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Advanced Chemical Synthesis
slide 2 28-Oct-11
Agenda
What’s New
Offering
Capabilities
Development Services
Facilities
slide 3 28-Oct-11
We are continually strengthening our
offering and technological know-how
Microreactor Technology
Multiple hundreds of kilograms per campaign
Several cGMP tons in just weeks
Nansha, China
Small-scale (200L) and large-scale (10m3) plants
Antibody Drug Conjugates (ADCs)
Lab-scale, development and commercial facility on-line
Highly Potent APIs (HPAPIs)
Large-scale (10m3) available
Complementary to existing launch trains (630L; 2.5m3)
slide 4 28-Oct-11
Agenda
What’s New
Offering
Capabilities
Development Services
Facilities
slide 5 28-Oct-11
Flexible production sites allow us to
meet a wide range of customer needs
Kouřim, CZ
Braine, BE
Portsmouth
Singapore
Slough, UK
Porriño, SP
Walkersville
Verviers, BE
Visp, CH
Hopkinton Visp – Switzerland 10L to 10m3 cGMP – over 700m3
(kilo lab, small-, mid- and large-scale)
Highly Potent API plant
Microreactor Technology
Antibody Drug Conjugate plant
cGMP phosgene plant
Backward integration (non-GMP/ISO)
Process R&D Services
Nansha / Guanhzhou
Nansha / Guahnzhou – China
Advanced Chemical Synthesis 6 x 250L cGMP
10m3 multi-purpose cGMP trains
Process R&D Services
Backward integration (non-GMP/ISO)
Peptides Solid and liquid-phase technologies
slide 6 28-Oct-11
Lonza’s capabilities and expertise
lead the industry
State-of-the-Art Technology
Integrated technology-driven production systems with
strong proprietary know-how
Continuously adapted broad bio/chemical technology
base and autonomous waste disposal systems
Global Footprint
Production facilities in Switzerland and China
Multi-purpose plants to handle any size project and
ensure seamless scale-up
Products
Early and Advanced Intermediates, APIs
slide 7 28-Oct-11
basic
research
disease
discovery
drug
discovery
drug
development
clinical
trials production packaging
marketing
sales
distribution
Discovery Development Manufacture Distribution
We offer a full range of cGMP
manufacturing services*
clinical
supply
lab supply
launch
supply
in- market supply
Small-scale plants
22 reactors
(up to 250L)
R&D (70 labs)
Launch-scale plants
27 multi-use trains
(250 - 3,000L)
Production sites (over 750m3)
kg labs (10 - 30L
glass vessels)
*Peptides excluded
slide 8 28-Oct-11
Agenda
What’s New
Offering
Capabilities
Development Services
Facilities
slide 9 28-Oct-11
Hazardous
HCN / ClCN /
chlorosulfonyl isocyanate
Ketene / diketene
Phosgene (cGMP)
Carbonylation
Highly Active
OEL ≥ 0.1 μg/m3 (8 hours)
Acetylene / ethylene
Cyclopentadiene
Malononitrile
Ethylene oxide
SOCl2 / Cl2 (g, l) / HCl (g)
POCl3 / PCl5
Chemical Technologies:
Hazardous & Highly Active Chemicals
slide 10 28-Oct-11
Chemical Technologies:
Asymmetric Reactions
With transition metal catalysts
Hydrogenation
Oxidation
Heck
Aldol
Others
Assymetric Reactions
With biocatalysts
Oxidation/Reduction
Transamination
Others
Racemate separation
Use of chiral building blocks
O
N H N
O
O
P h
O
N H N
O
O
P h
H H
S
N H N H
O
H H
C O 2 H
H 2 , Rh-cat*
S/C = 2000
7-50 bar
dr = 99 : 1 (+)-Biotin
Hydrogenation of C=C bond
slide 11 28-Oct-11
Chemical Technologies:
Organometallic
Organometallic
Grignard
Organolithium compounds
Sodium in liquid NH3
Organozinc compounds
(batch or microreactors)
Transition metal catalysts
(e.g. Heck-type reactions)
N
Cl
C O O C H 3
O
N
Cl
Cl
O
C O
C H 3 O H
C H 3 C O O N a
N
C O O C 2 H 5
C O O C 2 H
5
O
C O
C 2 H 5 O H
C H 3 C O O N a
P d ( O A c ) 2 dp P d C l 2 ( P h 3 P ) 2 dppb
94% 90%
Carbonylation of arylchlorides
slide 12 28-Oct-11
Oxidations
Peroxides / oxygen / air
Nitric acid
Biocatalysis
Chemical Technologies:
Oxidations
H
H
H
H H
O O2
Pd/Cu
N N
C O O H HNO3
150°C
Ammoxidation
Transition metal
complexes
slide 13 28-Oct-11
Ozonolysis
Continuous ozonolysis in loop
reactor (ss; 8 kg O3/h; -20°C)
Batch ozonolysis in 600L
vessel (ss/gl; 5kg O3/h;
optional -60°C)
Chemical Technologies:
Ozonolysis
Synthesis of 4-oxo-2-butenoic acid ethylester
O
COOEt
O O O H
O3, - 30°C
Methanol
CH3 SCH3 + CH3 CHO
COOEt COOEt
slide 14 28-Oct-11
Chemical Technology:
Reductions
Reductions
Catalytic hydrogenations (homo-, heterogeneous)
Metal hydrides NaBH4, LiAlH4...
Sodium in liquid ammonia
Raney nickel
Biocatalysis
C C H 3
N
N H 2
C N
N N
N H 2
P h
Na
H 2 O
PhNHNH 2
Reaction with Sodium Metal
slide 15 28-Oct-11
Low-temperature
reactions (down to -90°C)
2 x 2.5m3 vessels
(glass lined)
6.3 m3 vessel
(hastelloy)
10 m3 vessel
(stainless steel)
Chemical Technologies:
Reactions Under Special Conditions
High-temperature reactions (up to 250°C)
High-pressure reactions
Up to 25 bar
(batch reactor; 10 m3)
18L hydrogenator
(up to 100 bar)
Up to 100 bar
(loop reactor)
slide 16 28-Oct-11
Chemical Technologies:
Biotransformation
Feasibility to Production
High throughput screening
Strain collection (>700 strains)
Enzyme collection: lipases,
ketoreductases, trans-
aminases, enoate reductases
Strain/enzyme improvement
Classical mutation
Cloning, enzyme expression
in proprietary hosts
Process development
Fermentation
Integration into a
multistep process
Experience
Several large-scale processes developed (L-Carnitine, nicotinamide)
slide 17 28-Oct-11
Chemical Technologies:
Microreactions
Microreactor Capabilities
1,000 kg reaction mixture per week (per reactor)
cSSP; 100g/min; numbering-up
Fills gap between lab and large-scale production
Useful for very exothermic or fast reactions
Experience
Since 1992: Low-temperature organometallic “microreactions”
New lab installed summer 2005
slide 18 28-Oct-11
Chemical Technologies:
What We Don’t Do
Explosive chemistry
(azidation, limited nitration, diazomethane)
CS2 chemistry
Fluorine Chemistry
(exception: ethyl triflouroacetate)
Steroids
Beta lactam antibiotics
Dyes chemistry
Radio-labeled materials
slide 19 28-Oct-11
Small molecule conjugates represent
a new generation of biopharmaceuticals
Antibody Drug Conjugates
Monoclonal antibodies (mAbs) linked to potent cell-killing drugs
Unique Drug Delivery
Employing a rapidly internalizing mAb
Drug delivered to target cells
Reaction
Environment inside cell cleaves the linker
Cytotoxic drug released
Benefits
Until released, drug is inactive
Healthy cells spared many toxic effects of traditional chemotherapy
slide 20 28-Oct-11
The antibody’s role is to ferry the actual
drug directly to the target cell
Linker Technology: Enzyme cleavable,
highly stable in bloodstream
Drug Payloads: Highly potent,
scalable, synthetic
Cancer
Cell
Hybrid Technology
Combines specificity of therapeutic proteins (antibodies) with broad target range of small molecules
Significant efficacy in models that
are resistant to “naked” antibodies
(i.e. Fo5 breast tumor)
Acceptable safety in animal models
Linking Mechanism
Stable while circulating in the blood
Readily broken after cell entry
Usually fully synthetic
slide 21 28-Oct-11
Conjugate manufacturing requires
advanced technologies and know-how
Example: Monomethylauristaurin F-mAb Conjugate
Multi-step synthesis with cytotoxic material
Asymmetric synthesis on non-natural amino acids
Peptide coupling
Bioconjugation
N H
O
O
O O N
O H N N N
NH
Me
i-Pr
O - - -
O
O O
O
OH
HN
O H2N O
i-Pr NH
O N S cysteine
Toxic Payload Linker
Guidance System
Me
Me
Me Me
Me
Me
Me
Monoclonal Antibody
i-Pr
- - -
slide 22 28-Oct-11
Lonza is one of only a few CMOs
producing antibody drug conjugates
The Right Experience
A leader in mAb production
Broad small molecule and peptide expertise
SafeBridge®-certified facilities
Drug Toxin Technologies Handled
Maytansinoid – DM1 (Immunogen)
Aurostatin – MMAF or MMAE (Seattle Genetics)
Calicheamicin (Wyeth)
Doxurubicin (Various)
Pseudomonas exotoxin and Staphylococcal
enterotoxin (Various)
slide 23 28-Oct-11
OEL = Occupational Exposure Limit
Product Risk-Based Exposure Control
Active Pharmaceutical Ingredient (API) AHSK 3 ; OEL ≥ 10 µg/m3
Highly Potent API (HPAPI) AHSK 4 ; OEL ≥ 0.1 µg/m3
Highly potent active pharmaceutical
ingredients have different requirements
Additional HPAPI Specifications
Clean room facility
Air quality (ISO class 5)
Performing of all standard chemical reactions (gram quantities)
Air locks with separated material and personal flow
Dedicated lab equipped with an isolator
slide 24 28-Oct-11
OEL value
requirement
(micrograms) Development phases
Commercial quantities
10
1
0.1
0.01 10ng
Reactor
volume
(m3) under construction existing conceptual design
0.1 0.01 1.0 5.0 10 20 30 40 50
LP
train 102
LP
train 109
PCP
phase 1
API 1
API 2
PCP
phase 2
SSP
clean room
L-500
QC-lab
Lonza maintains a strong competitive
position in the highly potent API market
slide 25 28-Oct-11
Agenda
What’s New
Offering
Capabilities
Development Services
Facilities
slide 26 28-Oct-11
basic
research
disease
discovery
drug
discovery
drug
development
clinical
trials production packaging
marketing
sales
distribution
Discovery Development Manufacture Distribution
process
development
route selection
cGMP
manufacturing
support for regulatory
submissions
bio/catalyst design
analytical development
scale up
We offer a full range of analytical and
development services
clinical
supply
lab supply
launch
supply
in- market supply
slide 27 28-Oct-11
Agenda
What’s New
Offering
Capabilities
Development Services
Facilities
slide 28 28-Oct-11
Location
150km east of Geneva
Footprint
90 hectares
Key Facts
Many multi-use vessels
cGMP and non-GMP facilities
pharmaceuticals
nutraceuticals
animal healthcare
Low temperature capabilities
HPAPI/Conjugate capabilities
Our Visp, Switzerland site is home to
numerous cutting-edge facilities
Capacities
Kilo Lab (10-30L vessels)
Small-Scale (22 reactors up to 250L)
Mid-Scale (27 multi-use trains; 57
multi-use reactors 250-3,000L)
Large-Scale (10m3; total over 400m3)
cGMP phosgene plant
slide 29 28-Oct-11
Group Date Remarks
Swissmedic Nov. 2008 New facilities and routine GMP Inspection
FDA Oct. 2008 PAI on one product, no 483
MOH (Mexico) Oct. 2008 Product related inspection of Mexican authorities
SQS Sep. 2008 Yearly routine Check on ISO 9001
SQS Sep. 2007 Recertification ISO 9001 (Rev. 2000)
Swissmedic Sep. 2007 Inspection of new BPMP1P2
Swissmedic Oct. 2006 Routine GMP Inspection
SQS Sep. 2006 Yearly routine Check on ISO 9001
FDA Feb. 2006 PAI & Systems Inspection, no 483
SQS Sep. 2005 Yearly routine Check on ISO 9001
Swissmedic Sep. 2004 Routine GMP Insp. + add. Permission
SQS Sep. 2004 Recertification ISO 9001 (Rev. 2000)
SQS Sep. 2002 Yearly routine Check on ISO 9001
FDA / Swissmedic Apr. 2002 Inspection, 483, 6 citations
SQS Sep. 2001 Recertification ISO 9001 (Rev. 2000)Systems
SQS Sep. 2000 Yearly routine Check on ISO 9001
Lonza’s Visp facilities have a long
history of successful inspections
slide 30 28-Oct-11
Location
75 miles from Hong Kong
Footprint
.164 h.a.
Products
APIs
(Advanced) intermediates
Key Facts
Leading-edge R&D center
Swiss quality
Our Nansha, China site maintains
Lonza’s worldwide quality standards
Capacities
6 x 250L
10m3 multi-purpose trains
Pilot plant and additional large-scale
capacity planned
slide 31 28-Oct-11
Group Date Remarks
FDA Q4 2009 Inspection Expected
Customer Dec. 2008 Product / Project Specific
Customer Nov. 2008 Product / Project Specific
External Third Party Oct. 2008 Trial Audit
Lonza Sep. 2008 Corporate Quality Audit
Customers May 2008 Product / Project Specific
Lonza Apr. 2008 Corporate Quality Audit
FDA Feb. 2008 sFDA re-inspection
Customer Dec. 2007 Project / Product Specific
Lonza Nov. 2007 Standard Internal Audit
Customers, agencies and Lonza have
assured quality at our new Nasha site
slide 32 28-Oct-11
Location
Visp, Switzerland
Key Facts
Production began in 2008
Leading-edge R&D center
7 patent applications
(wide-ranging)
Nitrations, organometallic
reactions, 2 reactors, 1 lab
system
Several 200+ kg campaigns
high yield and quality
cGMP possible
Our industry-leading microreactor
facility is in Visp, Switzerland
Capacities
2 dedicated laboratories
Able to produce kg quantities
2 Integrated production units (c-SSP,
R01) under GMP conditions
slide 33 28-Oct-11
Why Outsource with Lonza?
Partnership Mentality
We are committed to ensuring your success
Available for long-term strategic, pipeline agreements
Experience = Reliability
Proven track record
Technical & project management excellence
Quality Assurance & Regulatory expertise
Lower Risk, Remain Flexible, Stay Focused
Avoid investment in potentially unused facilities
Improve flexibility and speed to market
Focus your resources on your core capabilities
slide 34 28-Oct-11
Small Molecules Backup
slide 35 28-Oct-11
Nansha, China
API Plant
Small-scale Plant
Launch Plant
Admin
R&D Services
slide 36 28-Oct-11
Cl S N
O
O
C O
NH3
NC CN
H2
ClCN
HCN
CH4
H2N CN
CO2
H
HH
H
CO
H H
H
O
OH
O
C
H
H
OO
O
Cracker
C3 - C8
Lonza’s backward integration provides
synergies and available supply
Acetylene
Ethylene
Carbon dioxide
Carbon monoxide
Hydrogen
Ammonia
Chlorosulfonyl isocyanate
Aminonitrile Malonodinitrile
Hydrogen cyanide Cyanogen
chloride
Ketene Diketene
Acetaldehyde
Acetic acid
slide 37 28-Oct-11
R O
O O
O O
O
R1
O
R2
O
XR3
R2
R1
O
XR3
R2
R1
HO
CO2H
NH R
O
O
X3C OR
O X
O
Y
OR
RO
O
OR
OR O
OR RO
O
O
O OH
OH
O
O
CCl3
O O
O H
H
+ H2NR2
squaric acid b-keto esters
vinyl esters
alkyl anhydrides
unsaturated esters, amides, and thioesters
alkoxy glutarates
ketones
N-acylamino acids
4-(trichloromethyl)-2-oxetanone
Chemical Platforms (1/11)
Ketene
slide 38 28-Oct-11
X O
R
O
XR
O
O
OH O
O
O O
O
O
O
HN
N H
O X
R OH
O
COOH
O O
O
XR
O
Cl
X = N, O, S
4-chloroacetoacetates
acetoacetate esters, thioacetoacetate esters, acetoacetamides
dehydroacetic acid
pyrimidinones
diketene acetone adducts
3-methylenebutanoic acid
butenoic acid
b-butyrolactone
Chemical Platforms (2/11)
Diketene
slide 39 28-Oct-11
O
Cl
O
OR
N OH
S
N
H2N
O
OR N
OH
S
N
H2N
O
OR
O
R1O
O
OR
O N
HO OR
O
N N
HO
Ar
OR O
O
Cl
O
OR
CN
N
N
Cl
OH R1
N
N
NH2
N
N H2N
Cl
O O
HO
O
Cl
O
OR
4-alkoxyacetoacetates
pyrazoles
pyrimidines
aminothiazoles
pteridines
2-hydroxyimine chloroacetoatetates
aminothiazoles
isoxazoles
2-cyano-4- chloroacetoacetates
tetronic acid
Chemical Platforms (3/11)
4-Chloroacetoacetates
slide 40 28-Oct-11
HCN
Me3Si CN
H2N
H2N CN
CN
O
CN
O
R1
R2
OH
NC
R NR2
CN R
NR2
CO2H NH2
R1
R2
RO
O
CN
R CN CN NC
R
1
O
R
2
CN
amino acids
b-cyanoketones
nitriles
1°, 2° and 3° amines
cyanotrimethylsilane cyanoformates
vinyl cyanoesters
oxalonitrile
diaminomaleonitrile
cyanohydrins
Chemical Platforms (4/11)
Hydrogen Cyanide
slide 41 28-Oct-11
SCN R NH
N N R1
R2 R1
R2
NH
OR RO
CN
N
N
N
Cl
Cl Cl
O CN R
NH
O
R
N
NH2
N OH
R O CN
R
NH O
OR
R
N Cl
N CN NC
Na +
-
triazines
Vince-Lactam
sodium dicyanamide
tetra alkylguanadine
thiocyanates
cyanate esters
benzonitriles
allylic cyanate esters
Chemical Platforms (5/11)
Cyanogen Chloride
slide 42 28-Oct-11
S
NH2 NC
NC
NH2 • HCI
CN
NC CN
R2 R1
N N
NH2
NH2 H2N
NC CN
CN
N N NH2
R1 H2N
R2 N N
CN
NH2
H2N
R
N N
H2N
CN
R
N N
OR RO
NH2
CN NC
cyanothioamides
aminomalononitrile
pyrimidines
2,4,6-triaminopyrimidine
2,4-dialkoxy-6-aminopyrimidine
aminopyrazoles
2-[2-(alkyl)phenyl]-1,1,2-
ethylenetricarbonitrile
Chemical Platforms (6/11)
Malononitrile
slide 43 28-Oct-11
N H
NH
N H
NC R1
N H
n N H NH
N H
CN
NH
N H
NC
N H
N N
NH2
H2N
S
NH2 N H
NH
H2N
N
N
NH2
H2N Cl
NC
N R
CN
NC
N N
N H2N NH
2
N N
N Cl Cl
N S
N
N
Cl
Cl Cl
N CN NC
Na +
-
poly guanidines
triazines
pyrimidines
alkyl malononitriles (thio)guanidines
3,5-diamino-triazol
Chemical Platforms (7/11)
Sodium Dicyanamide
slide 44 28-Oct-11
S
O
R2
O
N H
R1
O
S NH2 Cl
O
O
S
O
Cl
O
N H
R1
O
R1 X N
H S
O
O
Cl
O
R1 X NH2
O
R1 X N
H S
O
O
N R2
R3 O
R1 X N
H S
O
O
O R2
O
R1
O
R2
O
N H
S
O
O
Cl HN NH
O
O R1
R2
Cl S
O
O
N O
X = N, O, S
NH O
R3
R4 R1
R2
sulfamoyl chloride
2-azetidinones
pyrimidinediones
(Uracils)
sulfonylureas
X = N, O, S
ureas, carbamates,
thiocarbamates
Chemical Platforms (8/11)
Chlorosulfonyl Isocyanate (CSI)
slide 45 28-Oct-11
N
OH
O
N
OH
O
N N
H
O
N
OH
O
HO
O
N
O
N +
OH
O
O N
OH
O
O
N
OR
O
N
OH
O
HO
N
OH
O
N 6-Methylpyridine-
3-carbaldehyde
Nicotinic acid ester Nicotinic acid
Niacin (Vitamin B3)
Pyridin-3-ylethanone
Nipecotic acid
6-Hydroxynicotinic acid
2,5-Pyridinedicarboxylic acid
6-Methylnicotinic acid 2-Methyl-5-vinylpyridine
2-Acetylnicotinic acid
Nicotinic acid N-oxide
Chemical Platforms (9/11)
5-Ethyl-2-Methyl-Pyridine
slide 46 28-Oct-11
H H
2-Methyl-3-butyn-2-ol (MBI)
OH
H
OH
2-Methylbut-3-en-2-ol (MBE)
OH
HO
butynediol
derivatives
OH
HO
hexynediol
derivatives
O
H
3-Methyl-2-butenal butenediol
derivatives
OH
HO
H
H
hexenediol
derivatives
HO
H
H
OH H
H
Chemical Platforms (10/11)
Acetylene
slide 47 28-Oct-11
OH
OH
O
O
OR
OR
O
O
dialkyl squarate
O
O
+ N H
NH
squaraines
O
OH HO NR2 O
O NR2
OR O
O
OR O
O NR2
O
HO
RO
RO
OH
OH RO
O
O Cl
OH OH
OH OH
OH
OH HO
HO
Chemical Platforms (11/11)
Squaric Acid
slide 48 28-Oct-11
NH2 NH2 NH2
R
N H
N H
N H
R
R R R
R
H2
C2H4 C2H4
Indole synthesis
Additional Chemical Platforms
Alkylations and Cyclizations
