CUSTOMER ORIENTED TOLL MANUFACTURING TAILORED SERVICES INTERACTIVE PROJECT MANAGEMENT CUSTOM SYNTHESIS & API CONTRACT MANUFACTURING

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1 CUSTOMER ORIENTED TOLL MANUFACTURING TAILORED SERVICES INTERACTIVE PROJECT MANAGEMENT CUSTOM SYNTHESIS & API CONTRACT MANUFACTURING

2 CEPiA Within the Industrial Affairs Division of Sanofi, CEPiA (Commercial & External Partnership, Industrial Affairs) is an organization fully dedicated to third party activities. One of the key activities of CEPiA is to offer a broad range of innovative solutions including: Intermediates and Active Pharmaceutical Ingredients (APIs) supply Custom Synthesis & API Contract Manufacturing Pharma Contract Manufacturing CEPiA AT A GLANCE 200 CEPiA collaborators close to customers Around 200 APIs on catalogue sold in 80 countries API & Pharmaceutical CMO Services 30 % of Chemistry and Biotechnology industrial activities of Sanofi CUSTOM SYNTHESIS & API CONTRACT MANUFACTURING UNDER cgmp FOR APIs OR MULTI-STEP INTERMEDIATES TOLL MANUFACTURING Pre-registered or marketed compounds Technical transfer of existing process and analytical methods CUSTOMIZED PROJECTS NCE or NBE under clinical development: - From phase I to launch Process Development: - Chemical and biotechnological development - Analytical development - Physical quality studies - Clinical supplies PILOT PLANT PRODUCTION FROM TECHNICAL / ENGINEERING RUNS TO CLINICAL SUPPLIES CEPiA guarantees REACH compliance. - Process Engineering and scale-up - Process safety COMMERCIAL SUPPLY AT INDUSTRIAL SCALE QUALITY & REGULATORY SUPPORT

3 EXPERTISE FIELDS CHEMISTRY Oligosaccharides Peptides Oligonucleotides Corticosteroids and Hormones Prostaglandins Opiates and opioids Highly Active Products (HAP) Multi-step heterocyclic chemistry BIOTECHNOLOGY Plasmids Therapeutic proteins (Production / Extraction / Purification) - Extractive proteins - Recombinant proteins Monoclonal antibodies Viral Vectors

4 FOR A RELIABLE & LONG-TERM PARTNERSHIP CDA CONFIDENTIAL DISCLOSURE AGREEMENT RfP REQUEST FOR PROPOSAL PROJECT ASSESSMENT NBO NON BINDING OFFER CONTRACT NEGOCIATION CONTRACT TECHNICAL IMPLEMENTATION SUPPLY CLINICAL COMMERCIAL 1 WEEK 4-6 WEEKS 2 4 MONTHS 4-8 MONTHS* *Average time frame, depending on technology INTERACTIVE PROJECT MANAGEMENT Project team with all relevant functions Efficient activities coordination (planning optimization) Regular follow-up meetings to master operational and strategic project management COMPREHENSIVE CUSTOMER SERVICE Process development and commercial API production Fully integrated offer including Drug Product and packaging FOR THE SUCCESS OF YOUR PROJECT COLLABORATION BASED ON RESPECT Confidentiality and Intellectual Property Project timelines Environment a sustainable development (NYSE) Ethical Chart Sarbanes-Oxley compliance PROACTIVE SCIENTIFIC & COMMERCIAL RELATIONSHIP Proposals for potential improvements Flexibility and responsiveness to customers needs Life cycle management (COG improvements)

5 CUSTOM SYNTHESIS & API CONTRACT MANUFACTURING GLOBAL HEAD SCIENTIFIC & BUSINESS INTELLIGENCE EUROPE & ROW Tobias METZENTHIN, PhD Tel: France-Emmanuelle THOLE, Ph.D [email protected] Tel: Yannick LE STANC, Ph.D [email protected] Tel: Mourad SAADY, Ph.D [email protected] Tel: NORTH AMERICA Aude FAYOL, Ph.D [email protected] Tel: Arnaud MARTIN, Ph.D [email protected] Tel: Patrick CASTETS, MS [email protected] Tel: Bob HUANG, Ph.D [email protected] Tel: JAPAN Roger KRIEGL, Jr., MS, MBA, PMP [email protected] Tel: Hikaru OHSAWA, MS [email protected] Tel: Alan BENSON, MS, MBA [email protected] Tel: Chiho TADERA [email protected] Tel:

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7 CHEMISTRY & BIOTECHNOLOGY VERSATILITY OF EQUIPMENT INDUSTRIAL NETWORK SUSTAINABLE DEVELOPMENT FACILITIES AND TECHNOLOGIES EUROPE FOCUS Haverhill Elbeuf Ploërmel Frankfurt Antony Vitry Ujpest Vertolaye Mourenx Lyon Sisteron Aramon Garessio Brindisi Ankleshwar CEPiA s strengths are: High quality standards: excellent track record with Health Authorities Technical experts including Process Development and production sites Patents and legal representatives Quality Assurance and Regulatory Affairs support A global purchasing policy for an optimized supply chain of solvents and raw materials Security / reliability of supply: possibility of internal dual sourcing Financial stability Our core competency is process development in chemistry and biotechnology. This involves: Development, scale-up of APIs and intermediates processes from route scouting, laboratory development to kilolab and pilot plant scale Technology transfers of chemical and biotechnological processes to production Optimizing commercial processes through continuous improvements Respect of cost and timelines Jurong CHEMISTRY BIOCHEMISTRY BIOTECHNOLOGY HEADQUARTERS

8 STATE-OF-THE-ART PRODUCTION FACILITIES CHEMISTRY Multi-purpose equipment from pilot-scale to 20 m 3 Total volume reactor > m 3 Hydrogenations (up to 200 bar, up to 18 m 3 ) Temperature range (-120 C to 220 C) Reactors in stainless steel, glass-lined, hastelloy Continuous reaction processes High vacuum product distillations (rectification/thin-film) Large scale chromatography (reverse phase/ion exchange) Centrifuges, filter-dryers, stirred pressure filters Finished processing of APIs (milling, micronization, clean room packaging) Examples of hazardous chemicals handled at industrial scale: o NaN 3 (azidation, tetrazole formation) o Methylating agents (CH 3 Cl up to 15 bar, (CH 3 ) 2 SO 4 ) o Strong organometallic bases (NaNH 2, LiHMDS, BuLi) o Cyanides (NaCN, KCN) o Hydrazine (H 2 N-NH 2 ) o In situ generated borane (BH 3 ) BIOTECHNOLOGY BIOCHEMISTRY Upstream process: o Fermenters from 10 to 200 m 3 o Mammalian cell culture : 400 to L o Plasmids: dedicated facility with L reactor o Vaccines: viral culture up to L Downstream process: o Biomass separation by membrane or centrifuge technology o Excellence in viral safety : pre-viral / post viral zoning o Industrial chromatography (reverse phase, ion exchange diameter) o Filtration technologies: microfiltration, ultrafiltration and nanofiltration o Efficient networking with Sanofi Fill and Finish plants (integrated offer) CHEMISTRY & BIOTECHNOLOGY DEVELOPMENT CHEMISTRY Synthetic alternative route scouting Laboratory initial screening Scale-up from 10 ml to 20 L reactors Process optimization Definition of optimal operating procedures and critical parameters Preparation of impurities : full synthesis and / or isolation Preparation of reference standards Production support: o Process improvement o Troubleshooting BIOTECHNOLOGY BIOCHEMISTRY Upstream: o Microbiology and molecular biology o Virology: vector optimization o Enzymology o Fermentation o Media Optimization o Cell engineering and cell culture Downstream: o Extraction and filtrations o Refolding o Precipitation and crystallization

9 PROCESS ENGINEERING Thermal exchanges Material transfers Stirring Scale-up and scale-down studies Extraction and separation (Liquid/Liquid, Solid/Liquid) Industrial chromatography Modelization, equipment design and piloting Process intensification PHYSICAL QUALITY Crystallization design (polymorph and morphology screening) Filtration and drying processes Solid chain, milling, micronization Powder properties determination PROCESS SAFETY Thermal analysis Powder safety (granulometry, electrostatic properties explosion) Runaway reactor ENVIRONMENTAL DATA Biodegradability of effluent Ecotoxicity Support to waste water treatment plants PILOT PLANT BATCHES Technical batches (engineering, scale-up) Clinical supply Primary stability Registration (DMF) ANALYTICAL CAPABILITIES Development and validation of analytical methods Structural characterization Impurity identification, quantification and tracking Glycan mapping, peptide mapping, identification of aggregates Comparability studies Purity analysis Stability studies Trace analysis (organic or inorganic) QUALITY CONTROL In-Process-Controls (IPCs) Testing of raw materials & APIs Testing of standards and reference materials Cleaning verification and validation QUALITY ASSURANCE & REGULATORY SUPPORT cgmp compliance Regulatory support for filing Qualification of suppliers Release of materials

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11 ENZYMES PLASMIDS AND DNA VACCINES PROTEINS FRAGMENTS OF ANTIBODIES (Fabs) POLYCLONAL ANTIBODIES BACTERIA & YEASTS BIOPHARMACEUTICAL PRODUCTS (1 OF 2) MICROORGANISM FERMENTATION & EXTRACTION FROM INSULIN AND GROWTH HORMONE TO BIOPHARMACEUTICAL CMO SERVICE SANOFI 1984 Recombinant hgh through E.Coli fermentation HOECHST 1923 Production of extractive insulin 1936 Crystallized insulin 1976 Production of semi-synthetic insulin GENZYME 1994 Launch of Cerezyme 2001 Launch of Fabrazyme 2002 Launch of Aldurazyme 2006 Launch of Myozyme AVENTIS 1999 Recombinant insulin from E.Coli fermentation (Insuman ) 2000 Launch of Lantus 2004 Launch of Apidra SANOFI-AVENTIS 2005 Routine production of recombinant urate oxidase 2009 Purification of therapeutic proteins

12 PRODUCTION AND PURIFICATION OF THERAPEUTIC PROTEINS AND ENZYMES: FERMENTATION / PLANT EXTRACTION / ANIMAL ORIGIN From the 60 s, Sanofi has been a leader in the field of large-scale fermentation with the production of vitamins, antibiotics and steroids. In the 80 s, the production of recombinant proteins and enzymes has been a pillar of growth for the company. Fighting against Diabetes, Sanofi has become a leader in recombinant processing through its biosynthetic insulin business. Moreover, Sanofi has built a large library of microorganisms and non-natural enzymes, in order to have access to the optimized complex molecules. Expertise available from 3 centers of excellence: Frankfurt (Germany): specialized in fermentation and downstream process (DSP) Aramon (France): specialized in DSP to process natural extracts, plants, and animal milk Lyon-Gerland (France)-(former Genzyme plant): skills and capacities to process blood derivatives (site purifies Thymoglobulin from blood cells) Our upstream expertise covers: Strain building and optimization (molecular biology team in Frankfurt- Germany) Master cell bank cgmp production and storage High density fermentation up to 55 m 3 High throughput cell disruption techniques Inclusion body technology (processing, refolding) Our downstream expertise covers: Isolation techniques of a broad range of solutes and solids: continuous centrifugation, filtration, drying Process scale-up using in-house know-how and tools Large scale low to high pressure chromatographic techniques for the purification of proteins (glycosylated, multimeric) Continuous process and cost improvement using latest innovation (combining stainless steel and disposable equipment) A broad range of services to achieve your success: Biosafety risk assessment done by viral experts Fill & finish facilities to offer one-stop-shop (liquid and lyophilized vials, injectable syringes)

13 THERAPEUTIC PLASMIDS & DNA VACCINES Sanofi has an unique expertise with creation, production and purification of plasmids through in-house program. One compound completed international phase III studies: INDs and IMPDs submitted and drug substance validation completed. State-of-the-art workshop located in Frankfurt (Germany) is equipped with several trains of fermentation up to L with associated downstream process (DSP). Upstream process : Cell banking: master cell bank, working cell bank High cell density fermentation Downstream process : Specific equipment for continuous cell lysis Expertise in the purification of plasmids at large scale Technology available for the affinity chromatography of plasmids Specific technology and plasmid design: Sanofi patented pcor technology Batch size: 30 / 40 g High number of copies No antibiotic resistance gene Insertion of multimer resolution gene Example of a plasmid developed in-house: Double stranded circular DNA Supercoiled form Size: 1.5 million Dalton Contract manufacturing services offer: cgmp batches from preclinical phase to commercial scale Transfer of customer s process and analytical methods Fill & finish facilities Specific analytical expertise (to characterize and release material) CONTACTS MICROORGANISM FERMENTATION & EXTRACTION Europe: [email protected] [email protected] USA: [email protected] Japan: [email protected]

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15 PERFUSION & FED-BATCHES CHIMERIZATION AND HUMANIZATION mabs CHO CELLS MAbLaunch BIOPHARMACEUTICAL PRODUCTS (2 OF 2) MAMMALIAN CELL CULTURE INTERLEUKINS In a worldwide competitive and fast evolving environment, startup pharmaceutical and biotech companies need flexibility. Taking advantage of historical success, CEPiA offers to its customers a flexible and innovative solution to achieve success with their biologics projects, from development to commercialization.

16 A FULLY INTEGRATED ORGANIZATION TO PRODUCE MONOCLONAL ANTIBODIES & THERAPEUTIC PROTEINS FROM MAMMALIAN CELL CULTURE Sanofi offers biomanufacturing services from clinical phases to commercial scale: Expression vector construction mab chimerization and humanization Cell line development Biosafety risk assessment done by viral experts Strong analytical background with sophisticated glycosylated proteins Full range of analytical and regulatory support Fill & finish facilities to offer one-stop-shop Development and production of monoclonal antibodies and therapeutic proteins from two facilities. CAPI organization (Frankfurt, Germany) from early phase to phase III: 66 technical experts for development of mabs processes and analytical for in-house and customers purpose Perfusion and fed-batches Disposable and stainless steel bioreactors from 20 L to L Purification column from 20 cm to 60 cm Excellent track records Successful transfer of processes and analytical methods Analytical expertise to characterize proteins and release cgmp batches

17 BioLaunch organization co-located with Process Development (Vitry-sur-Seine, France): from phase III to commercial batches 60 scientists and technicians recently built state-of-the-art facility dedicated to mammalian cells bioproduction 3 modular stainless steel trains 2 separate seed trains from 100 L up to L 1 bioreactor of 2500 L and 3 bioreactors of L based on fed-batch processing broad range of associated downstream process (DSP) to achieve purification of mabs Through MabLaunch TM initiative, LFB & Sanofi combine their bioproduction capabilities to offer integrated CMO services from cell line development to commercial scale including clinical batches. CONTACTS MAMMALIAN CELL CULTURE Europe: [email protected] USA: [email protected] Japan: [email protected] VITRY-SUR-SEINE (FRANCE)

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19 GENE THERAPY SANOFI PASTEUR VIRAL VECTORS THERAPEUTIC VACCINES MERIAL VIRAL VECTORS FOR GENE THERAPY AND VACCINES APPLICATIONS GENCELL 1998 GENZYME photos : LBC Microscopie Electronique, Université François Rabelais, Faculté de Médecine et CHRU de Tours Sanofi has been a pioneer in the field of Gene therapy in the 80s through Gencell organization developping Viral Vectors. Sanofi through its vaccines division has a successfull history in virus production with launch of a large number of vaccines based on viruses. CEPiA offers its services to produce Viral Vectors through its Sanofi Pasteur and Genzyme divisions.

20 Lyon (France) a cluster of excellence to support external partners projects: Experts in Virology for vector optimization Upstream and downstream process excellence based on mammalian cell culture (suspension and adherent cell line on microcarriers), viral culture for vaccines production Engineering teams worldwide, working in close cooperation with equipment manufacturers Global knowledge management to implement the most recent technical innovations Analytical and regulatory services Fill & Finish facilities Sanofi team, with 20 years of experience, is a leading company in the production of viral vaccines (wild type or recombinant virus) and viral vectors. CEPiA offers a broad range of services such as, cell and virus banking, process scale-up to commercial scale manufacturing with various technologies (static culture, dynamic culture in single use bioreactors up to 1000 L).

21 Broad range of products upon request : - Adenovirus - Recombinant adeno-associated virus (raav) - Sendaï virus - Modified Ankara virus (MVA) - Lentivirus The teams, located in Lyon (France), have a significant track record and have a successful and diversified experience in process and analytical transfers. Sanofi Pasteur and Genzyme collaborate to establish a seamless project management. A new industrial platform in Lyon (France) combining expertise from Sanofi Pasteur and Genzyme is under construction and will be operational in 2015: m² - different technologies available: CEF (chicken embryo fibroblast) cell culture mammalian cell culture - techniques: cell factories, roller-bottles, single use bioreactors up to 1 m 3 CONTACTS Viral Vectors Europe: [email protected] USA: [email protected] Japan: [email protected]

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23 INNOVATIVE PLATFORM SCIENTIFIC EXPERTISE STATE-OF-THE-ART EQUIPMENT PEPTIDES & OLIGONUCLEOTIDES LIQUID & SOLID PHASE CHEMISTRY Our "Tides" Platforms are embedded in state-of-the-art infrastructures on 2 industrial sites: Haverhill (United Kingdom) Frankfurt (Germany), one of the largest industrial chemistry and biotechnology site. CEPiA offers customized services (manufacturing and analytical) from clinical phase to submission and launch (grams scale up to kilograms quantities), including regulatory support, as well as commercial supplies. cgmp API manufacturing can be combined with Drug Product and Devices technologies. Our facilities are regularly inspected by Health Authorities, including FDA, EMA and PMDA.

24 PEPTIDES DEVELOPMENT AND PRODUCTION Clinical Trial Quantities Commercial Batches Solid Support/Resin Resin + Peptide Synthesis Process Development Pilot Synthesizer L Production Plant Synthesizer 280 L Liquid phase peptide synthesis and synthesis of intermediates ( L) Solid phase peptide synthesis ( L) Crude Peptide Cleavage & Precipitaion Production Plant Production Plant Chromatography 1 Chromatography 2 Purification Chromatography 300/350 mm columns (lex, RP) Chromatography columns (lex, RP) in industrial network Vacuum - Distillation Lyophilization Isolation Lyophilizers (10 Kg + 40 Kg ice) Lyophilizer (100 Kg ice) Pure Peptide

25 Through Sanofi s 25 years experience in the field of oligonucleotides, CEPiA can provide different classes of Oligonucleotides such as DNA, 2 -O-Modified, phosphorothioate derivatives. OLIGONUCLEOTIDES DEVELOPMENT AND PRODUCTION Solid Support Oligonucleotide/ Support Oligonucleotide Solution Synthesis Deprotection & Cleavage Production Plant Oligo process Synthetizer up to 600 mmoles scale of crude Oligonucleotide ( Oligo Process with 12 independent amidite ports) Full analytical service: - Structural characterization - Development of analytical methods - QC testing for batch release - Full scope of analytical studies needed for filing Solvent supply lines, storage areas and waste management are designed according to the latest European standards. Chromatography Ultra-filtration Purification Desalting & Concentration Chromatography in industrial network CONTACTS Lyophilization Pure Oligonucleotide Isolation Lyophilizers TIDES Europe: [email protected] USA: Peptides [email protected] Oligonucleotides [email protected] Japan: [email protected]

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27 SYNTHETIC HEPARINOÏDS 200 CHEMICAL STEPS DEVELOPED 20 YEARS EXPERTISE OLIGOSACCHARIDES WORLDWIDE LEADER Sanofi has been involved in oligosaccharide chemistry since the 90 s and is recognized as a worldwide leader in API manufacturing in this field. Amongst this family of very active anti-thrombotic derivatives, Sanofi developed and marketed semisynthetic or fully synthetic heparinoïds. For the fully synthetic oligosaccharides, Sanofi has developed complex molecules which manufacture requires a high number of chemical steps (up to 80 chemical steps). For the projects, we develop a synergetic approach using a common building-blocks strategy based on our worldwide industrial network. Main advantages: Minimize the number of chemical intermediates Reduce lead time Increase security of supply Optimize cost of goods.

28 More than 200 chemical steps have been developed by our teams and more than 100 experts have been involved to ensure a high level of performance on this very specific chemistry being able to manage even at production scale: Activation of oligosaccharides throughout trichloroacetimidates, thioglycosides Coupling reactions (glycosylations): - stereoselective & stereospecific reactions - low temperature (down to -50 C at production scale) - anhydrous conditions (water contents below 10 ppm) Orthogonal protection/deprotection strategy Specific expertises in: - azidation - hydrazine handling In addition, our analytical department fully supports these development activities with: Chromatography techniques (HPLC, GC, IC, CE) with specific detection for molecules without UV absorption Mass spectrometry (Q-TOF, TOF, Ion-trap) and NMR (500 MHz and 300 MHz) to elucidate very complex chemical structures

29 TOOLS - FACILITIES Laboratories for oligosaccharide synthesis and analysis Kilolab facilities for production of small scale batches to support phase I to phase III clinical studies Kiloprep facilities for normal, reverse phase chromatography: Prochrom systems (50 to 300 mm) Pilot plant and production facilities: from 50 L to L Ion exchange dedicated purification facilities from grams to kilograms of APIs CONTACTS OLIGOSACCHARIDES Europe: [email protected] USA: [email protected] Japan: [email protected]

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31 OEB 5 COMPOUNDS OUTSTANDING FACILITIES ISO 7 CLASSIFICATION HIGHLY ACTIVE PRODUCTS HIGHLY SKILLED TEAMS CEPiA offers to customers to have their Highly Active Product (HAP) projects handled by the same experts who developed and manufacture the two marketed drugs: Docetaxel (Taxotere ) and Cabazitaxel (Jevtana )

32 Our high level of expertise acquired through solid and long lasting experience in handling cytotoxic compounds is strongly set on five principles: Extensive knowledge in Chemistry State-of-the-art facilities Highly trained team Environment, Health and Safety experts High standards in quality We are committed to sharing our scientific knowledge and experience in pharmacology and toxicology to support your project. Our internal team of experts in industrial hygiene can assess OEB* categorization for APIs and upstream intermediates only when necessary to minimize costs. We apply the OEB* index from 1 to 5 relative to the product toxicity. OEB* index corresponds to an OEL** range (see the following table). OEB* OEL** Range (µg/m 3 ) OEB OEB OEB OEB OEB 5 < 1 In addition, Sanofi has the highly specialized ability to handle HAPs with a single-digit nanogram/m 3 exposure limit. We have qualified several of our isolators to satisfy recent requirements. *OEB: Occupational Exposure Band **OEL: Occupational Exposure Limit

33 Our facilities for highly active compounds manufacturing are located near Paris (France), operated under cgmp procedures and are governed by Sanofi Quality Control. On the same site, two production units are suitable for technical transfer and process development, small scale production and large industrial scale manufacturing. These two units are operated in ISO 7 classification for OEB 4 and OEB 5 compounds and are regularly inspected by Health Authorities, including FDA, EMA & PMDA. All the production lines are equipped with the latest technologies in isolators, glove boxes, vessels and drying equipment. Machinery is fully or partially segregated with air control systems satisfying the most stringent requirements for product and personnel protection. Our volume range is L reactors in stainless steel, hastelloy and glass-lined for a total of 39 reactors (total volume of 10 m 3 ). Upon request, we provide milling and micronization services for HAP in ISO 7 room. The total staff is nearly 80, working in one or two shifts. Highly trained personnel are recognized for their ability to work meticulously and safely in contained environment. CONTACTS HAP Europe: [email protected] USA: [email protected] Japan: [email protected]

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