Lonza Peptides
“The trusted peptides partner,
serving your life cycle needs”
Updated 14 Apr 2011
Disclaimer
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.
The actual results may differ materially in the future from the
forward-looking statements included in this presentation due to
various factors. Furthermore, Lonza Group Ltd has no obligation to
update the statements contained in this presentation.
Note: All slides are incomplete without verbal comments.
14-Mar-16
slide 2
Nature: An unlimited source of inspiration!
“Predatory marine cone snails use a diverse mixture of peptides
known as Conopeptides in the capture of their prey …
Each cone snail may contain up to 200 peptides and given there
are over 700 cone snail species, … the library of bioactive peptides
using animal venoms is huge.”
14-Mar-16
slide 3
Nature: An unlimited source of inspiration!
Several peptides extracted from venoms are on the market:
Brand Name
Owner
Source
Captopril (Capoten)
BMS
viper venom
Prialt® (Ziconotide)
Airmid
cone snail venom
Byetta® (Exanatide)
Amylin-Eli Lilly
lizard venom
Eptifibatide (Integrilin)
Millenium/ Schering Plough
snake venom
14-Mar-16
Images FPO, Sources: www. sandesh.com,www.fotopedia.com,www.bangkokpost.com.
slide 4
Agenda

The Challenges of Custom cGMP Peptides Manufacturing

Customer Value Proposition

Lonza, The Right Peptides Partner
14-Mar-16
slide 5
Complexity by Molecular Weight
Chemical
Molecule
Peptide
Protein
Antibody
Cell / Tissue
Increasing Molecular Weight (MW)
Aspirin
(180 Da)
14-Mar-16
6mer
(804 Da)
Lysozyme
(14,700 Da)
Immunoglobulin G
(150,000 Da)
Surface of an
Animal Cell
slide 6
Process development know-how is
the key to future success

Right route selection from
the beginning based on
large-scale experience

Robust process
development

Process validation

Process optimization
14-Mar-16
slide 7
Capabilities and infrastructure are
critical to success
On average, producing 1 kg (net) of peptide generates over
5 metric tons of solvent.
Required Infrastructure

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14-Mar-16
Strategic (worldwide) sourcing
Raw materials in rail-tank-cars
Tank-farms
No open handling
Adequate warehousing
Solvent recylcing systems
Exhaust gas treatment
Waste Disposal
slide 8
Quality

Impurity Profile

Purity

Scalable Process

GMP
14-Mar-16
slide 9
HAPI Peptides
AHSK*


OEL
ADI
(Occupational
Exposure
Limit)
(Acceptable Daily Intake)
Mattplease add
challenges
1
> 1mg/m3
> 10mg/d
2
0.1-1 mg/m3
1-10 mg/d
3
0.01-0.1 mg/m3
0.1-1 mg/d
4
0.1-10 µg/m3
1-100 μg/d
5
1-100 ng/m3
0.1-1 μg/d
6
< 1 ng/m3
< 10 ng/d
Generic peptides like LHRH family are HAPIs, AHSK 5
(gosereline, decapeptil, leuprolide, busereline,
desloreline, triptorelin…)
Abarelix, degarelix are also AHSK 5
 Avoid cross contamination AND protect the people
 Low cleaning limit
* Lonza Occupational hygienic substance category
14-Mar-16
slide 10
Conjugate Peptides
Peptides are versatile platforms for product design
Lipid
PEG
Antibody
PEPTIDE
CPP
14-Mar-16
Sugar
slide 11
Purity
Purity challenges based on new regulation in 2010
95%
Pre-clinical
96-97%
Toxicology
Commercial
Phase I
>98.0%
Phase II
Phase III
European
Pharmacopeia 6.5
14-Mar-16
slide 12
FDA
New regulation will challenge peptide process development

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Stage 1: Process Design
Stage 2: Process Qualification
Stage 3: Continued Process
Verification
Process Life-cycle
Phase 0+1
14-Mar-16
Phase 2
Phase 3
Launch /
Production
Generic
slide 13
Agenda

The Challenges of Custom cGMP Peptides Manufacturing

Customer Value Proposition

Lonza, The Right Peptides Partner
14-Mar-16
slide 14
Global, Integrated, Strategic
Supply Chain

Broad network of suppliers

Negotiation power

Regular suppliers audit

Security of starting materials
supply (Group synergies,
back integration for raw
materials)
14-Mar-16
slide 15
Large-Scale Manufacturing Expertise

Multi-100 kgs of peptide API
production yearly

Large purification HPLC
capacity (up to 60 cm)

3 Technologies (SPPS,
HPPS,Recombinant DNA)

4 Sites (Belgium,
Switzerland, Czech
Republic, China)
14-Mar-16
slide 16
Benefit from Lonza synergies
during your peptide API development
14-Mar-16

Peptides Conjugates

Large-scale peptides for
non-pharma applications
(cosmetic, nutrition,
detergent, surfaces
treatment …)

Highly potent peptides

2nd generation process for
large-scale peptide
manufacturing via
recombinant technologies
slide 17
Quality by Design at Lonza
The definition
A maximally efficient, agile, flexible pharmaceutical
manufacturing sector that reliably produces high quality
drug products with less extensive regulatory oversight
A true answer to FDA expectations
Build quality in the process
 Based on sound science and knowledge
 Proactive to problems
 Control strategy based on risk assessment
 Continuous improvement and process verification
14-Mar-16
slide 18
Quality by design
A Tailored Approach in Process R&D
Process Life-cycle
process
selection
Phase 2
critical
attributes
risk
assessment
Process Design
Launch /
Production
Phase 3
design
space
control
strategy
Process
Qualification
Generic
continuous
improvement
Knowledge
Phase 0+1
Continued Process
Verification
The roadmap to process validation
14-Mar-16
slide 19
Full Regulatory Support
14-Mar-16
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DMF

CMC section
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Audit
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Inspection track records
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Corporate experience

Accreditation from Japanese
authorities
slide 20
Technology Development through
R&D Outsourcing
Modeling of Peptide Purifications
Study of Peptide Aggregation
Collaboration / thesis
Centrifugal Partition Chromatography (CPC)
Collaboration / Thesis
Nanofiltration and Molecular Imprinting
EU Program
Trade secret Automatic
Peptide Synthesizer
Collaboration
14-Mar-16
Continuous process
Thesis
SPPS and Methodology
Consulting and Route scouting
slide 21
Easy, Effective,
Regular Communication
Peptide
Specialists
Steering
Committee
QA
Customer
Worldwide
Sales
Presence
PM
Operations
Legal
Customerdedicated Data
SharePoint
We bring everyone to the table
In-house Video
Conference Tools
14-Mar-16
slide 22
Time Savings
We serve all
your life cycle
needs
Full In-house
Capabilities
30 Years of Peptide
R&D expertise
Large-Scale
Manufacturing
Know-How
14-Mar-16
slide 23
Costs Savings
Route selection, scaleup capabilities and
expertise (low-risk of
tech. transfer) based on
long-term customer
forecasts
Swiss Tax Structure:
Lonza to collaborate to
establish tax holiday
opportunities for
commercial deliveries
14-Mar-16
Strong expertise
in process scaleup and cost
improvement
Lonza Nansha
platform for ISO
needs
slide 24
Security of Supply
for Chemical Processes
Nansha, China
Small scale (100mg 10g non-GMP)
Braine, Belgium
Large scale (solid and
solution phase)
10 peptide chemists
50+ chemists/technicians
Visp, Switzerland
Large scale (solid and
solution phase)
USP + dedicated DSP
20+ chemists/technicians
Multi-Site
Financially Sound
14-Mar-16
Multi-Technologies
Backward Integrated
Peptides
slide 25
Flexibility
Unique Awareness of
Peptide Challenges
Four Shift
Systems
Experienced
Project
Management
Team
Multi-Site
Custom Synthesis Mindset
14-Mar-16
slide 26
You will benefit from IP protection

Product Life Cycle Management
meeting, including Lonza patent
support

Transparency on Lonza IP
strategy with our key customers
to better protect their products
from their competitors

We aim to protect a customer’s
product during its life cycle

Access to Lonza patents
portfolio
14-Mar-16
slide 27
Agenda

The Challenges of Custom cGMP Peptides Manufacturing

Customer Value Proposition

Lonza, The Right Peptides Partner
14-Mar-16
slide 28
Choose Lonza for: R&D
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14-Mar-16
Quality by Design
Specific R&D know-how to improve your processes
30 years of experience and successful track record
R&D peptide teams in Visp, Braine, Nansha
slide 29
Your small-scale samples platform

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milligram-scale
gram-scale
Preferred Collaboration with
California Peptide
Lonza, China
Early stage non-GMP services
to serve every step of your
product life cycle
Specific knowhow, fast and
low-cost efficient development
Dedicated peptide staff
IP protection
From mg to grams, Lonza has your small-scale platform
14-Mar-16
slide 30
Case Study: Successful Route Selection
O
NH2
O
NH2
O
OH
HO
HO
O
H2 N
O
H
N
N
H
NH
H2 N
O
N
H
O
H
N
N
H
O
O
H
N
O
N
H
HO
O
H
N
O
HO
O
O
O
N
H
N
O
O
HN
OH
O
H
N
O
O
H
N
N
H
O
N
H
H
N
O
N
H
O
HO
NH
OH
O
O
NH
Fuzeon® (T-20 Roche)
O
H2 N
HN
O
O
NHH2 N
HO
HO
O
O
HN
O
N
H
H
N
O
H2 N
O
NH2
O
O
N
H
H
N
O
HO
O
N
H
O
H
N
O
N
H
OH
O
O
H
N
O
O
N
H
NH
H
N
N
H
O
NH
H
N
O
O
OH
O
O
HN
O
NH2
HN
O
N
H
14-Mar-16
Source: 2004 Trimeris - NP2D event Zermatt, Switzerland
N
H
O
NH2
slide 31
Case Study: Quality by Design (QbD)
Bremelanotides ® (PT-141, Palatin Tech.)
O
N
H
O
H
N
O
O
O
N
H
H
N
N
H
O
O
H
N
H
N
N
H
O
OH
O
NH
N
NH
N
H
HN
+
NH3
O
H3 C
O
14-Mar-16
slide 32
Case Study: Quality by Design (QbD)
Catalyst


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Pd(Ph3)4
Pd(OAc)2 / P(oTol)3
PdCl2(Ph3)4
Factor Screening DoE
Design Space
yield Contour
150.00
79
80
81
88.5



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

14-Mar-16
HCOOH/DIEA
Dimedone
Morpholine
AcOH/NMM
Phenylsilane
Me2NH.BH3 (DMAB)
88
B: temperature
Scavengers / proton donor
82
83
147.50
876
145.00
86
Optimization DoE
85
142.50
84
80
81
82
83
83
140.00
80.00
85.00
90.00
95.00
100.00
Solution to selective Allyl/Aloc cleavage
A: rxn time
slide 33
Case Study: Synergies lead to Innovation
Semisynthesis of Bivalirudin®

Inhibition of Thrombin

Therapeutic value in angioplasty after acute myocardial infarction
Recombinant E. coli
(carboxy terminal fragment)
H-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-
+
Chemical Synthesis
(amino terminal fragment)
BOC-D-Phe-Pro-OSu
Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH
fragment condensation
deprotection
final purification
=
14-Mar-16
API (Bivalirudin®)
slide 34
Successful Regulatory Inspections
History: Lonza Braine, Belgium
Who
When
What
Remarks
FDA
2001
Pre-approval inspection
UCB Bioproducts Braine-l‘Alleud
FDA
2003
Follow up Inspection
UCB Bioproducts Braine-l‘Alleud
FDA
2005
Pre-approval inspection
Approval by 12 march 2006
FDA
June 2009
Successful GMP systems and pre-approval
inspection
FDA
February 2011
Pre-approval inspection
BI, Nansha
Korean FDA
November 2007
Pre-approval inspection
Approval, June 2008
EU Regulatories
December 2008
GMP inspection
Successful GMP inspection
14-Mar-16
slide 35
Lonza’s Visp & Nansha facilities
have a long history of successful inspections
14-Mar-16
slide 36
Let’s Share Our Peptides
Future Together!
Experienced Teams
Peptides Excellence
Customer Service
Road to Success
14-Mar-16
© Wolfgang Staudt
slide 37
Thank You