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Single Use Bioreactor Scale up: Introduction of a 2000L SUB
Equipment Train in 12 months
Finesse CellWorld San Fransisco April 2017
Claire Walsh BSc, MSc
BioProcess Skills and Technology,
Operations, Janssen Sciences Ireland
ONE TEAM Making the Difference for Patients WORLDWIDE0Finesse CellWorld San Francisco
Presentation overview:• My Story
• Janssen Sciences Ireland
• Janssen Process overview
• Brief overview of the original 1000L SUB project
–Project drivers and scope–Timeline
• Outline of the 2000L SUB Project
–Project Drivers and scope–Timelines–Engineering Run data, including Raman probe
data• Benefits and Limitations
• Q & A1April 2017Finesse CellWorld San Francisco
My Story
• Completed a BSc in Biochemistry and an MSc in Biotechnology in University College Cork
• Completed a Student Placement in PDMS in Janssen
• Travelled and worked in Australia before returning to Janssen to work in multiple roles including New Process Development Projects, Global Standardisation Projects, New Product Introductions/Tech transfers, Daily Process Support and Engineering Projects
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CorkJanssen Pharmaceutical SciencesJanssen Sciences IrelandDePuyJanssen R&D
LimerickVistakon
DublinJ&J ConsumerJ&J Medical Janssen Alzheimer ImmunotherapyJanssen (Marketing)
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CorkJanssen Pharmaceutical SciencesJanssen Sciences IrelandDePuyJanssen R&D
LimerickVistakon
DublinJ&J ConsumerJ&J Medical Janssen Alzheimer ImmunotherapyJanssen (Marketing)
Janssen Sciences Ireland
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Key Products include: Simponi, Stelara, Darazalex, Prezista, Invega Sustenna and Risperidal
Focus for the future
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Focus for the future
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Janssen Process overview
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• Clinical Suite (SUBs)
–Single Use Technology
–Fed batch process
• Commercial Suite – Stainless Steel Bioreactors– Perfusion process
Janssen Process overview
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• Clinical Suite (SUBs)
–Single Use Technology
–Fed batch process
• Commercial Suite – Stainless Steel Bioreactors– Perfusion process
Janssen Process overview
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Clinical Suite (SUBs)
Single Use TechnologyFed batch process
• Commercial Suite – Stainless Steel Bioreactors– Perfusion process
Janssen Process overview
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• Clinical Suite (SUBs)
–Single Use Technology
–Fed batch process
• Commercial Suite Stainless Steel BioreactorsPerfusion process
Disposable Cell Culture Process Train: Project Drivers
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Decision to move JNJ Platform from Perfusion to Fed Batch─ Historically Janssen Cell Culture Processes were
perfusion based
Outsource of Upstream Fed Batch Processing to CMOs─ Limited in house experience in Fed Batch
Decision made to provide back-up internal supply chain capacity for Fed Batch material
1000L SUB Project Scope
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• Capability for pre-clinical, clinical and commercial production
• Project must deliver−2 x 1,000 Single Use Bioreactors −The capability to have 2 Single Use Bioreactors in
operation with 9 months notice
• Project cannot interfere with the current clinical / commercial manufacturing schedule or approved Operational areas
• Project must cost less than $21m including all works
• The new suite must be integrated into existing Automated Systems
• Multi product capability on a campaign basis
• Maximize use of disposable technologies
Why choose to go disposable?
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• Batch Turnaround time
• Product change over capabilities
• Cleaning validation requirements–Disposable technology supports pre-clinical/early
phase production
• Installation and Qualification–Reduction in overall IOQ activities
• In-house historical disposables experience
What was the equipment selection criteria?
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• The following criteria was applied to the equipment and disposables selection process:– Bag film defined as CX514 material – An Integrator with GMP experience– Availability of novel disposables– The control system needed to integrate into the existing site
systems– Customizable Assemblies
What did the Project Deliver?
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Fully Disposable PreCulture Train
Single Use Bioreactors (SUBs)1 x 250L Seed SUB2 x 1000L Production SUB
Single Use Mixers (SUMs)Harvest Collection SUMDPC (Chromatography) StepsMedia Prep
Disposable Bio-containers for sampling and media/buffer storage
Extensive array of disposable assemblies
Project timelines
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October 2010 to July
2011
• Engineering Design, Procurement and Construction (10 months)
July 2011 to November
2011
• Commissioning and Qualification and Engineering Runs (16 weeks)
December 2011 to Feb
2012
• First Phase 1 Clinical Campaign (12 weeks)
Original Suite Layout
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Cell Culture Suite 2 Layout
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What happened next?
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• Huge amount of experience gained using disposables
• On-going Process Improvements building in extra reliability and decreasing both set-up and turnaround times
• Increasing demand in the clinical suite
………Requirement to increase capacity
2000L SUB Project Scope
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• Additional fed batch capacity required
• Install and Qualify a 2000L SUB and associated equipment train
• Detailed design required in order to maximize capacity with footprint available
• Relocate an existing processing suite to remodel for 2000L SUB
• Suite handover within 12 months
• Project must cost less than €5.1m including all works
Cell Culture Suite 2 pre-2000L SUB
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Cell Culture Suite 2 incl. 2000L SUB
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Cell Culture Suite 2
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Cell Culture Suite 2
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Cell Culture Suite 2
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Cell Culture Suite 2
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Cell Culture Suite 2
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Cell Culture Suite 2
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Project timelines
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Oct 2015 to Mar 2016
•CAR approval, Engineering Design, Procurement and Construction part 1
Mar 2016 to Aug 2016
•Construction part 2•Equipment FAT•Commissioning and Qualification
Aug 2016 to Sep 2016 (12 weeks)
•Engineering Runs
•First GMP batch thawed in PreCulture 16 Nov 2016
Complete Disposable Cell Culture Train
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PreCulture Fully Disposable
250L, 500L, 1000L and 2000L SUB Capacity
2000L and 3000L SUM Capacity
DPC and VIN SUM capacity
Process Flow (up to Viral inactivation)
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MediMea
250L/500L Seed SUB to 1000L/2000L Production SUB
2000L/3000L SUM
PreCulture Process Flow
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• Historical experience with disposables technology here (common process to the Commercial suite)
• Flask Stages from 125mL to 500mL capacity
• Wavebag stages from 2L to 50L capacity
Seed and Production SUBs
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• Seed SUB250L and 500L CapacityDeltaV Recipe Driven ControlOption to use as both a seed and a production SUBProcess duration ≤ 4 days (Product dependent)Process parameters: pH, DO, Temp, Agitation
• Production SUB1000L and 2000L capacityDeltaV Recipe Driven ControlProcess duration ≤ 21 days (Product dependent)Process parameters: pH, DO, Temp, AgitationMedia and Antifoam addition
Harvest Train
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• Centrifuge Use (not all products) Non-disposable
• Depth Filters (POD filters)– Fully disposable assembly train– Pressure sensors pre and post filter set-up
• Polishing filter post Depth Filters
• Harvest Collection SUM (2000L and 3000L capacity)– Agitation– Temperature control– Sampling points
3000L SUM: New Technology
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3000L SUM: New Technology
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Process Monitoring in the SUBs
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• pH – Controlling probes:
Electrochemical probe– Optical pH probes in the
process of being proved out
• DO– Controlling probes:
Electrochemical probe– Optical pH probes in the
process of being proved out
• Temperature– Thermowell built into the
disposable SUB bag
• Agitation – Built in sheath in the
disposable SUB bag– Shaft inserted into the
sheath prior to each batch
– This is then connected to the motor to drive the impeller
• Pressure– Built in Pressure Sensor
in the disposable SUB bag
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2000L SUB, 1000L SUB and Small Scale Satellite RunRaman Data
Engineering Run Cell Culture Data Comparison
Cell Growth Comparisons
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Cell Performance Comparisons
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Metabolite Data
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Raman Background
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Correlated the spectra to the off-line dataModel developed for each key process parameter (eg: Glucose, Lactate) you’re interested in measuring. Model development is time intensivePossible future applications include:─ Potential for use as an inline monitor, therefore
reducing the reliance on off-line instruments─ Feed cycle optimisation
* Research funded by the Irish Research Council
Raman Data: Glucose
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2000L SUB
5L Scale
Black Dots: Daily Off-line measurements
Red Line: Raman Data
Raman Data: Ammonia
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2000L SUB
5L Scale
Black Dots: Daily Off-line measurements
Red Line: Raman Data
Raman Data: Lactate
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2000L SUB
5L Scale
Black Dots: Daily Off-line measurements
Red Line: Raman Data
Benefits
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System Set up time and turnaround time
Increased Flexibility for Operations
Cross contamination risk reduction
C & Q: time savings
Reduced Capital Investment and Rapid install time
No Cleaning Validation requirements
Ease of Product Change over
Footprint saving
Design Flexibility (Bag re-design, quick and easy)
Incorporation of new technology (quicker)
Great relationship and customer experience with Finesse
Limitations
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x Scale up limitations
x Lack of a sight glass in the bag design
x Lead times on bags
x Leachables and Extractables studies
x No confirmation of integrity pre-use
x No pressure transfer
x Minimum mixing volume (other options becoming available)
Acknowledgments
• Liz Dooley
• Nicola Sheehan
• Seán Coomey
• Anne O’Leary
• Dan Olden
• 2K SUB Core Project Team
• Carl Rafferty (funded by the Irish Research Council)
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• Engineering Team in Cork
• C & Q Team in Cork
• Operations team in Cork
• Automation
• Finesse and their Support Team
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Summary
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Implemented Fully Disposable Cell Culture
Equipment Train
Installed on time and within budget
Minimal disruption to existing Operations
Integration with existing site systems
Replication of design including scale up
Data to prove successful scale up
In line with the Credo to customer and patients
Back-up Slides
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Details sent to Cell World
• Business case for 2000L SUB train – clinical capacity constraint etc.
• Background on the Design of the 2000L SUB Suite
• Engineering run and scale up data (including Ramen data)
• Comparison between Stainless Steel Manufacturing and Single Use Technology
Abstract (max 200 words):
1. CREATIVE DESIGN | Overview of the design process for the delivery of the new Cell Culture manufacturing suite. Sharing of lessons learned.
2. MEASURING SUCCESS | To demonstrate our success, we will openly share our process data comparisons of engineering runs vs lab scale for the 2000L SUB train.
3. BREAKING TRADITION | Janssen experience of breaking away from Stainless Steel manufacturing and giving Single Use a well-deserved seat at the table.
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Disposable Cell Culture Process Train
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Pre Culture 30ml – 50LSeed – SUB 250LProduction -SUB 1000L
Harvest -2000LMedia -500LProcess Vessels –200-500L
Media Preparation
• 500L Single Use Mixer (WV >100L)
• Recirculation Line
• Powdertainer addition port
• Liquid addition Lines
• Media Transfer Train
–0.45/0.22 10” Durapore filter–2 x 0.1um 4” Opticap Filters (sterile boundary)–200L Media Storage Bags
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Prove out of probes
• Advantages– Proven Technology– Process Range
• Disadvantages– Autoclaved– Polarisation Time -DO(~6Hrs)– Contamination Risk
• Advantages– Ease of Use– Integral to the Bag– Good correlation with e chem
• Disadvantages– Technology in early
development– Limited GMP instances
Electrochemical Optical
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DO Probe Trends – Batch 1
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0102030405060708090
0 2 4 6 8 10 12 14 16 18
% D
isso
lved
Oxy
gen
Culture Days
Batch 1 Reusable DO Batch 1 Single Use DO
DO Probe Trends – Batch 2
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0102030405060708090
100
0 2 4 6 8 10 12 14 16 18
% D
isso
lved
Oxy
gen
Culture Days
Batch 2 Reusable DO Batch 2 Single Use DO
DO Probe Trends – Batch 3
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0102030405060708090
0 2 4 6 8 10 12 14 16 18
% D
isso
lved
Oxy
gen
Culture Days
Batch 3 Reusable DO Batch 3 Single Use DO
pH Probe Trends – Batch 1
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6.5
6.6
6.7
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
0 2 4 6 8 10 12 14 16 18
pH
Val
ues
Culture DaysBatch 1 Reusable pH Batch 1 Single Use pH
Single Use pH Evaluation
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6.5
6.6
6.7
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
0 2 4 6 8 10 12 14 16 18
pH
Val
ues
Culture DaysBatch 2 Reusable pH Batch 2 Single Use pH
+ Procurement
+ Engineering Design
+ Construction
+ Commissioning
+ Qualification
Phase 1 Clinical Campaign+ Clinical Campaign
+ Engineering Run
14Dec11
Cell Culture Suite 2 - Project Milestone Map
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