase 1-3)
Clinical (Phase 1-3)
& Commercial
& Commercial
TOX
TOX
FIH
Tox
8
Amgen Singapore Facility Differs from
Conventional Design in Specific Ways
• Central manufacturing suite
•
•
•
•
Cell culture through viral filtration
Closed cell culture (aseptic connections)
Closed harvest system
Reduced personnel and maintenance activities
• Area classification
• Closed Processing Systems allow for most operations to occur
in an ISO 9 central manufacturing suite
• In-line testing and rapid microbial methods allow for
enhanced process control and detection and response
to potential quality issues
The Closed Processing Controls Negate the Need for
Conventional Physically Segregation of Cell Culture,
Harvest, and Purification
Column
chromatography
and viral
inactivation
Purification Operations:
• CIP and SIP to render
closed
Harvest
Operations
Harvest:
• rotating mechanical
equipment, cell debris
Bioreactor
operations
Inoculum Prep
UF/DF
Nano
filtration
DS Fill
Bioreactor Operations:
• CIP and SIP to render
closed
Single use and sterile connection technology provides for superior
segregation and contamination controls
Facility Design and Operation Mitigates
Risk of Product Contamination
• Closed operations
• Aseptic connectors or aseptic tube weld
• Gamma-irradiated components and tubing
• No process transfer piping
• Concurrent cell culture, campaign harvest and
purification
• Faster production cycles, reduced hold times
• Single-use equipment
• No process transfer piping
• No stainless steel hold tanks or reactors in central suite
• 95% reduction in surface area requiring cleaning
Examples of Sterile Connections
Tubing Weld
Aseptic Connectors
Connected Purification Process Reduces the
Need for Large Hold Tanks
FVIP Feed
Column 1
Surge Tank
Column 2
FT – Viral Filtration
Overall Time
with Cleaning
Total Process
Time: ~10-14 hrs.
UF/DF
P
Ultrafiltration
Diafiltration
Viral Filtration
Design Controls Enable a Combined Solution
Preparation Area
• Engineering controls to eliminate cross-contamination
• Solution mixing vessels in segregated alcoves
• HEPA filtered downflow above vessels
• Antistatic single use plastic powder transfer sleeves and
connections to mixing vessels
• Mixing vessels are single use
• Gamma-irradiated single use vessels and tubing
However, Single Use Systems (SUS)
have created a complex supply chain
• A science- and risk-based approach is used to
characterize raw materials
• It is critical to understand the underlying science with
each technology in the supply chain to reduce the risk
• The science drives raw material specifications and
change controls for suppliers
• Understanding the process and raw material inputs
can control the risk of unexpected performance
• Working transparently with suppliers is key to risk
mitigation
15
What are we doing to understand the risk
profile for single use plastic technologies?
Elements of the Risk profile includes:
• Supply Chain
•
•
•
•
On-site technical due diligence visit to supply chain
Build relationships with key technical personnel at supplier
On-going Technical group exchanges
Industry competitive intelligence
• Raw Material Characterization and Biological Impact
•
•
•
Review of supplier validation technical package
Characterization studies to link variability for form, fit and function
Extractables and Leachables with model solvents
• Raw Material Qualification
•
•
Correlate raw material variability to process parameters
Finalize raw material specifications based on process variability
• Continuous monitoring / verification of performance
•
•
Correlate supplier process variability to film performance
Establish quality control testing to insure consistent performance
16
The level of understanding will depend
on risk and application
Impact to process
System Complexity
Low
Moderate
Low
Buffer Storage
Concentration
Moderate
Transport
Mixing
High
Clarification
Shipping
High
Freeze
Recovery
Cell Culture
Fermentation
Fill and Finish
Thaw
Purification
Product Storage
An understanding of three key areas is required:
1. Supply chain and manufacturing process
2. Material characterization and biological impact
3. Continuous monitoring / verification of performance
17
What are we doing to understand the risk for
integrity of the bioreactor bags?.....
•
Key levers for impact :
•
•
•
•
Variability in film
Variability in the welding process
Strength of weld
Bag design
• What is the variability of each stage (lot-to-lot)?
• What incoming, in line and release testing is
used?
• Benchmark bag handling techniques
• Can we predict “good” and “ bad” bags?
18
The disposable supply chain for single
use systems is complicated
POLYMERS
CONVERTING
ASSEMBLY
Monomers
Catalysts
Additives
Molding
Extrusion
Casting
Welding
Mechanical
STERILIZATION
Gamma
E-beam
PACKAING
SHIPPING
Boxes
Bins
Shippers
Each step can impact the quality, cost, and performance of the product
Establishing transparency and a change control process is critical to reducing
the risk profile
19
Polymer Morphology is a function of the equipment
and process used to extrude the film…..
Blown Film Process
Processing Equipment determines polymer morphology of the film surface and the
levels of extractables remaining in the film
20
Process control is critical to producing
quality film….
Bubble
Blow up ratio
Freeze zone
Collapse
Guage
Temperature
Temperature
Gauge
Black specs
Feed
Moisture content
Rate
Bulk Density
Weighing accuracy
Polymer Formulation
Winding
Temperature
Gauge
Rate
Extruder
Blocking
Die/Air ring
Screw design
Design
Wear
Temperature
Temp Profile
Temp Control
Screw speed
Backpressure
21
Films and leachables can impact
processes in various ways
• Impact on other process steps
• Small concentrations of preservatives can interact with silicone
tubing, depressing filter bubble points
• USP Class VI testing is NOT representative of cell culture
requirements
• Consider impact of films on media and SUS performance
• Impact on cholesterol dependent cells
• Impact of multiple passages
• Users have reported sensitivity of certain cell lines to certain films
• We have made similar observations for bags used for
media holds
22
Advances in Analytical Technology Are Providing
Opportunities for PAT Improvement Across the
Manufacturing Process
• Process Analytical Technologies are “a system for
designing, analyzing, and controlling manufacturing
through timely measurements…with the goal of
ensuring final product quality.”
Raw Materials
Drug Substance
Process
Labs (release and
in-process)
Drug Product
Process
Cold Chain
Management
PAT includes data acquisition and application from raw
materials to patient delivery
Traditional Paradigms for QC Testing Limit Real-time,
Data-driven Decisions and Impact Disposition Cycle Time
Workflow
Incoming QA/
Manufacturing
Sampling
Chain of
Custody
QC Testing
Electronic
Systems
Data for
Decision
Analytical cycle time limits information availability for real-time decisions
MoF analytical and testing strategy is to
move Product Testing On Line/At Line
HPLC
Cap. electro.
Identity bioassays
Host cell protein
ProA ELISA
Host cell DNA
MMV DNA qPCR
Color, app., clarity
Osmolality
pH/conductivity
UV concentration
Potency
Bioburden/endotoxin
Current
QC/Micro Lab
Automation
At-line
Bioreactor analysis
UV concentration
Light scattering
Bioburden
Endotoxin
pH/conductivity
Color/Clarity
Rapid UHPLC
Appearance
Cap. electro.
Identity bioassays
Myco./MMV qPCR
Near Future
Bioreactor analysis
UV concentration
Light scattering
Bioburden
Endotoxin
pH/conductivity
Color/Clarity
Appearance
Mass Spec
Rapid UHPLC
Myco./MMV qPCR
Future
Handheld Technology can be used for Raw
Materials and Cell Culture Medias
AAA, bench-top NIR or FTIR
Analysis
Legend:
Duration: 0.5 to 3 days
Current Process
Proposed Process
Incoming
Raw Material
Verifies RM
Doc,
Appearance &
Container
Integrity
Raw
Material
ID
Passing
ID
Release RM
for Process
RMIM
Raman
NIR
Raman
Pass
OR
Supplier:
SRE Program (i.e.
implement Raman for
certain raw materials)
Spectra
MVA Analysis to increase RM
understanding
Duration: < 1 hour
Fail
A
OR
C
RMIS:
Spectral and
eCoA data
storage
A. Single Outlier - Troubleshoot
B. Clustering – Sudden Change
C. Drifting – Gradual Change Over Time
Part of RM Info Mgmt (RMIM) Initiative
B
600
400
Process Analytical Technology Provides for
Better Control During Purification
200
0
mAU
%HMWS
UV
SEC
Lot 1
Lot 2
1000
10
800
8
On-line MALS Detection for HMWS Control
• Comparison of UV 20% peak max and on-line
MALS triggers for peak pooling, assessment of
resulting product quality by off-line SEC
• Different elution profiles from lot to lot affect
product quality due to variable HMWS in tail
7
6
%HMWS
400
4
200
2
0
kDa
mAU
%HMWS
158
1000
10
156
SEC
UV
MALS
Lot 1
Lot 2
HMWS
1548
800
152
6006
150
1484
400
146
2002
144
142
0
kDa100
%HMWS
158
10
156
110
120
130
140
150
160
170
150
160
170
150
160
170
Elution Volume, mL
MALS
SEC
154
8
152
6
150
20% Peak Max trigger
5
4
600
6
148
4
146
2
144
MALS trigger
142
0
kDa 100
158
3
2
110
120
130
140
Elution Volume, mL
MALS
156
1
154
152
0
150
Lot 1
Lot 2
148
146
144
• On-line MALS detector provides predictive
measure and better control of product quality
142
100
110
120
130
140
Elution Volume, mL
Real-time data for peak pooling improves product consistency
Implications of PAT Strategy for
Manufacturing
• Integration of operational quality control with
manufacturing
• Facility design should allow for at-line testing
• Production testing personnel should integrate into
manufacturing organization
• Scaling data-based decision making capabilities
• PAT will increase relevant, actionable data acquired
• Facility staff needs
• Increasing real time quality assurance on the floor
• Flexibility to accommodate both current and future
molecules
Thank You!