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Your Source for High Quality Products & Services
Supplement Custom Synthesis
TrustTrust
www.pharma zell.com
Partnership
Service
Speed
Flexibility
Partnership
Flexibility
Service
Speed
PharmaZell offers• Active Pharmaceutical Ingredients (API)• Advanced Intermediates• Custom Synthesis (Development & Manufacturing) • Analytical and Regulatory Services
from laboratory scale to commercialization
MultiplicityMultiplicity
Custom Synthesis at PharmaZell
PharmaZell draws upon a long history of successful custom synthesis projects, performed on a proprietary basis for fine chemical and pharmaceutical companies worldwide.
In addition to advanced intermediates (cGMP and non-cGMP),PharmaZell specializes in production of kilogram to multi-ton quantities of active pharmaceutical ingredients (APIs) for all quantities of active pharmaceutical ingredients (APIs) for all stages of clinical trials through commercialization.
Custom Synthesis
PharmaZell is now active on four sites
Raubling, Germany
Copenhagen, Denmark
Chennai, India
Vizag, India
Site founded 1947 1927 1996 2007
Production scale
Pilot & commercial
Pilot & commercial
kg-Lab & commercial
Kg-Lab & commercial
Employees* 130 40 200 85
Compliance cGMP cGMP cGMP cGMP
Total reactor volume (m 3)
> 100 29 65 expandable
Key characteristics
Group Head Office
Production of Controlled Substances
Attractive labor & raw material cost structures
Gradually expandable
R&D center
* Number of employees as per 31st of December 2007
PharmaZell Site Raubling , Germany (close to Munich)
� API Production since 1947
� Fully Integrated Site:
- R&D, Pilot Plant, Commercial Production- QA/QC, Sales & Marketing- Project Assessment & Management- Project Assessment & Management
� FDA Inspected (1979, , , , ,2004, 2007)
Activities:
�Process Development
�Custom Manufacturing
- of new APIs- of advanced Intermediates
�Analytical Method Development
Site Raubling
Pilot plant at site Raubling , Germany (I)
� 900 m2 working area on 3 levels, established in 2000,operates under cGMP (typical batch sizes 5 -100 kg)
� About 4,000 L total glass lined reactor capacity(from 70 L to 2,000 L reactor sizes)– further expandable(from 70 L to 2,000 L reactor sizes)– further expandable
� Electrochemical & Electrodialysis plant (on demand)
� Distillation Unit, centrifuges, filter dryers, double conedryer, tray dryer
� Pressure range 5 mbar vacuum to 10 bar pressure
� Temperature range -15°C to 230°C
� Controlled areas (class 100,000) for drying and handlingof APIs
Pilot Plant Raubling
Pilot plant at site Raubling , Germany (II)
Reactors (all reactors carry distillation heads)• 70 L glass lined
• 100 L glass lined for hydrogenation and pressure reactions
• 350 L glass lined• 500 L glass lined• 800 L glass lined• 800 L glass lined• 2,000 L glass lined• 200 L Stainless Steel • Continous Plug Flow Reactor
Filtration, Drying• 0,25 m2 Stainless Steel Agitated Filter Dryer• 0,4 m2 Hastelloy Agitated Filter Dryer• Polypropylene Filter Press• Stainless Steel Filter Press• Basket Centrifuge, Stainless Steel ( 50 cm drum diameter)• Basket Centrifuge, Corrosion Resistant, (80 cm drum diameter)• Double Cone Dryer (400 L) • Vacuum Tray Dryer
Distillation: Distillation Column (3 m) with Fall Film Evaporator
Equipment listPilot Plant Raubling
Multi Purpose Equipment at site Raubling , Germany�44 m³ multi purpose stainless steel reactor capacity
(800 L – 5,000 L reactor sizes).
� 53 m³ multi purpose glass lined reactor capacity(2,000 L –14,000 L reactor sizes).
� 6 Multi purpose Basket Centrifuges, Automatic Heinkel Centrifuge, Filter presses, Stainless Steel Agitated Filter Dryer.
� Double cone dryers (1 m3), 2 paddle dryers, Wyssmont dryer.
� Air Jet Mill, Micronization Unit.
� Pressure range 30 mbar vacuum to 10 bar pressure.
� Temperature range -10°C to 180°C
Multi Purpose Plant Raubling
Finishing plant at site Raubling , Germany
� Completed in June 2000
� 4 separate production lines for crystallization, centrifugation, drying and milling
� Controlled areas for product handling
Finishing Plant Raubling
GEA Pharmaceutical A/S Copenhagen , Denmark a PharmaZell company
� API Production since 1927
� Fully Integrated Site:
R&D, Pilot Plant, Commercial ProductionQA/QC/RA, Project Management
� cGMP compliant (product specific certificates)
Activities:
�Process Development
�Custom Manufacturing
- of new APIs- of Advanced Intermediates- including controlled substances
(e.g. Amphetamines, Opioids)�Analytical Method Development
Site Copenhagen
Multi Purpose Equipment at GEA siteCopenhagen , Denmark
� Working area on 3 levels, pilot plant included in the plant,operates under cGMP (typical batch sizes 5 - 1000 kg)
� 16 reactors with about 29,000 L total capacity, 2/3 ofwhich is glass lined (from 100 L to 5,000 L reactor sizes)which is glass lined (from 100 L to 5,000 L reactor sizes)
� 300 L Hydrogenation reactor (up to 6 bar)
� 4 closed agitated filter dryers
� 1 fluidised bed opposed jet mill for micronizing
� Temperature range -40°C to 180°C
� Utility systems: -steam, cooling systems, pressurised air, nitrogen-solvent tank farm with direct pipeline to reactors.
Multi Purpose Plant Copenhagen
PharmaZell Site Chennai , India
� Inauguration in 1996
� 100% owned by PharmaZell
� German Management
� Attractive labor and raw material cost structure
� Fully Integrated Site(R&D, Kilo-Lab, Production, QA/QC)
Activities:
� Process Development� Custom Manufacturing� Production
- of mature APIs - and Intermediates
� Analytical Method Development
Site Chennai
Kilo-Laboratory at site Chennai , India
� 200 m2 working area, start-up 2004, (typical batch sizes 1-20 kg)
� 500 L total glass lined reactor capacity (50, 100 & 200 L reactor sizes) – further expandable(50, 100 & 200 L reactor sizes) – further expandable
� Additional reactors: 2 glass (10L & 20 L) and 1 StainlessSteel 200 L
� 10 mbar vacuum
� Temperature range – 10°C 150°C
� Centrifuges, double cone dryer, tray dryer
� Segregated area (controlled area) for drying and handlingof finished products
Kg-Plant Chennai
Multi Purpose Equipment at siteChennai , India
� 23 m3 glass lined reactor capacity (reactor volumes: 1,000 L – 6,000 L)
� 41 m3 stainless steel reactor capacity (reactor volumes: 500 L – 6,000 L)
� 6 Centrifuges; between 90 -120 cm drum diameter, topand bottom discharge
� 3 Filter presses, 1 Sparkler Filter
� 2 Cone dryers; 2 Fluid Bed Dryers – Stainless Steel
� 2 Blender/Stainless Steel
� Various Mills
Multi Purpose Plant Chennai
Chemical Capabilities In general: Large “toolbox” of chemical reactions suitable for multi-step syntheses.
Particular expertise in the field of:
• Electrochemical Reactions• Diazotization• Nitration (100% Nitric Acid)• Nitration (100% Nitric Acid)• Hydrogenation• Halogenation
• Epichlorohydrine Chemistry• Reactions with Acid Chlorides• Amino Acid Chemistry• Carbohydrate Chemistry• Pyrimidines• “GEA specials”
• Crystallization• Milling and Micronization
• Controlled Substances (synthetic and opioid)
Chemical Capabilities
Overview
Chemical Capabilities
� Electrochemical Reactions- High yields- Less waste compared to classical chemistry- High selectivity- Low investment cost
e.g. Electrolysis with divided cell type
Cathode Anode
• S-S bonds• -N=N-diazo compounds• NO2-reduction/nitrocompounds
e.g. Electrolysis with divided cell typeChemical Capabilities
Electrochemical reactions
Chemical Capabilities
�Electrochemical Reactionse.g. Electrodialysis
Separation of water soluble molecules and salts
•desalination of sugar solutions
• desalination of amino acids and derivatives
Anion Exchange Membrane Cation Exchange Membrane
Chemical Capabilities
Electrochemical reactions
Chemical Capabilities
� Diazotization
Technical expertise or the handling of Diazonium Salts
as Suspensions and Solutions
O
CO2HOH
O
R/ NaNO2
H2N
O
R
HO
CO2H
N N
R/ NaNO2
water, HCl
NH2
HO3S
CO2H
OHNaNO2
N
HO3S
N
CO2H
OH
+
Chemical Capabilities
Diazotization
Chemical Capabilities
� Nitration (100% HNO 3)
N
O
HNO3 100% N
ONO2
Chemical Capabilities
Nitration
NN
O NN
O COOH
O CF3
NO2
O CF3
HNO3 100%
Chemical Capabilities � Hydrogenation
O
OH
O
OH
CO2HCO2H
OH
Pd/ H2
O2N
OH
H2N
OH
HN
NH
O
O
NO2
CO2H
HN
NH
O
O
NH2
CO2H
OR1
R2
R1
R2
OH
ee 96%
Pd/ H2
RaNi/ Hydrazine
RaNi/ H2
Chemical Capabilities
Hydrogenation
Chemical Capabilities
� Epichlorohydrine Chemistry
OH
OO
Cl
O
O
O
O
O
OH
NCH3
H
NH2
O
NH2
ONH
OH
NH2
O
HO
Cl
O
1.Epichlorohydrine2. iso-Propylamine
+
OCH3
O
OOCH3
OH
ClO
+
Chemical Capabilities
Epichlorohydrine
Chemical Capabilities � Reactions with Acid Chlorides
HOO
NH
O
OO
O
Aryl OO
O
Aryl
Cbz Chloride - Thionylchloride - Acetylchloride - Arylchlorides
H3CO
NH2
S S
NH2
OCH3
OO
H3CO
NH
S S
HN
OCH3
OO
O
O
O
O
Cbz Chloride
O
OH
HOO
OH
N OORO
O
OR
O
Aryl
O
O
O
ArylCl
Arylchloride Acetyl Chloride
stereocontrolled
R1
NH2
OH
O
SOCl2/ R-OH R1
NH2
OR
O
Chemical Capabilities
Acid Chlorides
HS
NH2
O
OH
HN
N
S
OHO
OO
Thiazolidine-carboxylic acid (D)D-Cysteine
Chemical Capabilities
� Amino acid chemistry: Cysteine and Derivatives
HS
NH2
O
OH
H
S
NH2
O
OH
H
S
NH2
O
OH
H
HS
NH
O
OH
H
HO
O
O
N
S
S
OO
NAC
Lysin-Carbocysteinate
Lysine-N-Acetylcysteinate
Thiazolidine-carboxylic acid-methylester
Thiazolidine-carboxylic acid-arginine-salt
S-Methylcysteine
Carbocysteinate
L-Cysteine
Arg
Chemical Capabilities
Amino acids
Chemical Capabilities
� Amino acid chemistry: Protected/activated Amino acids
Examples
Amino acids: Protection/Activation:
CysteineTryptophanTyrosineArginineAsparagineGlutamineNorleucineLysine
Boc (t-Butyloxycarbonyl)
Fmoc (9-Fluorenylmethyloxycarbonyl)
Cbz (Carbobenzyloxy)
Npys-Cl (3-Nitropyridinyl-2-sulfonylchlorid
Z (Benzyloxycarbonyl)
H-ONSU (N-hydroxysuccinimide)
DCC (dicyclohexylcarbodiimide)
Chemical Capabilities
Amino acids
Chemical Capabilities � Amino acid chemistry: Short Chain Peptides (liquid ph.),
selected examplesa.) Cholecystokinine (CCK)Fragments for modified CCK
H-Arg-Asp-Tyr(SO3H)-Thr-Gly-Trp-Nle-Asp-Phe-NH2
b.) Sweetener b.) Sweetener
NH
O
H2N
CO2H
NH
H
O
c.) Fragments for Somatostatine
NPS-Lys-Thr-Phe-Thr-Ser-Cys-OtBuNPS-Lys-Asn-Phe-Phe-Trp-OHBOC-Ala-Gly-Cys
Chemical Capabilities
Amino acids
Chemical Capabilities
� Carbohydrate chemistry
O
OO
OMsOO
H3CCH3
H3C
H3CO
OO
OHOO
H3CCH3
H3C
H3C
Diacetoneglucose
Diacetonefructose
O
O
HO
OH3C
CH3
O
O
CH3
CH3
N
H
OO
N
O
O
Chemical Capabilities
Carbohydrates
HOO
OH
ROO
OR
N
NH
O
O
O-Alkyl
ROO
OR
O-Alkyl
ROO
ORCl
R: H, Toluoyl
R: Toluoyl
R: Toluoyl
HOO
OH
OH
O
OH
O
OHOH
OHOMs
HO
O
OHOH
OHOH
HO
HO
OH
OH
OH
Glucose Fructose
Deosyribose
Ribosides
Mesylglucose
Chemical Capabilities
� Pyrimidines
N
NH
O
O
NH2
N
NH
O
O
N
NH
O
O
O
O
O
NO2
KNOSKA
6-Methyluracile
N
NH
O
O
N
NH
O
O
R1
H
N
NH
O
O
NH2
N
NH
O
O
N
NH
O
O
N
NH
O
O
NO2
OH
O
OH
O -
O
M+
R2
5-Methyluracile
Orotic Acid
Orotic Acid Salts
5-Amino-orotic Acid
5-Nitrouracile
5-Aminouracile
Chemical Capabilities
Pyrimidines
Chemical Capabilities
� “GEA specials”
R Cl RPd
CO2H CO2HCu
Chemical Capabilities
“GEA specials”
Cl H2N Cl NH
Cl
Cu
ClSO3HR
O
R
O
SO2Cl
CO2H
R
PCl3
H3PO3 R
HOP
P
O
O
OH
OH
OH
OH
Process/Process Development
� Electrochemical Cells (Lab, pilot and commercial scale)
� Electrodialysis cells (Lab, pilot and commercial scale)
� Plug flow reactor (Lab & pilot scale)
� Batch, Semi-batch and Continuous Operations(all scales)
�“Mettler Lab Max” for Process development &Calorimetric data generation (lab scale)
� Micro-reactor (lab scale)
� Milling and Micronization (commercial scale)
� Crystal morphology and particle size control (all scales)
Processes
Close Customer Interaction in all Phases of Process Development
Max. 4 L Scale
• Process Design• Process Optimization• Lab procedure• Critical Parameters
Client cooperation
70 - 2000 L Scale
200 - 14000 L Scale
• Scale up & Technical Adaptions
• Supply of Materials for Clinical Trials
• Stability Testing
• Process Validation • Cleaning Validation• DMF Filing
(CTD Format)
Reformulation/Extension
Loss of share to
Generics
KGOriginator
Generic
European Sites Indian Sites
Manufacturing in Europe and Asia:At your service over the lifecycle of an API
Production sites on
0 5 10 15 20 30 40
Patent
expiry
Market
launch
ANDA
two continents
Years
Custom Synthesis at PharmaZell
Depending on the needs of our customers, our services can be provided as comprehensive solutions or in modular form andit is up to our customers to decide for either distinctive parts or package solutions .
We do believe in open and transparent communication ; fromWe do believe in open and transparent communication ; from
• Consulting our customers in the early phases in order to offeroptimum service packages to
• Establishing regular project related means of communication(e.g. reports, teleconferences) and to
• Finalization of the projects with the deliverables as agreed upon.
Custom Synthesis
Our Service Approach