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CARBOGEN AMCIS Company Overview Who we are CARBOGEN AMCIS is a Swiss leading provider of drug development and commercialization services, offering Custom Development & Manufacture of APIs. Our Mission is to help pharmaceutical industries: Bring new generation medicines to market Reduce time and risk associated with the drug development Take chemistry off the critical path by providing… …Innovative Chemistry Solutions 2 Locations Dishman facilities & offices CARBOGEN AMCIS Local sales CARBOGEN AMCIS Dishman CRAMS Manchester United Kingdom Early / Late Phase Neuland Switzerland Early / Commercial Phase Bubendorf Switzerland Late Phase / Commercial Riom France Early Phase Aarau Switzerland Early /Commercial Phase Bavla India Late Phase/ Commercial Bavla India Late Phase / Commercial Shanghai China Late Phase / Commercial Company History 2012 Acquisition of CARBOGEN AMCIS SAS in Riom, France 2005 2007 Investment in High Potency Facility in Bubendorf Creation of CARBOGEN AMCIS Ltd in Manchester, UK 1990 2006 Foundation CarboGen Spin-off of the University of Zurich focused on research services and early-phase API supply Creation of CARBOGEN AMCIS AG 2008 2006 Acquisition of CARBOGEN AMCIS AG by Dishman Pharmaceuticals and Chemicals Ltd 2000 1982 Foundation AMCIS joint an pharma company focused venture with on PR&D and cGMP manufacturing Acquisition of CarboGen and AMCIS by Solutia New High Potency Facility in Ahmedabad, India Business Units & Company Structure Dishman Group Dishman Pharma Services Dishman Marketable Molecule Dishman Specialty Chemicals Dishman Vitamins & Chemicals CARBOGEN AMCIS Manchester United Kingdom Early/Late Phase Riom France Early Phase Dishman Disinfectants Dishman CRAMS Neuland Switzerland Early/Commercial Phase Bubendorf Switzerland Late Phase/ Commercial Aarau Switzerland Early/Commercial Phase Bavla India Late Phase/ Commercial Bavla India Late Phase/ Commercial Shanghai China Late Phase/ Commercial Dishman Group Key Facts Established in 1983 Public company quoted on BSE US $300 M turnover company Year on year growth approx. 30% since 2004 More than 1000 technical staff Global presence – manufacturing sites – Europe (5), – India (2), – China ISO 9001:2000, ISO 14001:2004, OHSAS18001:2007 Successful audit history – FDA inspected May 2006 (Bavla), Feb 2010 (Naroda), March 2012 (Bavla, Ahmedabad) – EDQM/TGA inspected June 2009 (Bavla), TGA: Sept 2011 (Bavla) – DCGI / WHO: July 2006, Feb 2010, May 2012 – Korean FDA Feb 2013 ( Naroda ) – Accreditation as foreign manufacturer for Japan CARBOGEN AMCIS Key Facts Over 20 years experience 6 sites (3 in Switzerland, 1 in the United Kingdom, 1 in France and 1 in India) Over 200 chemists, with >40% Ph.D. Well over 500 projects per annum 75% of projects are return customers Over 100 projects involving production, 30% HiPo 15 Commercial products Successful audit history Since 2006 part of the Dishman Group FDA, Swiss Medic, French Health Agency (ANSM), Korean FDA Accreditation as foreign manufacturer for Japan Our Added Value Technology We continuously invest in new technologies to stay at the forefront of chemical service providers. Service Our customers benefit from the most efficient, flexible, collaborative and seamless experience possible. Partnership Our long-term business success is our customer’s longterm success. Business Focus: Client Satisfaction Sole focus on the pharmaceutical sector Highest quality standards Exclusive custom synthesis No proprietary products All compound IP belongs to the customer Flexible and tailored solutions Impressive in-house technologies to support different types of chemistry Product lifecycle management through the Dishman Group Ongoing review/implementation of new technology – – – – Chromatography (SMB, SFC) Drug Product Services High Potency ADC Our Services Early Phase Late Phase Commercial Phase Process Research and Rapid Supply of APIs prepared according to non cGMP Process Development and cGMP Manufacture Process Optimisation FDA audited Drug Substances (DS) / API Manchester (UK) 500 Kg I non GMP Research Preclinical Phase I Phase II Phase III Aarau (CH) 50 Kg I GMP Research Preclinical Phase I Phase II Phase III Neuland (CH) 50 Kg I GMP Research Preclinical Phase I Phase II Phase III Preclinical Phase I Phase II Phase III Bubendorf (CH) 200 Kg I GMP Market Market Our High Potency Services Early Phase Late Phase Commercial Phase Process Research and Rapid Supply of APIs prepared according to non cGMP Process Development and cGMP Manufacture Process Optimisation FDA audited Drug Products (DP) Riom (FR) 4000 vials I GMP Preclinical Phase I Phase II Phase III Preclinical Phase I Phase II Phase III Market Bavla (India) 200 Kg I GMP Phase I Phase II Phase III Market Shanghai (China) 350 Kg I GMP Phase I Phase II Phase III Market Drug Substances (DS) / HAPI Bubendorf (CH) 75 Kg I GMP Drug Substances (API) & Drug Products Drug Substances / API Drug Products Process Research Pre-Formulation Services Route scouting Formulation Services Route development Development and optimization of lyophilization cycles Process Optimization Aseptic filling Scale-up Process Validation (Media Fill Testing) cGMP Manufacturing cGMP chromatography from g to 100s Kg scale Lifecycle Management Liquid forms, semi-solids and injectables PR&D Laboratory October 2010 - confidential 13 Regulatory Consultancy Support and guide customers through successive phases High quality documentation for successful due diligence Maintain experience and avoid handovers Support for the success of a projects for future license, sale or funding Common & best practices What is necessary at which stage of development What adds additional value Commercial Supply Manufacture started in 1996, no product recalls 15 Commercial products 3 Oncology commercial products (parenteral application) Multiple products undergoing validation (including lifecycle), including several HiPo 1-2 NDA filings annually Commercial supply into the major markets (US, EU, Japan, Korea, Australia, Brazil) Regulatory Support CMC support for IND, IMPD, NDA and MAA Multiple DMFs (US, EU, Japan) CTD (Common Technical Document) format Post-Approval Change Documentation Type II Drug Master Files (DMFs) European Drug Master Files (EDMFs) Track Record of Quality SwissMedic Japan March 2012 – Aarau, Neuland Accreditation as foreign manufacturer for Japan since 2009 March 2012 – Bubendorf No major findings FDA September 2011 – Bubendorf No 483’s noted on this or any previous FDA audit ANSM (French Health Agency) May 2012 – Riom No major findings 2013 – Korean FDA Customers >25 different customer audits annually At least 4 different (Top 10 Pharma) customer ESH audits annually Lifecycle Management Track record of successful technology transfer of processes to Dishman Group – >15 processes transferred to date including RSM, intermediates and launched APIs Continuous monitoring of process performance Continuous evaluation and implementation of process improvements (Lean and 6-sigma techniques) In depth experience of managing the post-approval change processes of all main regulatory bodies Continuous monitoring of the changing requirements Transition management to generic supply Experience of filing CEPs at the EDQM Quality Assurance Strategy “Fit for Purpose” supply chain Quality by Design approach Strategy agreed up front Fully compliant with ICH-Q8,9, 10 & 11 Classical & Lifecycle validation approach according to FDA guideline Expedite filing through registration batch approach PAR studies Optimisation by statistical DoE as required Product quality risk assessment Analytical Services Overview Characterization • Structure Elucidation • Absolute Configuration • Solubility Profile • Salt Screening • Polymorphism • Particle Sizing • Compatibility • Impurity Profiling • Solid State Characterization • Drug Product Characterization Control • Method Development • Inpurity Tracking • Method Verification • Specification Development • Specification Justification • Method Validation • Raw Material • IPC • API • Release Analysis • Method Transfer • Reference Standards Stability • ICH Stability • Stress Stability • Drug Substance Stability • Drug Product Stability • Degradation Profiling Equipment for Drug Products GMP Production Stability Chambers 5 Isolators Safe location in Switzerland Laminar Flow Hoods Fully GMP validated and mapped 1 GMP Freeze Dryer Terruzzi 1.2 m² CIP+SIP Operational at ICH conditions 1 Autoclave Stringent IQ, OQ, and PQ 1 Dry Heat Oven Routing calibration Continuous monitored (24/7) Dedicated Formulation and Pre-formulation Labs Monitoring systems FDA compliant (21CFR Part 11) Solid Forms (oral drugs) Real-time access to data via LIMS-System Liquid Forms (injectables) Equipment for API Manufacturing 70 general-purpose reactors (from 6 L to 4500 L) 5 cryogenic reactors (40 L to 3000 L) High temp reactor (200 L) High pressure autoclaves (range of scales) Hastelloy filter dryers (from 0.25 to 1 m2) Temp range: -100°C to +160°C Pressure range: 1 mbar to 25 bar Milling / Micronization Milling Equipment Site Type Scale Sieve Size (mm) GMP Category NE IKA MF 10 basic 5 – 500 g 0.25 – 3 0 - II AA Jetpharma MC-one 0.5 – 500 g N/A 0 - II AA Frewitt TC-150 1 – 12 Kg 0.5 / 1 / 5 a 0-I BU Frewitt 100 Kg 1 a 0-I NE Quadro Comil U10 1 – 12 Kg 0.279 / 0.6 / 1 / 4.7 a 0-I AA Jetpharma MC-50 0.5 – 2 Kg N/A a 0-I Lab Pilot / Manufactutring Wet Milling Equipment Site Type Loop Milling Volume (L) Transfer Milling Volume (L) Feed (L/hr) d90 (µm) GMP Category Mobile* IKA Magic Lab 0.5 - 5 0.5 - 5 ≤ 120 20 – 50 a 0 - IV Mobile* IKA Magic Lab 0.5 - 5 0.5 - 5 ≤ 120 20 – 50 a 0 - IV Mobile* IKA Process Pilot 2000/4 10 - 100 100 - 1000 120 -500 20 – 50 a 0 - IV Mobile* IKA Process Pilot 2000/4 Atex 10 - 100 100 - 1000 120 -500 20 – 50 a 0 - IV Mobile* IKA DR 2000/5 100 - 400 400 - 5000 ~ 2500 20 – 50 a 0 - IV Lab Pilot / Manufacturing * Aarau, AA (CH): up to Category II, Neuland, NE (CH): up to category II, Bubendorf, BU(CH): up to category IV; Bavla (IN): up to category IV Freeze and Spray Drying Site Lab Type Productivity Range Ice Capacity Condenser T (°C) # Trays GMP a Category BU (mobile) Lyo Zirbus 2x3x3/5 max 300 g/run * max 4 Kg/run - 80°C 3 (2 L) Riom Telstar Lyobeta 20 (1) 7.2 L/run (bulk) max 12 Kg/run - 80°C 4+1 0 - IV NE Büchi Mini Spray Dryer B290 up to 100 g/h* n.a. -10°C n.a. 0 - II AA Telstar Lyobeta 20 (2) max 1 Kg/run* max 30 Kg/run - 80°C 4+1 a 0 - II Riom Terruzzi (3) 14.4 L /run (bulk) max 30 Kg/run - 80°C 4+1 a 0 - IV 0 - IV Pilot / Manufacturing * (Solutions: 10% w/w) (1) Max 2'480 vials (2R) - Automatic stoppering possible (2) Automatic stoppering possible (3) Max 3'952 vials (2R) - Automatic stoppering possible Chromatography Services g to Kg SMB Licosep 10-50 Binary Separations racemates Flash Chromatography Biotage 400 L System Multi-component separations 200-2000 g/d 1-5 kg/d August 2013 - confidential 2x Preparative HPLC Knauer + Dan-process 10 cm ID Columns Multi-component separations Preparative HPLC Novasep 20 cm ID column 5 and 15 cm ID columns for HiPo Multi-component separations 20-350 g/d 100-1500 g/d 25 Preparative HPLC Novasep 30cm and 45cm ID column Multi-component separations Preparative MPLC Verdot/Armen Large-scale Normal phase 0.4-30 kg/d 500-10000 g/d High Potency Capabilities Highly Potent APIs for (pre)clinical trials and commercial use Riom France Aseptic Filling Bubendorf Switzerland Laboratories Up to 10 L Bavla India Shanghai China Kilo-Scale Manufacturing Facility Pilot Plant Manufacturing Facility Large-Scale Manufacturing Facility Large-Scale Manufacturing Facility Up to 250 L Up to 1600 L Up to 1600 L Up to 8000 L Up to 4000 vials OEL<1g/m3 OEL<0.1g/m3 OEL<0.1g/m3 OEL<10g/m3 OEL<0.1g/m3 OEL1-100g/m3 Up to Category IV Up to Category IV Up to Category IV Up to Category III Up to Category IV Up to Category III HiPo Manufacturing – Cat III HiPo Analytical Capabilities October 2010 - confidential 28 Categorisation HiPo Criteria Category 0 Category I Category II Category III Category IV Potency (1) > 500 > 100 100 – 10 10 – 0.1 < 0.1 OEL range (2) 5000 – 1000 1000 – 100 100 – 10 10 – 1 1 – 0.05 * Toxicity oral LD50 > 1000 1000 – 300 300 – 50 50 – 5 <5 NOAEL (4) > 100 100 – 10 10 – 1 1 – 0.1 < 0.1 Acute adverse effects None Slight Moderate; reversible Moderate – severe; reversible Severe; irreversible Chronic adverse effects None None Slight – moderate Moderate; irreversible Severe; irreversible – lethal Genotoxicity None None None – (+) Ames Test (+) in a battery of studies (+) in a battery of studies (3) (1) Dose [mg/d] (2) g/m3as 8h – TWA (3) mg/kg, rat (4) 28d, mg/Kg, oral rat * Standard value based on industrial hygiene data. Lower equipment or process specific values possible, depending on additional measures Project Management Communication Customer Management Purchasing Project Leader Chemists CARBOGEN AMCIS Steering Committee Ad hoc communication Weekly Report Regular Phone Conference Technical Visits 30 Management Sales Project Leader Chemists Flexible Approach Open Business Model Framework Agreement One-off Project FTE Agreement Manufacturing 31 Project • Payment terms • Forecasting • Termination Project • Resource level • Payment terms • Renewal • Termination Project Project • Payment terms • Termination Project • Project budgets • Payment terms • Termination Project • Budget ($/Kg) Project • FTE Rates Project • Overall budget Project • Deliverables CARBOGEN AMCIS Advantages Long track record in handling complex and long synthetic processes 500+ projects in 2011 100+ projects involving production (30% of which are HiPo) Comprehensive package Within available budget & timelines Tailored based on customer preferences 40+ Stability Studies One-stop-shop to limit the number of suppliers to be managed for drug products and substances 20+ Chromatography projects Commercial track records Phase appropriate development Lifecycle management Robust, reproducible & industryscalable process High quality infrastructure (nonGMP, cGMP) Experience from a broad customer base Flawless audit history 126 standalone analytical projects 50+ R&D projects What‘s New ? – Bubendorf, Switzerland ~ 4 Mio USD invested ~ 1 Mio USD invested cGMP clean room for antibody drug conjugates (ADCs) cGMP suite for High Potency Chromatography Sterile room (grade D/ C) Equipment Available: OEL <1 µg/m3 8h-TWA 3 Walk-in-Barrier Hoods HPLC 10 and 15 cm ID column Pressure Cascade (+30 Pa, +15 Pa, 0 Pa, -15 Pa) Equipment Available: Isolators, Barrier Systems and Walk-in fume hoods Bio-safety cabinets (grade C) Dry oven sterilizer and autoclave for sterilization 50 - 500 g/day 1000 ml/min at 70 bar What‘s New ? – Riom, France Investment: ~ $950,000 USD Implementation of a new VHP (Vaporized Hydrogen Peroxide) disinfection system Acquisition of 2 new aseptic filling isolators New Bag-In/Bag-Out system for HEPA filters exchange Increased level of sterility assurance in terms of disinfection, air-tightness and air flow Grade A (ISO 4.8) compliant throughout the entire process What‘s New ? – Bavla, India New High Potency Kilo-lab (~ 110 m2 floor space) Class 100.000 Separate material and personnel airlocks Negative Pressure Cascade among corridor/airlocks/operational areas(+15 Pa, 0 Pa, -15 Pa) HEPA Filters for air in and out (AHU single pass) [8hr TWA]: 50 ng/m³ > OEL < 1 μg/m³ 3 reactors (glass lined and SS) equipped with charging isolators 1 Agitated Nutsche Filter Drier (ANFD) equipped with discharging isolator Thank you! Name Surname, Ph.D. Title Tel: xx-xxx-xxx-xxx CARBOGEN AMCIS Hauptstrasse 171 CH-4416 Bubendorf Switzerland