applying new biologic manufacturing technologies...qc lab mechanical support manufacturing utilities...
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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
Up to 15 fold greater protein output
per unit volume
Key Technical Advances Operational Benefits
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
Mechanical
Support
Manufacturing
Utilities
Warehouse
Admin and
Amenities
Amgen Rhode Island750k sq ft ~$1,000M
Amgen Singapore 170k sq ft ~$200M
~75% size reduction
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
Cu
rren
t
pilot plant clinical plant commercial plant
pilot plant commercial plant
Mo
F
CommercialClinical
(Phase 3)
FIH
TOX
Commercial
Process
Development
(CPD)Clinical
(Phase 1/2)
FIH
2KL
2KL 2KL 2KL
20KL
2KL
Clinical (Phase 1-3)
& CommercialTOX
Technology Transfer
TT
Titer < 5 g/L
Titer 20 g/L
(Dmab)
>5 Bioreactors
4-6 Bioreactors
TTTTTT
CommercialClinical
(Phase 3)
FIH
TOX
Commercial
Process
Development
(CPD)Clinical
(Phase 1/2)
FIH
2KL
2KL 2KL 2KL
20KL
2KL
Clinical (Phase 1-3)
& CommercialTOX
Technology Transfer
TT
Titer < 5 g/L
Titer 20 g/L
(Dmab)
>5 Bioreactors
4-6 Bioreactors
TTTTTT
FIH
Tox
Early
PD
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
Bioreactor
operations
Harvest
Operations
Column
chroma-
tography
and viral
inactivation
Na
no
filtra
tion
Inoculu
mP
rep
UF/DF
DS Fill
The Closed Processing Controls Negate the Need for Conventional Physically Segregation of Cell Culture, Harvest, and Purification
Purification Operations:
• CIP and SIP to render
closed
Harvest:
• rotating mechanical
equipment, cell debris
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
Aseptic Connectors
Tubing Weld
FVIP Feed
Column 1 Column 2
Viral Filtration
UF/DF
Surge Tank
P
Total Process
Time: ~10-14 hrs.
Overall Time
with Cleaning
FT – Viral Filtration
Ultrafiltration
Diafiltration
Connected Purification Process Reduces the Need for Large Hold Tanks
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
For Internal Use Only. Amgen Confidential.
16
17
System Complexity
Low Moderate High
Imp
ac
t to
pro
cess
Low Buffer Storage ConcentrationClarification
Recovery
Moderate Transport
Shipping
Mixing Cell Culture
Fermentation
High Freeze
Thaw
Fill and Finish 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
The level of understanding will depend on risk and application
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
19
POLYMERS
Monomers
Catalysts
Additives
CONVERTING
Molding
Extrusion
Casting
ASSEMBLY
Welding
Mechanical
STERILIZATION
Gamma
E-beam
PACKAING
SHIPPING
Boxes
Bins
Shippers
The disposable supply chain for single use systems is complicated
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
Polymer Morphology is a function of the equipment and process used to extrude the film…..
20
Processing Equipment determines polymer morphology of the film surface and the
levels of extractables remaining in the film
Blown Film Process
Process control is critical to producing quality film….
21
Feed
Moisture content
Rate
Bulk Density
Weighing accuracy
Polymer Formulation
Extruder
Screw design
Wear
Temp Profile
Temp Control
Screw speed
Backpressure
Die/Air ring
Design
Temperature
Bubble
Blow up ratio
Freeze zone
Guage
Temperature
Winding
Temperature
Gauge
Rate
Blocking
Collapse
Temperature
Gauge
Black specs
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
Raw Materials Drug Substance
Process
Labs (release and
in-process)
Drug Product
Process
Cold Chain
Management
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.”
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
Analytical cycle time limits information availability for real-time decisions
Incoming QA/Manufacturing
SamplingChain of Custody
QC TestingElectronic Systems
Data for Decision
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
Bioreactor analysis
UV concentration
Light scattering
Bioburden
Endotoxin
pH/conductivity
Color/Clarity
Bioreactor analysis
UV concentration
Light scattering
Bioburden
Endotoxin
pH/conductivity
Color/Clarity
Appearance
Current Near Future Future
Rapid UHPLC
Appearance
Cap. electro.
Identity bioassays
Myco./MMV qPCR
Mass Spec
Rapid UHPLC
Myco./MMV qPCR
QC/Micro Lab
Automation
At-line
Handheld Technology can be used for Raw Materials and Cell Culture Medias
Raw
Material
ID
Release RM
for Process
Raman
Supplier:
SRE Program (i.e.
implement Raman for
certain raw materials)
A
BC
MVA Analysis to increase RM
understanding
A. Single Outlier - Troubleshoot
B. Clustering – Sudden Change
C. Drifting – Gradual Change Over Time
Part of RM Info Mgmt (RMIM) Initiative
Verifies RM
Doc,
Appearance &
Container
Integrity
Incoming
Raw Material
Spectra
NIR
RMIS:
Spectral and
eCoA data
storage
RMIM
AAA, bench-top NIR or FTIR
Analysis
Duration: < 1 hour
Duration: 0.5 to 3 days
Pass Fail
Legend:
Current Process
Proposed Process
Raman
OR OR
Passing
ID
• Comparison of UV 20% peak max and on-lineMALS triggers for peak pooling, assessment of resulting product quality by off-line SEC
• Different elution profiles from lot to lot affectproduct quality due to variable HMWS in tail
• On-line MALS detector provides predictivemeasure and better control of product quality
Process Analytical Technology Provides for Better Control During Purification
On-line MALS Detection for HMWS Control
Real-time data for peak pooling improves product consistency
0
2
4
6
8
10
%HMWSSEC
Elution Volume, mL
100 110 120 130 140 150 160 170
142
144
146
148
150
152
154
156
158
kDaMALS
400
600
800
1000
mAUUV
200
Lot 1Lot 2
0
0
1
2
3
4
5
6
7
Lot 1 Lot 2
%H
MW
S
20% Peak Max trigger
MALS trigger
0
2
4
6
8
10
%HMWSSEC
Elution Volume, mL
100 110 120 130 140 150 160 170
142
144
146
148
150
152
154
156
158
kDaMALS
400
600
800
1000
mAUUV
200
Lot 1Lot 2
00
2
4
6
8
10
%HMWSSEC
Elution Volume, mL
100 110 120 130 140 150 160 170
142
144
146
148
150
152
154
156
158
kDaMALS
400
600
800
1000
mAUUV
200
Lot 1Lot 2
0
HMWS
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!