2. Siegfried
Actives
2_2
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
3. Siegfried
Overview Actives
2_3
Siegfried Group: Profile
• Global presence: 4 sites in EU & US
• >130 years in pharma industry
• Listed on the Swiss Stock Exchange
(SWX)
• Concentration on the development
and manufacturing of APIs,
intermediates, and finished dosage
forms incl. inhalation products
• Total work force: approx. 800
• Annual sales CHF: > 350 mio
• >120 commercialized products in last
40 yrs
4. Siegfried
Overview Actives
2_4
Siegfried Group: Vision
To be a world-class partner in
developing and manufacturing drugs
that improve human life.
A leader in:
• Speed
• Reliability
• Flexibility
5. Siegfried
Overview Actives
2_5
Siegfried Group: Divisions
Siegfried Actives Siegfried Drug Product
Development and Development and
manufacture of active production of
pharmaceutical finished dosage
ingredients (API). forms.
Exclusives:
• Custom process and • Custom packaged
method development products
• Custom manufacturing • Inhalation products
services • Manufacturing and supply
chain services
Multi Clients: • Regulatory services
• Supply of generic APIs
• Opiate APIs
• Controlled substances
•DEA license
6. Siegfried
Overview Actives
2_6
Siegfried Group: Locations
Plus various
agents
around the
world
Siegfried Pharma Headquarters Siegfried UK Alpine Dragon Siegfried Shanghai
Development GmbH Siegfried Ltd Branch office Pharma Sourcing Office
Munich, Germany Siegfried Actives Stockton, UK Wuwei, China Shanghai, China
Höchstädt, Germany Siegfried Drug Product
Zofingen, Switzerland
Siegfried (USA), Inc. Siegfried (Malta) Ltd SCI Pharmtech, Inc.
Pennsville, U.S.A. Malta Taipei, Taiwan
7. Siegfried
Actives
2_7
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
8. Siegfried
Services Actives
2_8
Meeting Customer Needs
Service offering Customer value Goal
• Key account and • Speed –
product from inquiry to
management delivery
• Project • Reliability –
management on time, in budget, Maximize
and at expectation your benefit
• Supply chain
management • Flexibility –
tailored service solu-
• Regulatory support tions meet changing
needs
• Quality
management
9. Siegfried
Services Actives
2_9
Project Management Offering
Project planning • Addressing customer requirements
• Target setting and scope definition/tracking
Project execution • Dedicated project management (PM)
• Tracking & Communication
Chemical • Extensive corporate Expertise
development • Scale-up experience of over 500 processes
Team management • Cross-functional project teams
• Joint Customer/Siegfried team
10. Services Siegfried
Actives
2_10
Project Management - Life Cycle
Solid finished dosage forms
Full-scale production*
Kilo lab/pilot plant*
Laboratory development
Laboratory feasibility study
Technical Transfer Package,
project evaluation & quotation
Project
Confidentiality agreement Management
Customer inquiry
* Location depends on capacity, capability &
regulatory needs
11. Services Siegfried
Actives
2_11
Project Management - Project Leadership Team
External role
Customer
BD/Project
Internal role Manager
Development Purchasing
Project
Leadership
Production Team (PLT) Quality
Pilot Plant Analytic
Point to Point contacts are set at project inception
12. Siegfried
Services Actives
2_12
Project Management Benefits
• Single point of contact for project
• Timely communication
• Ease of doing business
• Reliable project delivery
• Flexibility & speed
“Exceed Customer Expectations”
13. Siegfried
Services Actives
2_13
Supply Chain Management
Production planning • Maintaining flexibility while optimizing
efficiency
Manufacturing • Multipurpose facilities
• Highly trained personel
• Short cycle times
Inventory management • Optimizing availability and working capital
• Managing safety stock
• Purchasing
• Worldwide sourcing of key raw materials with
permanent presence in China
14. Siegfried
Actives
2_14
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
15. Siegfried
Chemical Development Actives
2_15
Overview
Process development leading to scaleable and robust processes by
• Process research and development of APIs and key intermediates
• Evaluation of new synthesis routes
• Analytical development
• Process optimization
• Scale-up and pilot services
• cGMP compliant small scale production
• Supporting services: Logistics / In-house safety tests / Quality assurance
16. Siegfried
Chemical Development Actives
2_16
Key Technologies – The Siegfried Difference
• High Potency 1.0µg/m3 (OEL 3) in production and
pilot plant
• High Potency 0.1µg/m3 (OEL 4) in development
• Cryogenics
• Micro Reactor Technology
• Spray-Drying
• Expertise in Polymorphology & Crystallization
• Process Safety Laboratories
• Small-scale & Pilot cGMP Production
• Analytical Method Development & API Release
Testing
17. Siegfried
Chemical Development Actives
2_17
Key Expertise
Team 30 Ph.D. Chemists
4 full time Project Managers
4 full time Analytical Project Leaders
12 Chemical Engineers
29 Lab Technicians (3 year apprentice)
12 Chemical Operators (3 year apprentice)
Experience • Methods validated according to ICH
guidelines; >500
• Process evaluation for more than 1900
compounds
• Scale up of more than 500 processes
• Ability to run 50 development projects in
parallel
18. Siegfried
Chemical Development Actives
2_18
Lab, Kilolab & Pilot Plant
Laboratories:
• 10 laboratories
• 30 Ph.D. chemists
• 83 staff
Kilolab:
• Steel and glass-lined reactors (30-
60L)
• Temperature range -60oC to 220oC
• Coated centrifuge
• Mettler Reaction Calorimeter (RC1)
• Automated synthesis workstation
• Mettler LabMax with IR for IPC
Pilot plant:
• Steel & glass-lined reactors (250-
500L)
• Hydrogenation reactor (steel 250L)
• Centrifuge
• Stainless steel paddle dryer 250L
• Alpine & Fitzpatrick mills
19. Siegfried
Development Building Actives
2_19
3.4.5.5
cGMP Wall
• cGMP wall to separate operating
room and technical part
• Minimized cross-contamination
• Efficient cleaning possible
• Remote-controlled valves
• Feed tanks & receivers equipped
with weight sensors
• Reactor monitoring by TV
cameras
20. Siegfried
MRT at Siegfried Actives
2_20
Reaction Candidates
Best suited for reactions with the properties:
• Fast, preferred within seconds
• Mixing controlled
• (highly) Exothermic
• Narrow temperature window between
the desired reactionandside product
formation
• Safety concerns
• Catching short lived intermediates
21. Siegfried
MRT at Siegfried Actives
2_21
Capabilities
Materials of Construction Glass, SS/Hastelloy
Temperature range explored so far: -60 C to +300 C
Pressure range explored so far: 100 bar
Reactor capacity: 200 mL/min = 290 L/day = 9
MT/month
Integration into Pilot done (glass unit)
Integration into Plant mobile unit for Mfg areas
22. Siegfried
MRT at Siegfried Actives
2_22
MRT Reactions
Reaction type O R
• Aromatic boronic acid MgX DCM
OMe
• Metalorganic reaction (doubel de-
protonation) OH O R
Cl O
• Pinacolato-dichloromethylborane B
B(OH)2 Cl O OH
formation RO O
• Demethylation or MeO-Aryl
R O CONH2 R'
• Nitration of an aromatic system CONH2 RHN
OR
• Epoxide opening with ammonia H O
• Hetereocyclization (Barbiturate) O
R NH2 R' Cl
• Multi-step sequence; deprotonation, NH
RHN
silylation, alkylation, hydrolysis NO2 OH O N O
H
• a-Alkylation of a carboxylic acid
• O-Nitration of an aromatic alcohol CO2H Ary OH HO OH CO2R
(Cl)
• Mono-nitration of an aliphatic diol
• Nitration of an aliphatic alcohol
• Ammonolysis of an ester
CO2H HO ONO2
Ary ONO2 CONH2
• Oxidation with hydrogen peroxide Alk (Cl)
23. Siegfried
MRT at Siegfried Actives
2_23
Case Study: DCM-BPin
Reaction Scheme and Paths to By-Products
Desired Transformation O
B O
LDA O Li+ O Cl
Li O O
B- B
Cl Cl Cl Cl Cl O Cl
O
Cl
DCM-BPin
Side-Reactions
carbenes and Cl
their degradation other un-identified
O O Cl by-products
products
B O B
O O
24. Siegfried
MRT at Siegfried Actives
2_24
Case Study: DCM-BPin
100%
80%
60% Product
Starting Material
40% By-Products
20%
0%
batch -55°C 0°C -40°C
25. Siegfried
Actives
2_25
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
26. Siegfried
Chemical Production Actives
2_26
Chemical Reaction Capabilities
More than 200 chemical reactions possible in-house, with specific expertise in:
• Alcoholysis, alkoxylation, amidation • Hydrogenation with catalyst or
• Bromination, chlorination hydrides
• Chloromethylation, chlorosulfonation • Organometallic reactions
• Cyanidation, decarboxylation • Nitration, Mannich reaction
• Dehalogenation, diazotation, • Phase transfer reaction
Diels-Alder • Resolution of racemates
• Epichlorohydrine reaction, • Sandmeyer reaction
formulation
• Friedel-Crafts, Gattermann, Grignard
27. Chemical Production Siegfried
Actives
2_27
Capabilities & Capacity (1)
Capacity Zofingen Pennsville
Number of reactors 120 52
Output/year [tons/year] >1000 >300
Output range [tons] 0.5 – 500 0.05 – 150
Range of reactor
800 – 5000 350 – 7600
volumes [litres]
Total reactor volume [m3] 360 200
Drying capacity [m3] 25 30
-15 to +165
Temperature range [°C] -80 to +250
special equipment up to 350
28. Chemical Production Siegfried
Actives
2_28
Capabilities & Capacity (2)
Capacity Zofingen Pennsville
Pressure range 1 mbar to 40 bar 1 mbar to 20 bar
Distillation capacity [m3] 5.5 3
Crystallization capacity [m3] 32 40
Solvent distillation [m3] 22 8
Short path distillation KD10 -
Centifuges, Filter Centifuges, Filter presses,
Product isolation
presses, Nutch Nutch
Frewitt Impact Mill,
Mills Fitzpatrick
Universal, Sieves
29. Chemical Production Siegfried
Actives
2_29
Pilot and commercial spray dryer
Pilot Spray Dryer:
•Model - Anhydro PSD 52 CC.
•Evaporation rate at max temp =
4kg/h water or 20kg/h organic
solvents (e.g. acetone)
•Max inlet temp = 250 C
30. Chemical Production Siegfried
Actives
2_30
Pilot and commercial spray dryer
Commercial Spray Dryer:
Model - Anhydro MS 400 CC
Water evaporation rate at max
temp = 12 kg/hr or 60kg/h organic
solvents (e.g. acetone)
Max inlet temp = 250 C
31. Chemical Production Siegfried
Actives
2_31
3.5.4.3
Process Technology
Biazzi high pressure reactor
• 2.0 m3 stainless steel reactor
• Reactions up to 40 bars
• Catalyst charging vessel
• Mott filter to remove catalyst
• Enlarged heat exchange surface
32. Chemical Production Siegfried
Actives
2_32
3.5.4.7
Isolation
Packaging
• Room classification D
(<100,000 particles per cubic foot
air allowed)
• GMP floors and walls (Terazzo)
(easy to clean)
• Personnel / material air lock
33. Siegfried
Actives
2_33
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
34. Siegfried
Compliance Actives
2_34
Quality Management
Siegfried Compliance
Chemical Development, sites Zofingen, Pennsville
API production, sites Zofingen, Pennsville
Pharmaceutical Development, sites Zofingen, Munich
Final dosage forms production, site Malta
Quality Quality Regulatory Safety, Health &
Assurance Control Affairs Environment
35. Compliance Siegfried
Actives
2_35
Regulatory Documentation
• Complete registration files or parts thereof
• CMC-parts for NDAs/ANDAs
• Drug master files (DMF type II) for EU or US (currently more than 20 US
DMFs)
• Manufacturing documentation for submission and update of IND
• Certificates of Suitability to the European Pharmacopeia (CEP)
• Support during registration incl. response to deficiency letters
• Support after filing with maintenance of the registration documentation
36. Siegfried
Compliance Actives
2_36
Outstanding Track Record
Zofingen Pennsville
Authority Date Result Authority Date Result
RFS Nov 2002 GMP Certificate FDA May/June 2003 NAI
FDA June 2003 NAI FDA Sept 2004 NAI
RHI Feb 2004 GMP Certificate FDA June 2006 NAI
RHI Nov 2004 GMP Certificate FDA Dec 2007 NAI
FDA Aug 2006 NAI FDA Jan 2008 NAI
RHI Nov 2006 GMP Certificate FDA Dec 2008 NAI
RHI Dec 2006 GMP Certificate FDA May 2009 NAI
RHI Feb 2007 GMP Certificate
RHI June 2007 GMP Certificate
FDA Nov 2007 NAI
RHI June 2007 GMP Certificate
FDA July 2008 NAI
RFS =Regionale FachStelle für Arzneimittel
RHI =Regionales Heilmittel-Inspektorat)
FDA = Food & Drug Administration
37. Siegfried
Actives
2_37
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
38. Siegfried
Multiclients (Standard Products) Actives
2_38
Commitment to Controlled Substances Market
• Product range of over 20 different controlled products
• Opiate Technology platform for the development of novel APIs with
customers
• One out of five NRM import license holders in the U.S.A.
• Long-term Supply Positions for key Narcotic Raw Materials (NRM)
• GMP manufacturing sites in Pennsville, U.S.A. and Zofingen, Switzerland
• Maintain an excellent track record with regulatory authorities such as
DEA and Swissmedic
40. Siegfried
Actives
2_40
Overview
Siegfried
Services
Chemical Development
Chemical Production
Compliance
Standard Products
Formulation
41. Siegfried
Formulation Actives
2_41
Solid Oral Dosage Forms
• Granules
• Powder mixtures With immediate, sustained or
• Tablets modified release profiles
• Filmcoated tablets
• Hard gelatine capsules
42. Siegfried
Formulation Actives
2_42
Capabilities
Analytical and Pharmaceutical Development of all kinds of Solid Oral
Dosage Forms for the EU and US Market
• Compatibility Studies
• Small Scale Formulation Work
• Clinical Trial Batches
• Analytical Method Development
• Full GMP validation of analytical methods and manufacturing
process
• Tech-transfer and Process Optimization
• Stability testing according to ICH
• Source Documents for Registration
43. Siegfried
Formulation Actives
2_43
Pharmaceutical Development - Technologies
Broad Range of Technologies for Oral Solid Dosage Forms
• Powder Blending
• Wet Granulation with High Shear Mixer
• Fluid Bed Spray Granulation/ Drying
• Roller compaction
• One-pot Granulation
• Pellet Extrusion and Spheronisation
• Tablet compression
• Coating (Granules, Pellets, Tablets)
• Hard Gelatin Capsule Filling (Granules, Powder, Pellets)
44. Siegfried
Formulation Actives
2_44
Pharmaceutical Development - Equipment
Equipment Type Capacity
Freefall blender Turbula blender 200 ml – 10 l
Rhönrad blender 50 / 100 l
Roller compactor (June 07) Powtec RCC 100x20 50g – 10kg / h
High shear mixer Diosna P 1-6/2/4/10/25/50 0.5-50 l
Fluid bed granulator/ drier, Mini Glatt 200 ml l
Wurster (Pellets) Glatt GCPG 3 / 1 5, 7 l (Wurster 5, 7 l)
Glatt GPCG 15 pro (Q3 2006) 42 l (Wurster 20l)
Oscillating sieve Frewitt TC 150 0.6/0.8/1.0/1.2 mm
Frewitt MF3
Rotating sieve Frewitt TC Lab 0.6/0.8/1.0/1.2 mm
Tabletting machines Excenter press: Korsch EK0 up to 12‘000 tablets/hour
Rotary press: Fette Perfecta
Rotary press: Korsch XL 100
Hardgelatin capsules filling Zanasi LZ/64 up to 4000 capsules /hour
maschine with 100% weight control Sade Weight controller up to 3000 caps or tabl./ hour
Coater Glatt GC 300 1-3 l
Glatt GMP II 2l, 9l, 24, 56l
Stirring container Glatt 25 l
One-pot granulator Diosna VAC 50 (10, 25, 50) 10 – 50 l
Extruder Nica E140 0.5 - 2kg/min
Spheronizer Nica S 450 0.4 - 2kg/min
Drying oven (vacuum) Heraeus VT 6130 M 3- 5 kg
45. Siegfried
Conclusion Actives
2_45
Why Siegfried?
Siegfried Actives is fast:
• From inquiry to delivery
Siegfried Actives is reliable: • Ease of doing business
• Custom development services
• Delivering on promises
• Custom manufacturing services
• Standard API supplies
• Security of supply
• Regulatory experience • Regulatory expertise
• Optimizing total cost of
Siegfried Actives is flexible: ownership for you
• Tailored services to best meet
customer requirements
