Innovative Solutions for Manufacturing of Next … · Innovative Solutions for Manufacturing of Next Generation Cell Therapies . Dr. Nina Bauer | Lonza Ltd | Basel | 25 April 2017

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

C E LLW OR LD ¦ S A N FR A N C IS C O ¦ A P R IL 2017 2

| C E LLW OR LD ¦ S A N FR A N C IS C O ¦ A P R IL 2017 3

Content

◼◼ Introduction to Lonza

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The Patient-Specific Cell Therapy Market: CAR-T/TCR

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Scaling Robustness: From Lab Scale to Large Volume

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Achieving Commercial Viability: Manufacturing Platforms

◼◼ Summary


Content


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◼◼ Summary


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


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


Content


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◼◼ Summary

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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


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


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Example: CAR-T for Acute Myeloid Lymphoma


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


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

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Patient blood








CAR-T Therapies Need for Scale and Automation


Content


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◼◼ Summary

| C E LLW OR LD ¦ S A N FR A N C IS C O ¦ A P R IL 2017

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



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

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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


% C

D3+

T-c

ells


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


Content


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◼◼ Summary


CAR-T Therapies – Need for Automation

• Scale to meet commercial demand

• Robustness to avoid product failure

• Cost to achieve commercially viable therapies

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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



Process Translation: Upscale and Automation C

AR-T

+ C

ells

(%) 50-

25-

Manual Upscale Automation

1x 50x 50x

Fold Expansion

- 50

- 25

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Patient-Scale Manufacturing From Manual to Automation: The CocoonTM Platform



Content


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Overcoming Bottlenecks: Viral Raw Materials

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◼◼ Summary

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CAR-T Therapies A Complex Manufacturing Process


Patient blood







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CAR-T Therapies Cost Drivers


FTEs

Logistics

Facility (environmental monitoring, scale etc.)

QC, release testing


Raw Materials

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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


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


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


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

Documents

Innovative Solutions for Manufacturing of Next … · Innovative Solutions for Manufacturing of Next Generation Cell Therapies . Dr. Nina Bauer | Lonza Ltd | Basel | 25 April 2017