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Dr Nina Bauer | Lonza Ltd | Basel | 14 September, 2016
Innovative Solutions for Manufacturing of Next Generation Cell Therapies Dr. Nina Bauer | Lonza Ltd | Basel | 25 April 2017
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Forward-Looking Statement
Certain matters discussed in this presentation may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved. Investors are cautioned that all forward-looking statements involve risks and uncertainty and are qualified in their entirety. The actual results may differ materially in the future from the forward-looking statements included in this presentation due to various factors. Furthermore, except as otherwise required by law, Lonza Group Ltd disclaims any intention or obligation to update the statements contained in this presentation
The information contained herein is believed to be correct and corresponds to the latest state of scientific and technical knowledge. However, no warranty is made, either expressed or implied, regarding its accuracy or the results to be obtained from the use of such information. For research use only. All trademarks belong to Lonza or its affiliates or to their respective third party owners. ©2016 Lonza. Inc. All rights reserved
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
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Lonza Pharma&Biotech
1897
Foundation of Lonza
1983
Start of biotechnology
research activities in Visp
(CH)
2011
Expansion of Cell Therapy
Manufacturing to Tuas, Singapore
Launch of 4D-Nucleofector™ LV
Unit
2016 1996
Acquisition of Celltech Biologics
2007
Acquisition of Cambrex
(Lonza Walkersville)
2010
Acquisition of Vivante (Lonza
Houston)
2012
Lonza Houston’s First 2000L Viral Batch
2008
Acquisition of Amaxa (Lonza
Cologne)
Partnership Agreement with
Octane
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Lonza – Cell and Gene Therapy Network Strategic investments for global network with high standards
Cologne GER
Tuas Singapore
Portsmouth US
Walkersville US
Houston US
Tokyo Japan READY 2017
Cell Therapy Viral Therapy Biosciences joint sites
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
|
Patient-Specific Cell and Gene Therapy Market
Patient-specific therapies 48% of the development pipeline Significant growth CAGR 2010-2015 24% Key segment immune therapies (e.g. CAR-T)
Allogeneic,
52%
Patient-Specific,
48%
0
20
40
60
80
100
120
140
160
180
200
2010 2011 2012 2013 2014 2015
Patient-Specific CT Products Phase III Phase II Phase I Preclinical
2010-2015 CAGR
24%
Sources: Citeline March 2016
Num
ber o
f Pro
duct
s
Clinical Pipeline
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CAR-T Therapies A Complex Manufacturing Process
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Patient blood
T-cells Genetic engineering; viral or non-viral Reprogrammed
CAR-T cells targeting malignant cancer cells
Cancer patient/ donor
Inactive Virus w/ Gene
Chemotherapeutic pre-conditioning
Cancer patient/ donor
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Example: CAR-T for Acute Myeloid Lymphoma
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14 day process per patient
770 patient processes
running in parallel
Performing a process step every other day for 385 patients
Total of 495 discrete process actions per day
Implications for:
Cost, space, manpower, instrumentation, logistics, cleaning, sterility, deviations, cross contamination, ultimately severe implications for patients
Initiating 55 new patient processes per day
Ending 55 patient
processes per day
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Example: CAR-T for Non-Hodgkins Lymphoma
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14 day process per patient
3836 patient processes
running in parallel
Performing a process step every other day for 1925 patients
Total of 2475 discrete process actions per day
Automation is required for out-scaling!
Initiating 274 new patient processes per day
Ending 274
patient processes
per day
|
Patient blood
T-cells Genetic engineering; viral or non-viral Reprogrammed
CAR-T cells targeting malignant cancer cells
Cancer patient/ donor
Inactive Virus w/ Gene
Chemotherapeutic pre-conditioning
Cancer patient/ donor
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CAR-T Therapies Need for Scale and Automation
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
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Non-Viral Technologies and Nucleofection
14
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NEW! Large Scale Nucleofection 4D-Nucleofector™ LV
For research use only. Not for direct use in humans or for diagnostic purposes
New functional add-on unit for 4D-Nucleofector™ System Allowing for closed, scalable Nucleofection of larger cell numbers in the range of 1x107 to 2x109
Flexible 1 ml or 20 x 1 ml filling configurations Can be operated via 21CFR part11 compatible software Tested for many cell types, including human T cells and CD34+ cells
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Two Large-Scale Formats 1 mL Nucleocuvette™ Cartridge & LV Nucleocuvette™ Cartridge
Automatic filling via reservoirs (or bags) 20x1mL
Manual filling via sterile injection port
1mL
|
Demonstrated Scalability DNA Vector & CRISPR/Cas9
Transfection of human PBMCs with pmaxGFP™ Vector
0
20
40
60
80
100
100 µL 1 mL LV10 mL
100 µL 1 mL LV10 mL
EO-115 FI-115
Cell conc.: 3-5x10e7/mLSubstrate: 20 µg/mL
Effiency (%) PI neg cells (%)
0
10
20
30
40
50
60
70
Day 2 Day 4 Day 6 Day 8
% In
dels
X UnitVolume: 20 µLCells: 5x10e7/mLCas9: 300 µg/mL…
LV UnitVolume: 4 mLCells: 2.95x10e7/mLCas9: 150 µg/mL…
Data kindly provided with permission by M. Porteus, Stanford University
Transfection of Cas9/gRNA ribonucleoprotein into pre-stimulated human T cells
Data represent the mean of various independent experiments
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% C
D3+
T-c
ells
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Human T cells were transfected in small scale (100 µL) or large scale (1 mL) with either GFP mRNA or ZFN mRNA
Cel1 analysis at different time points post transfection
Data kindly provided by C. Bovolenta, MolMed S.p.A., IT and P. Genovese, San Raffaele Telethon Institute for Gene Therapy, IT
X Unit 100 µL
LV Unit 1 mL
Exp 1 Exp 2
1x10e8 cells/mL
Demonstrated Scalability ZFN mRNA Transfection
X Unit 100 µL
LV Unit 1 mL
Exp 1 Exp 2
1x10e8 cells/mL
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
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CAR-T Therapies – Need for Automation
• Scale to meet commercial demand
• Robustness to avoid product failure
• Cost to achieve commercially viable therapies
|
Octane Cocoon™ Manufacturing Platform
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Closed, Automated, Scalable
Multiple unit operations integrated into a closed, disposable unit Digesting, seeding, washing, perfusion,
expansion, harvesting, concentrating, washing
Maintains temperature and gasses
Monitors pH and DO
Integrated 4ºC Cold Chamber for process reagents Media, enzymes, other additives
Information logging and control Electronic batch records
Full sample and product traceability
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CAR-T Optimization and Scale-Up Considerations
Real-time analytics to evaluate product
Successful Lentiviral transduction Multiplicity of infection? Donor-to-donor variability
Feeding / expansion strategy Culture time length Appropriate scale-up of culture Cytokine selection
3 28
Activation conditions using CD3/CD28 beads Volume? Time? Donor-to-donor variability
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Process Translation: Upscale and Automation C
AR-T
+ C
ells
(%) 50-
25-
Manual Upscale Automation
1x 50x 50x
Fold Expansion
- 50
- 25
|
Patient-Scale Manufacturing From Manual to Automation: The CocoonTM Platform
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Content
◼◼ Introduction to Lonza
◼◼
The Patient-Specific Cell Therapy Market: CAR-T/TCR
◼◼
Overcoming Bottlenecks: Viral Raw Materials
◼◼
Scaling Robustness: From Lab Scale to Large Volume
◼◼
Achieving Commercial Viability: Manufacturing Platforms
◼◼ Summary
|
CAR-T Therapies A Complex Manufacturing Process
C E LLW OR LD ¦ S A N FR A N C IS C O ¦ A P R IL 2017 27
Patient blood
T-cells Genetic engineering; viral or non-viral Reprogrammed
CAR-T cells targeting malignant cancer cells
Cancer patient/ donor
Inactive Virus w/ Gene
Chemotherapeutic pre-conditioning
Cancer patient/ donor
|
CAR-T Therapies Cost Drivers
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FTEs
Logistics
Facility (environmental monitoring, scale etc.)
QC, release testing
Cancer patient/ donor
Raw Materials
|
Complete Solutions for Patient-Scale Manufacturing
Development & manufacturing
platforms
Proven expertise
Customer focus
Full service offering
Successful research tool portfolio with >900 products
Decades of experience in cell and viral-based GMP experience
> 40 viral GMP projects, >70 clinical cell therapy products
4D-Nucleofector™ LV Unit
Autologous automation with the Octane CocoonTM
Viral vectors and vaccines (including AAV, Adeno, Lenti and others)
Cell factory to bioreactor, and 2D to 3D
Gene modified cell therapies
From pre-clinical to commercial drug product supply
From virus seed development to process validation
Outscalable patient-specific manufacturing options
Flexible offerings suiting customer needs from small biotech start-up to large pharmaceutical company
Global footprint
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Investment of ~110 mn CHF since 2010 Early Technology Adopter
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Thank You
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Viral Manufacturing Keeping Step with T-Cells
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pre-clinical phI/IIa phIIb phIII
T-cells >100 >50 >10 doses
Viral vectors doses
Commercial CAR-T
product
Robust and
scalable process
Inducible producer cell line Harvesting
technologies Fill finish operations
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Viral Manufacturing Services Access to fully
characterized cell lines used in GMP operations
Mammalian and insect cell cultures
Inducible producer cell line
Robust and
scalable process
Optimization of critical cell culture parameters
Process scale-up to 2000L
Experience with broad range of virus types, incl. AAV and lenti
Harvesting technologies
Optimization of cell lysis and harvest clarification conditions
Development of chromatographic purification methods
Fill finish operations
In-house expertise Entirely new business
unit dedicated to drug product
Pearland, Houston, 2017: Clinical and commercial
manufacturing Viral vectors Virally modified cell products incl.
CAR-T
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