APPLYING OLD KNOW HOW TO NEW CHALLENGES: THE MANUFACTURING OF EMERGING THERAPEUTIC MODALITIES - UWE GOTTSCHALK, PHD CHIEF SCIENTIFIC OFFICER | ...
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Applying old Know How to New Challenges: The Manufacturing of Emerging Therapeutic Modalities Uwe Gottschalk, PhD Chief Scientific Officer | Lonza Pharma Biotech Zeta Symposium March 11-13 2019, Graz
Additional Information and Disclaimer
Corporate
• Lonza Group Ltd has its headquarters in Basel, Switzerland, although Lonza Group Ltd can give no assurance that these
and is listed on the SIX Swiss Exchange. It has a secondary expectations and estimates will be achieved. Investors are
listing on the Singapore Exchange Securities Trading Limited cautioned that all forward-looking statements involve risks
(“SGX-ST”). Lonza Group Ltd is not subject to the SGX-ST’s and uncertainty and are qualified in their entirety.
continuing listing requirements but remains subject to Rules
217 and 751 of the SGX-ST Listing Manual. The actual results may differ materially in the future from the
forward-looking statements included in this presentation due
• Certain matters discussed in this presentation may constitute to various factors. Furthermore, except as otherwise required
forward-looking statements. These statements are based on by law, Lonza Group Ltd disclaims any intention or obligation
current expectations and estimates of Lonza Group Ltd, to update the statements contained in this presentation.
2
Lonza and Lonza Pharma & Biotech At a glance Lonza Pharma & Biotech | Overview | 2018
Lonza at a glance
Key Figures
“A trusted supplier to the pharmaceutical, biotech and specialty ingredients markets”
Active Patent
Families Countries with
Manufacturing and Offices / Sites Sales in 2018
R&D Facilities
in CHF
Worldwide
Successful Product-
Related Audits in
2018
Founded Employees
by the End of
2018
Key figures include recently acquired Capsugel
Lonza Pharma & Biotech | Overview | 2018 4
Lonza at a Glance
Delivering synergies with connected technology platforms and fields of expertise
Pharma & Biotech Specialty Ingredients
Custom Development Consumer Coatings &
Health & Nutrition Composites
Custom Manufacturing
Consumer Product Agro Ingredients
Ingredients
Delivery and Bioscience
Solutions Water Care
PRESCRIPTION PREVENTION PROTECTION PRESERVATION
Lonza’s Healthcare Continuum Spans All Our Businesses
Lonza Pharma & Biotech | Overview | 2018 5
Our offer spans across broad range of technologies
Chemical Biologics
Drug substance technologies in mammalian and
small molecules, Bioconjugates microbial expression
HAPI, cytoxics, systems, cell, gene and
intermediates viral therapy
Oral
dosage forms Parenteral
Drug product & delivery drug product
systems services
Hard capsules
Soft capsules
Lonza Pharma & Biotech | Overview | 2018 6
Lonza supported >300 large molecule
therapies* in 2018
305
therapies in clinical
25
commercial APIs and
development intermediates
* Includes mammalian and microbially expressed medicines, bioconjugates, cell and viral therapy
Lonza Pharma & Biotech | Overview | 2018 7
Lonza supported >500 small molecule
therapies* in 2018
270
therapies in clinical
265
commercial APIs and
development intermediates
* Includes chemicals, HPAPI, peptides; includes dosage forms and delivery systems programs
Lonza Pharma & Biotech | Overview | 2018 8
Overview of Recent Key Investments and Growth Projects
Enabling Lonza to evolve our offerings with new technologies and new business models
Faster, agile,
Business models
commercial Exclusive licence
manufacturing Akuous for in vivo
New
gene therapy
gene to BLA2 Collaborative
(Anc AAV1)
Innovation Center
Customer Customer
Cell & gene therapy opening
monosuite monoplant
Sanofi JV (biologics) (Houston, TX, USA) (small molecules) (Haifa, IL)
2017 2018
Technologies
Dosage & delivery U.S. biologics clinical
(small molecules) development 2K biologics Small-scale biologics
6K mid-scale
Acquisition Capsugel (Hayward, CA, USA) single-use (Guangzhou, CN)
hybrid biologics
& Micromacinazione (Portsmouth, NH, (Singapore, SG)
USA)
Cell & gene EU site Parenteral dosage in silico & in vitro CocoonTM
(Geleen, NL) forms for biologics services for biologic autologous cell-
(Basel, CH) drug design therapy
1Anc AAV: Ancestral Adeno Associated Virus (Cambridge, UK) manufacturing
2BLA:
3API:
Biologics License application
Active pharmaceutical ingredient
system
Ibex™ Solutions in Visp (CH) – Expansion with New, Innovative Offerings
Launching Ibex™ Design and Ibex™ Develop with offerings from preclinical through to commercialization – including fill & finish
Existing Lonza Site
IbexTM SolutionsAdaption to a changing market
2006
1980s Microbial 2010
Small Viral vector
molecules gene therapy
1996
Mammalian &
monoclonal 2017
antibodies Capsugel
2007
ADCs
Cell therapy
11Five Technologies That Will Disrupt
Healthcare By 2020*
Artificial Intelligence: CAGR of 42% to reach $6.6 billion in
Immunotherapies: Checkpoint inhibitors growing at 139% CAGR
Liquid Biopsy: Potential to monitor tumors non-invasively
CRISPR/Cas9: Disrupting the way R&D is conducted and products are developed
3D Printing: Game changer for organ or tissue repair
*http://www.forbes.com/sites/reenitadas/2016/03/30/top-5-technologies-disrupting-healthcare-by-2020/#32b7aca36252Going forward, where do we expect Disruption?
Therapeutic Modalities Disruptors
Antibiotics Microbiotics/Phages
Vaccines RNA/Nucleic Acids
Proteins mRNA/Gene Therapy/IPSCs
Cell Therapy (allogeneic) Exosomes
Gene Therapy Gene Editing/CRISPR
Enabling Platforms
Single Use technologies Integrated process chains
Mammalian cell culture Synthetic biology
Centralized large scale facilities GMP in a box/Point of care
(Pharma Model) manufacturing
High Throughput Screening Predictive in silico toolsInnovation Waves in Biomanufacturing
Personalized
Continuous
Single Use
FermentationThe Evolution of Cancer Therapeutic Agents
Small Peptide Protein Antibody Immune
Molecule Cell
Increasing Molecular Weight (MW)
Ibrutinib Thymosin alpha L-Asparaginase Immunoglobulin G Surface of a T-
(440 Da) (10 kDa) (14,7 kDa) (150 kDa) Cell
16Antibodies were the Starting Point for Targeted Therapies
1997 2011 2015
17The cell and gene therapy market
A global, growing market
130 78
Europe
& Israel Asia
500+
Cell and gene therapy
companies worldwide, developing 24
Japan
over 1,300 products
257
Market growth of 27% North America
(CAGR 2014-2017)
3 13
South
Australia &
America
New Zealand
Citeline Dec 2017
18Industrialization of Cell and Gene Therapy Manufacturing
Our Cell and Gene Therapy Network
A global footprint
Geleen, Netherlands
Portsmouth, USA
Nikon CeLL innovation Co., Ltd.*
(Walkersville, USA)
Tokyo, Japan
Houston, USA
Largest dedicated cell & gene facility in the world
Tuas, Singapore
Cell & Gene Therapy Cell & Gene Therapy including Viral Vector Gene Therapy
*This facility is owned and operated by Nikon CeLL innovation Co., Ltd. under Nikon-Lonza Partnership.
20End to End Single Use Manufacturing
A Reality in Viral Vector Production
rs
e rato
Sepax
Inoculum
Stage
Viral Products
tion
sets)
or l ib
ve s
ACS,
s
e nti a
t hold
Inoculum Bulk Fill &
R, wa
pump
Unit Operations
s
Expansion Filtration
Cl iniM
i on
ve s
i on
r
ls
e
diffe r
a teri a
t
r oduc
isrup
t
fil trat
ovial s
R , wa
or ST
a
g /
r
*
a
n
in
,
2991
p
arati o
n, ce ll
tion m
er s, d
aphy
s (tub
ffer, p
i a pre
r eact
ors ST
g, cry
flow
(product rather than suite
ion
COBE
atogr
fi ltra t
ola tio
r pre p
Fl ask
ge niz
nsfer
ction
ct fil l
ifug a
anki n
, med
ntial
dependency)
a, bu
rea ct
fi ll
Chrom
,
Production
Homo
Produ
Produ
Ta nge
Shake
El utra
All tra
Mic ro
Cel l is
Centr
Buffe
UF/DF
Medi
Cel lb
See d
Fee d
Bul k
Bioreactor
Houston-Viral Products 100L Wave n.a. n.a. 1
Houston-Viral Products up to 2000L SUB n.a. n.a. 1
Houston-Viral Products - Cell Therapy n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.
* disposable flow
* disposable
path flow path
Cell Polishing
Separation & and Virus single-use, disposable
Filtration Filtration
steel
fully disposable path, alternatively buckets single-use
Capture and
Viral UF/DF
Inactivation
21Use of Single Use Technologies for Clinical Supply of Protein
Drugs
2015
100% 100% 30% 79% 100% 96%* 0% 100%
Clinical
2016
100% 100% 69% 100% 100% 92%* 0% 100%
Clinical
2017
100% 100% 73% 100% 100% 95%* 8% 100%
Clinical
Seed Production Bulk
Inoculum Harvest Buffers Chromatography Ultrafiltration
Reactor Reactor Fill
Wave System Sterile bags Levtech Mixer
Sterile bottles
POD System Sterile bags
Disposable
Chromatography
Sterile bags flowpath
Single Use
Bioreactor
Sterile bags Sterile filter capsules
Sterile bags
Levtech Mixer
Sterile filter capsules
Automated and
Sterile bags manual UF rigs
Sterile filter capsules
Pre packed
Tank Liners Sterile bags columns Membrane
Tank Liners Tank Liners chromatography
Thaw Fill
22Allogeneic vs Patient-Scale Manufacturing
Allogeneic model Patient-scale model
Generation
MCB/WCB
Master
Cell Bank
Working
Therapeutic cell
Cell Banks
production
Lot: Patient
Doses
Therapeutic cell
vs
production
Lot: Patient
Doses
• off-the-shelf • patient-specific, often gene-modified
• large batches • Small batches (patient-scale)
• one donor – many patients • one donor – one patient – one batch
23Lessons learned from 25 Years in Mammalian Cell Culture
now applied to 3D – The Quantity Aspect
Product Titre (mg/L)
600 Cell
9550
Factories
8300
5900
3560
80 times higher
1900 efficiency
140 330 Lonza launches GS™
40 590 Expression Platform
1990 1992 1994 1996 2000 2003 2005 2008 2009
YEAR
One 200L Bioreactor
24Lessons learned from other Industries
“Automation applied to an efficient operation
will magnify the efficiency.
Automation applied to an inefficient
operation will magnify the inefficiency.”
Bill GatesManufacturing Footprint for 1 Trillion Cells/batch
2D manufacturing 3D manufacturing Exosomes - The next “Small” Things
356
ft2
3375 ft2
26Patient-Specific Manufacturing – Facts and Strategies
Big batches are here to stay, but Nobody will stop
Personalization …
Number of drug products
Number of patients per group
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf
28CAR-Therapies Complex Manufacturing
Multiples source of errors: 14 steps 57h Hands-on Time
Reprogrammed CAR-
T cells targeting
malignant cancer
• Robustness to avoid product failure cells
T-cells Genetic engineering; viral
• Efficiency to achieve commercially or non-viral
viable therapies
Patient
• Scale-out to meet commercial blood
demand Inactive Virus
w/ Gene
• Proximity to patient due to logistical
challenges Chemotherapeutic
pre-conditioning
• Key components to reduce the Cancer patient /
donor
complexity in the supply chain Cancer
patient/
donor
29The Manufacturing Process and its Implications
Example: CAR-T for Acute Myeloid Lymphoma *AML in US
20,830 new cases p/y in
2015
14 day process
per patient
Initiating 55 new Ending 55
patient processes 770 patient processes patient processes
per day per day
running in parallel
Performing a process step every other day for 385 patients
Manufacturing Space: ~70.000 sqft Total of 495 discrete
Headcount: ~3.700 process actions per
Risk of Process Failure: High day
Implications for:
Cost, space, manpower, instrumentation, logistics, cleaning, sterility, deviations, cross
contamination, ultimately severe implications for patients
30Looking for a Manufacturing Solution Looking at automation, but what type of automation?
Conventional Automation
Radical Change of Concept
Automation (Robotic / Autonomous (Intelligent &
Non Integrated) Fully Integrated)
32Manufacturing Facility
Efficiencies
120%
100%
80%
60%
40%
20%
0%
suite space facility build-
out/maintenance
conventional Cocoon™ Trees
35Allogeneic vs Patient-Scale Manufacturing
Allogeneic model Patient-scale model
• Scaled Up and • Scaled out and
Centralized Decentralized
• Integrated and contained
• Automated and controlled
• Single Use
36In Conclusion: Single-Use Concepts are early in the Point of
Care Roadmap
Longer Term
Near-Term (15-20 yr)
(5-10 yr) • Implantable biologics
factories
Now • Patient-Scale, • Cell-free systems on
Decentralized mircrochips
• Single Use • On-demand
manufacturing • Bedside manufacturing
concepts
• Future Facility
Legacy SBCN ¦ 14. May 2018
• “Blockbuster”
pharma models
37To conclude Pharma&Biotech The future of biomanufacturing will not just be an extrapolation of the past; change is accelerating Personalization will be the next mantra Personalized anufacturing will benefit from biomanufacturing legacy – and vice versa
the next solution…
We’ll find it together.
Bioprocessing Asia – Malaysia 2018 39You can also read
