1. NON CLINICAL DEVELOPMENT OF DRUG SPECIALITIES ________________________ Bernard MARCHAND

2. ExploExplo ProjectProject Preclinical Stage A Phase I Phase II Phase III NDANDA Post NDA Preclinical Stage B Bio Pharmaceutical Research TOXICO ADME Salt Selection Phase I Formulation PK Interactions PB/PK PK/PD Up scaled Formulation Toxicological and kinetics Expertises Population Kinetic Interspecies metabolism comparison Pharmaceutical File New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis

3. Pharmacokinetic PharmacokineticToxicologyPhysicochemistry Preclinical Development New targetsNew tools coming from development RESEARCH PHARMACOLOGY CHEMISTRY Structure Activity Relationships BIOPHARMACEUTICAL SCREENING DEPARTMENT Hits Identification Lead Optimisation Candidat Selection Analytical methods, Absorption Metabolic stability Solubility,Specific questions...

4. HTSSDS Preclinical Development Clinical Trial 1 drug1- 3 drugs 30 - 3 drugs 300 - 30 drugs Lead OptimisationBack-up  Intestinal absorption  P450 Isoenzymes  Metabolic Stability  Inhibition  Metabolic pathway  Induction  Other parameters  BBB permeation/Cell toxicity DISCOVERY PROCESS & BIOPHARMACY DESCRIPTORS

5. MAJOR TECHNICAL EVOLUTIONS IN BIOPHARMACY * ** ** * * * * * * * * * * * * * * * ** HPLC LC/MS/MS ANALYTICAL DETECTION SAMPLE PREPARATION CELLLULAR MODELS (Caco2, hepatocytes) GENETIC TOOLS (Human DNA) Automation (96 wells) SUBCELLULAR MODELS Hepatic Microsomes (animal + man) BIO INFORMATIC Data Analysis Modelisation Cassette Dosing

6. ABSORBED FRACTION SOLUBILITY Fraction of the dose solubilised in the intestin SOLUBILITY Fraction of the dose solubilised in the intestin ABSORBED FRACTION PERMEABILITYSOLUBILITY LIPOPHILY PERMEABILITY Molecular Weight Nitrogen Oxygene Hydrogen Bonds Ionisation PERMEABILITY Molecular Weight Nitrogen Oxygene Hydrogen Bonds Ionisation

7. Caco2 PERMEABILITY MODEL Different Transport Mechanisms - Transcellular (passive) (lipophilic) - Paracellular (passive) (hydrophilic) - Transcellular (active) (transportors) - Efflux Process (PGP) HUMAN ENTEROCYTE CELLS

8. IntestinIntestin Liver General Circulation HEPATIC BARRIER Metabolism Rate Component of the terminal half time Metabolic Bioavailability (first pass effect) Metabolism rapidity LIPOPHILY

9. PREDICTION OF IN VIVO METABOLIC BIOAVAILABILITY Km vitro Vm vitro Km vivo Vm vivo g prot/g liver and g liver/animal Metabolic Biovailability Q*fu*Vm*S/(Km+S) Blood Flow Q+fu*Vm*S/(Km+S) Plasma Proteins Concentration IN Concentration OUT Metabolites Concentration Ka Dose

10. SIMULATION IN RELATION TO DOSE predicted clinical doses 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0,01 0,08 0,64 5,12 40,96 327,68 2621,44 SimLin Dose (mg/kg) DOG + + + MAN 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0,01 0,080,64 5,12 40,96 327,68 2621,44 SimLin Dose (mg/kg) + Metabolic Bioavailability Biodisponibilité métabolique In vivo/In vitrocorrelation in one species : Mixture of products (cassette dosing 5/Rat - 50/Dog

11. 1A2 6% 2A6 2% 2C9 10% 2C19 4% 2D6 30% 2E1 5% 3A4 43% NATURE AND NUMBER OF INVOLVED P450 Interest in screening : - Avoid one polymorphic enzyme - Avoid metabolism by only one P450 Metabolic Stability ± specific inhibitors

12. Enterocyte humain : transport et métabolisme UGT UGT 1A6 1A6 3A4 3A4 UGT UGT 2B27 2B27 3A4 3A4 hOATP-B(?) MRP-3 MRP-1 MRP-(5?) BCRP ISBT LRP MRP-1(?) MRP-2 P-gp (MDR- 1) PepT1 ASBT Na + /SLGT1 SPNT1 Dipeptide Tripeptide Transporters MCT (drug/H + co- transporter) SANGVEINEPORTESANGVEINEPORTE INTESTININTESTIN Noyau 1A13A41A2 Jonctions serrées

13. BLOOD BRAIN BARRIER MODELE Transport Study (filter +/- cells) Astrocytes (confluent in 3 weeks) Ringer HEPES Drug 6 wales plates BBCE (confluent and differenciated in 1 week and ready to use for 5 days) Basolateral Apical LC-MS-MS Quantitation (10, 15, 20, 30, 45 min) Co-culture of Bovin Brain Capillary Endothelial Cells with rat astrocytes (Pr Ceccheli - Lille)

14. CORRELATION Caco2/BHE R = 0.74

15. SCREENING IN TOXICOLOGY MutagenesisMutagenesis Ames II Automatised Micronucleus ? Morphology, Viability, Glutathion level Cellular Toxicology with cryopreserved hepatocytes ? In vitro model answering in vivo issues Ex : vacuolisation on cultured fibroblastes Toxicogenomics ?

16. Global approach Significant gene induction or repression Cells / Tissues RNA Hybridization Database mining and mecanistic interpretation Image analysis TOXICOGENOMICS

17. maxmin ControlPhenobarbital CYP2B CYP3A RESULTS

18. Gene Category Selected Genes Apoptosis Cell cycle DNA damage/Repair Inflammation Oncogene Stress response Peroxisome Proliferators Transcription factors, growth factors Plasma transport Phase I Phase II Phase 0/III CYPs regulating nuclear factors Bax, Bcl-2, Bcl-X, c-myc, c-fos, caspase 7-8,CD 27, TNF, Smp30 Cyclin A-B1- D1/2/3-E1, cdK 2-4-6,JNK-1, Telomerase GADD45, GADD153, MGMT, p16, poly(ADP-ribose) synthetase IL 1, IL-6,IL11, IL-15, cyclooxygenase-2 c-jun, c-myc, elk-1 Oxidative stress genes, ApoJ, Hsp70, Heme oxygenase 2, SOD Enoyl coA hydratase, PPAR , Acyl coA oxidase C/EBP , I  B- , NF  B, erk-1, p38, HGF, TGFB RII albumin, transferrin CYP P450s (22), FMO, EH, MAO GST (4), UGT(10), SULT(4) MDR1, MRP (6), BSEP, OATP (4), OAT (2), OCT (2) CAR, PXR, RXR, GR 175 human genes involved in drug metabolism at the hepatic level

19. HANDLING THE DATA Databases for correct data use, the new challenge for tomorrow ? Tools for rapid assessment of metabolism are available but how we handle the data has not yet been completely mastered Data base Log K ’Calculated LogP, Rate of metabolism Solubility, LogP Caco-2 Papp Microsomal Km/Vm IC50 inhibition n-in-one dosing CYP450 Km, Vm Ki inhibition constant induction potential n-in-one dosing in Man ? Sorting molecules with Warnings and Metabolic SAR Sorting molecules with in vivo scaled up data and Metabolic QSAR Sorting molecules with partial or total rebuilding of the entire population Theoretical approach HTS SDS Preclinical development 1st administration to Man Back up

20. PRECLINICAL STUDY PROGRAMME Stage BStage A 4 months 6 months -Dose Ranging (3-7d) Rat + Non-Rodt - Ames test - Mouse Lymph. -Drug Subst. Analyt. Chem. - Degradation - 4 wk Tox Rat + Non-Rodt - Acute studies Rat + Mouse PO & IP or IV - Rat Bone Marrow micronucleus - Choice of Salt - Tablet Formul. + Stability - Assay Validation - Plasma Stability - TK 4 wk Rat - TK 4 wk Non-Rodt - TK Micronucleus - Def. PK Non-Rodt - Induct. Potential Rat + Non-Rdt* * if Rat positive - Enzymes identif. (human) - Intersp. Comp. 14 C -  Label. Cpd - Assay developt - TK DoseRanging Rat+ Non-Rodt - PK Rat - Prel. PK Non-Rodt - Blood/Pl.Ratio - Prel. Metab. in vivo Rat - Prel. Prot. Bind. - Inhib. Potential - Intersp. Comp. - Feasibility label. cpd 200 g 2.5 kg

21. Regulatory Toxicology – Early Programme #   Phase I requirements * Single dose toxicity Repeat dose toxicity studies Genotoxicity studies Reproductive toxicity studies * Other requirements Pharmacology (actions relevant to the proposed route) Safety pharmacology Pharmacokinetics (preliminary studies on absorption, distribution, metabolism and excretion) and in vitro metabolism studies # ICH M3 : Nonclinical Safety Studies

22. Regulatory Toxicology – Later Programme #   Phase II, III marketing application requirements * Chronic dose toxicity studies Carcinogenicity studies Reproductive toxicity studies Appropriate toxicity/genotoxicity studies on metabolites, impurities and/or excipient * Other requirements Additional safety pharmacology (if necessary) Additional genotoxicity studies (if necessary) Phamacokinetics (studies on absorption, distribution, metabolism and excretion) # ICH M3 : Nonclinical Safety Studies

23. Duration of Toxicity Studies # * NOTE in US and EU, as an alternative to repeat dose studies, single dose toxicity studies with extended examinations may support single dose human trials Minimum duration of toxicity Duration of clinical trials RodentNon –rodent Single dose2 weeks*2 weeks Up to 2 weeks2-4 weeks*2 weeks Up to one monthone monthone month Up to 3 months3 months3 months Up to 6 months6 months6 months - 1year > 6 months6 months1 year To support phase I and II trials in EU and phase I, II and III trials # ICH M3 : Nonclinical Safety Studies

24. The battery can be completed with additional test(s) when necessary. Should permit to discard at the beginning of development potential genotoxic carcinogen compounds   AMES TEST: detection of reverse mutation on S. typhimurium and E. coli (= procaryotes)   MOUSE LYMPHOMA : detection of forward mutation on cell lineage (= eucaryotes) can also detect clastogenic effects IN VITRO IN VIVO   MICRONUCLEUS on rat bone marrow: detection of chromosome breaks = clastogenicity PRECLINICAL STUDIES GENOTOXICITY : Standard Test Battery

25. - ACUTE : Route: intended for human -If oral route for human : ORAL + PARENTERAL (IV or IP) Species: MOUSE and RAT Examinations : MORTALITY CLINICAL SIGNS/ BEHAVIOR GROSS OBSERVATION AT NECROPSY (Histopathology for gross lesions)  Acute toxicology profile MNLD = Maximal non-lethal dose MLD = Minimal lethal dose PRECLINICAL STUDIES GENERAL TOXICOLOGY

26. - SUBCHRONIC and CHRONIC Route :intended for human Species :Rodent = RAT Non-Rodent = DOG or MONKEY Dosing :daily (or twice daily), 3 doses + control Duration :up to 6 months (rodents) 9 to 12 months (non-rodents) Investigations : pluridisciplinary contributions  Define NOEL : No Effect Level or NOAEL: No Adverse Effect Level TARGET ORGANS - BIOMARKERS PRECLINICAL STUDIES GENERAL TOXICOLOGY

27. Clinical observations behavior Toxicokinetic/Metabolism (enzyme induction/inhibition) Bodyweight Food/Water intakes Necropsy Gross observations  40 organs/tissue samples Histology process HistopathologyElectron microscopy Urinalysis Blood Hematology red, white cells and platelet counts Biochemistry 20 to 25 parameters STANDARD TOXICOLOGY EVALUATIONS

28. - EMBRYOFETAL TOXICOLOGY : Hysterectomy - uterus content: implantations, resorptions… - external - visceral examinations of fetus - skeletal  Teratogenic effect? - FERTILITY : Reproductive performance Male : sperm analysis + histopathology of gonads and accessory glands Female : oestrus cycle PRECLINICAL STUDIES REPRODUCTIVE TOXICOLOGY

29. - PERI-and POSTNATAL TOXICOLOGY Parturition Lactation Physical, sensory and behavioral development of pups Second generation study Species :Rodent = RAT + Non Rodent = RABBIT (Lagomorph) for embryofetal studies PRECLINICAL STUDIES REPRODUCTIVE TOXICOLOGY (contld)

30. These studies remain necessary to detect non-genotoxic carcinogens. Two species: RAT and MOUSE Two-year duration: LIFE SPAN for these species Investigations :. Clinical observations and mortality. Feed and water intakes. Palpations: for detection of masses (subcutaneous, mammary glands,…). Necropsy gross observations organ weights histomorphologic evaluations  40 tissues or organs + masses. Statistical analysis  Conclusion about carcinogenic potential PRECLINICAL STUDIES CARCINOGENESIS

31. Plasma Concentration 1000 100 10 01234 5 Time (h) Toxicity treshold Peak effect Toxic effects Toxicokinetics Pharmacologic effects Pharmacokinetics TOXICOLOGY

32. Toxicological Requirement   Depending on toxicity, a frequently used “safety margin” for volunteer studies is 10 fold between dose which produces toxicity in animals and dose given to humans   First dose can be 1/100 of NOAEL   Final dose can be 1/10 of NOAEL   Plasma data on drug will give levels at which toxic effects may be expected and so must not be exceeded   Awareness that animal data not necessarily predict clinical toxicity

33. PRECLINICAL STUDY PROGRAMME Pre- Project Stage B Stage A 4 months 6 months 2 months 1 month Decision PointPreclinical Research -Dose Ranging (3-7d) Rat + Non-Rodt - Ames test - Mouse Lymph. -Drug Subst. Analyt. Chem. - Degradation - 4 wk Tox Rat + Non-Rodt - Acute studies Rat + Mouse PO & IP or IV - Rat Bone Marrow micronucleus - Choice of Salt - Tablet Formul. + Stability - Assay Validation - Plasma Stability - TK 4 wk Rat - TK 4 wk Non-Rodt - TK Micronucleus - Def. PK Non-Rodt - Induct. Potential Rat + Non-Rdt* * if Rat positive - Enzymes identif. (human) - Intersp. Comp. 14 C -  Label. Cpd Check List Preclinical Summary Board Committee Development Decision - Production clinical batch Phase I (capsule) Investigator brochure - Clinical Assay - Plasma Stab. (man) - TK assay (transfer to CRO) - TK Dose Ranging ReproTox - WBA Rat - Mass Bal. Rat & in vivo Met. - Def. Prot. Bind. (label. cpd) - Dose Ranging ReproTox - Assay developt - TK DoseRanging Rat+ Non-Rodt - PK Rat - Prel. PK Non-Rodt - Blood/Pl.Ratio - Prel. Metab. in vivo Rat - Prel. Prot. Bind. - Inhib. Potential - Intersp. Comp. - Feasibility label. cpd 16 kg 200 g 2.5 kg IMPD

34. PHASE 1 STUDIES Dosing 600-900 samples in real time

35. TARGET ORGANS (TISSUES) GASTRO INTESTINAL TRACT BLOOD CIRCULATION First pass effect Portal vein LIVER 1 10 100 1000 04812162024 Time (h) Concentration ABSORPTION DISTRIBUTION Cmax tmax + ELIMINATION Administration EXCRETION Bile AUC Exposure ORAL ROUTE SINGLE DOSE PK

36. 1 10 100 1000 04812162024 Time (h) Concentration 1 10 100 1000 04812162024 Time (h) Concentration Integration of physiological parameters and in vitro measurements Q tissues Q muscles Q portal v. Q hepatic. a Q heart Kp liver Vmax Km f abs Kp heart Kp lung Kp tissues Kp muscles

37. Bioavailability Inter/intr a subject variability Drug-drug interaction Intestinal absorption Metabolic stability Metabolic pathways P450 Isoenzymes Inhibition potential Induction potential Prediction of the main drug characteristics with respect to the entire population Rebuild (predict) of the in vivo situation Evaluation of simple drug metabolism parameters DMPK ISSUES IN DRUG DEVELOPMENT

38. PREDICTIONS IN VIVO Interindividual variability CYP1A1 CYP1A2 CYP2C9 Extreme subjects of the simulation Time (h) Concentration (µM)

39. IN VIVO PREDICTIONS Drug-drug interactions 1 10 100 1000 Concentration 04812162024 Time (h) + inductor + inhibitor + +

40. PHASE II PK/PD

41. Simulations Dissolution model : Relationship between In vitro and In vivo dissolution PK/PD model : Relationship between plasma concentrations and effects Pharmacodynamic objectives Sustained release formulation Why a modelling approach? A clinical study per formulation PK model : Absorption, distribution, elimination

42. FORMULATION RESEARCH Oral Route Tablets and Capsules Fast Dissolving Forms Slow Release Formulation Delayed Formulation Injectable Route Bolus and Infusion Slow Release Formulation Transdermal Route Patches Iontophoresis devices Transmucosal Route Buccal Nasal Pulmonary

43. ORAL ROUTE/PROLONGED RELEASE HYDROPHILIC MATRIX  Gastro intestinal fluids penetrate the polymer layer which, consequently, swells and forms a gel which controls the release kinetics of the drug substance H2OH2O HPMC

44. ORAL ROUTE / HYDROPHILIC MATRIX In vitro dissolution profile 0 50 100 0481216 Prolonged Release Immediate Release % H

45. ORAL ROUTE / HYDROPHILIC MATRIX 0 20 40 60 80 0244872 Immediate Release Prolonged Release [ng/ml] H In Vivo

46. ORAL ROUTE / PROLONGED RELEASE SEMI SOLID LIPOPHILIC MATRIX Control of the release kinetics is obtained by the choice of the excipient and by its hydrophilic-lipophilic balance (HLB). Manufacturing process, excipient melting, drug substance dispersion in the molten mass and, pouring into hard gelatin capsules

47. ORAL ROUTE SEMI SOLID MATRIX STABILISATION

48. Multiparticulate dosage form as small spherical reservoir beads (0.5 à 1.5 mm diameter) Dissolution rate controlled by a semi- permeable membrane ORAL ROUTE / PROLONGED RELEASE MICROPARTICLES

49. PROLONGED RELEASE MICROPARTICLES Filters Coating solution Hot air Semi permeable membrane Drug substance + Excipients

50. ORAL ROUTE SUSTAINED RELEASE MICROPARTICLESIR P R IR 3 x day PR 1 x day

51. ORAL ROUTE / DELAYED RELEASE 0 20 40 60 80 100 120 024681012141618 Time (h) Drug substance released (%)

52. ORAL ROUTE / DELAYED RELEASE

53. ORAL ROUTE DELAYED AND PROLONGED RELEASE MICROPARTICLES Plasma Concentration In vitro dissolution rate

54. ExploExplo ProjectProject Preclinical Stage A Phase I Phase II Phase III NDANDA Post NDA Preclinical Stage B Bio Pharmaceutical Research TOXICO ADME Salt Selection Phase I Formulation PK Interactions PB/PK PK/PD Up scaled Formulation Toxicological and kinetics Expertises Population Kinetic Interspecies metabolism comparison Pharmaceutical File New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis

55. POPULATION KINETIC

57. Therapeutic window Therapeutic window Relation conc. / effects Relation conc. / effects Side effects Side effects Toxicity Toxicity etc. etc. Absorption Absorption Distribution Distribution Metabolism Metabolism Elimination Elimination etc. etc. Status of the patient Status of the patient Age, weight Age, weight Stage of the illness Stage of the illness Associated pathologies Associated pathologies Associated treatments Associated treatments Compliance Compliance etc. etc. Administration routes Administration routes Formulation Formulation Tolerance - addiction Tolerance - addiction Drug interactions Drug interactions Genetic Polymorphism Genetic Polymorphism etc. etc. Clinical Factors Pharmacokinetics OtherFactors Activity - Toxicity Clinical PKcs Regimen

58. ExploExplo ProjectProject Preclinical Stage A Phase I Phase II Phase III NDANDA Post NDA Preclinical Stage B Bio Pharmaceutical Research TOXICO ADME Salt Selection Phase I Formulation PK Interactions PB/PK PK/PD Up scaled Formulation Toxicological and kinetics Expertises Population Kinetic Interspecies metabolism comparison Pharmaceutical File New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis

59. Pharmaceutical File COHERENCE Analytical Methods Impurities Degradation products FORMULATION DESCRIPTION Diluting and lubrification agents Added excipients REGULATORY CONSTRAINTS % Qualification

60. PHARMACEUTICAL DEVELOPMENT 2 Definitions : Drug substance = Active substance (New Chemical Entity or existing drug substance ) Drug product = medicinal product = Finished product (tablets, capsules, …)

61. BEGINNING OF PHARMACEUTICAL DEVELOPMENT (1)  Physicochemical properties of the new drug substance  solubility in water at different pH values  kinetics of dissolution as a function of particle size ........  Stability of the drug substance itself  stress conditions (acidic or basic pH, oxidation, temperature)

62. BEGINNING OF PHARMACEUTICAL DEVELOPMENT (2)  Choice of salt and cristalin form for development - Solubility - Stability  Chemical compatibility drug substance/excipients  Formulations for phase I

63. TYPES OF FORMULATION / ORAL ROUTE  Release of the drug substance  Immediate release (IR)  Modified release (MR)  prolonged release  delayed release

64. IMMEDIATE RELEASE TABLET  Drug substance  Diluant (lactose, mannitol....)  Binder (povidone,HPMC, maltodextrin....)  Desintegrating agent (sodium starch glycolate,…)  Flowing agent (silica, talc....)  Lubricant (magnesium stearate, stearic acid....)

65. THE IDEAL FORMULATION (1)  Easy to manufacture, with a robust process giving always a quality product  Delivering the drug substance as needed according to its intrinsec pharmacokinetic properties (half-life, site of absorption......) and to the therapeutic needs :  prolonged release for a once-a-day formulation of a drug substance with a short half-life  quick Cmax to get an effect quickly  lower Cmax to decrease side effects ......   Stable throughout the storage period   chemical stability of the drug   no evolution of the dissolution profile

66. INTERNATIONAL CONFERENCE OF HARMONISATION : I.C.H. PROCESS  Since 1990  The aim: to standardize the studies to be performed for the registration of a new product in the 3 main geographical areas : USA/Canada Japon European Union  3 topics Safety (guidelines S) / Toxicology Efficacy (guidelines E) / Clinical development Quality (guidelines Q) / Pharmaceutical development

67. I.C.H. PROCESS Example : Stability for zone II  Drug substance :  3 batches  packaging representative of industrial packaging  Drug product :  3 batches (the size of 2 out of 3 is more than 1/10 that of industrial batches)  packaging chosen for the market   Conditions :   25°C/60%RH throughout shelf-life   30°C/60%RH (65%RH in 2005) 1 year   40°C/75%RH 6 months   Time of analysis :   0, 3 months, 6 months, 9 months, 1 year, 18 months, 2 years, 3 years

68. MARKETING AUTHORISATION FILE DRUG SUBSTANCE  S.2 Preparation/synthesis  S.3 Characterisation (Physico-chemical properties, structure and qualification of impurities)  S.4 Control of drug substance  S.7 Stability

69. MARKETING AUTHORISATION FILE DRUG PRODUCT  P.1 Description and composition  P.2 Process development/validation  P.3 Manufacturing process  P.4 Excipients  P.5 Control of drug product  P.7 Container closure system  P.8 Stability  shelf-life and storage conditions

70. Change in Production Site Improvment of Analytical Technics Improvment  Stability  Stability New Specifications  Solvants  Impurities  Stability  Stability New Specifications  Solvants  Impurities Up dating of the CMC File

71. PHARMACOPEAPHARMACOPEA 1st WAY SETTING THE SPECIFICATION OF THE ACTIVE PRINCIPLE 2nd WAY Consensus within competitorsBefore patent issue Monopole situation

72. PHARMACOPEA FOR PERINDOPRIL STRUCTUREIsomere S S S S S31 isomeres as potential impurities < 0.1 % TRACING IMPURITY

73. 1st pathway: Standard analysis criteria :  purity profil  dissolution  content 2nd pathway : Qualitative and Quantitative Analysis of the Formulation COPIES AND COUNTERFEITS How to distinguish Real from False ?

74. Suspicion of counterfeited Servier drug Analysis of a whole truck content  official ceremony to distroy the unlegal product EX : SUSPECTED DRUG China Indonesia Suspicion of counterfeit but appeared to be parallel import through Australia then ???... Indonesia Malte Suspicion of parallel import finally proved to be counterfeits

75. ExploExplo ProjectProject Preclinical Stage A Phase I Phase II Phase III NDANDA Post NDA Preclinical Stage B Bio Pharmaceutical Research TOXICO ADME Salt Selection Phase I Formulation PK Interactions PB/PK PK/PD Up scaled Formulation Toxicological and kinetics Expertises Population Kinetic Interspecies metabolism comparison Pharmaceutical File New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis

76. PHARMACEUTICAL DEVELOPMENT Staff : 150 Analytical methods Stability & Purity analysis Formulation Drug Delivery Orléans Vignat TOXICOLOGYGidy Staff : 109 General Toxicology Reproductive Toxicology Mutagenesis Cancerogenesis Drug Safety Research Center Gidy Orléans Bel Air PHARMACOKINETICS London Orléans Staff : 136 (3 sites) Screening ADME studies PK/PD Relationships Population kinetics Wexham, London Courbevoie Orléans Courbevoie BIOPHARMACY