Slide 1Slide 2Long Road to a New MedicinePharmaceutical R&D ProcessSlide 5Slide 6The Discovery PhaseThe Exploratory Development StageSlide 9Exploratory Development StageSlide 11Exploratory Development - SummaryThe Full Development StageSlide 14Slide 15Slide 16Slide 17Slide 18Main Objectives of Chemical DevelopmentSlide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Allotropes of Tin and Napolean’s ButtonsSlide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40BibliographySlide 42Slide 43Slide 44Slide 45Part I:Chemical Development inthe Pharmaceutical Industry Overview of Pharmaceutical R&D Drug Discovery and Drug Development What is Chemical Development? General Aspects of Chemical DevelopmentPart I TopicsLong Road to a New MedicineLarge Amounts ofCandidate Medicine SynthesizedProject Team and PlansSynthesis of CompoundsEarly Safety StudiesFormulations DevelopedExtensiveSafety StudiesScreeningStudies in HealthyVolunteers Phase ICandidate Medicine Tested in 3,000-10,000 Patients (Phase III)Studies in 100-300Patients (Phase II)Clinical Data AnalysisNew MedicineIdeaDiscoveryFull DevelopmentRegistrationExploratoryDevelopmentOOHOOHOOOONNOOHHOOHNHCH3ClClPharmaceutical R&D ProcessIdeaIdeaDrugDrug12 - 15 Years12 - 15 YearsDiscoveryDiscoveryExploratory DevelopmentExploratory DevelopmentFull DevelopmentFull DevelopmentPhase IPhase IPhase IIPhase IIPhase IIIPhase III0 15510Preclinical PharmacologyPreclinical PharmacologyPreclinical SafetyPreclinical SafetyClinical Pharmacology & SafetyClinical Pharmacology & SafetyProductsProducts7,000,000 Compounds ScreenedHigh risk: $800 million+7,000,000 Compounds ScreenedHigh risk: $800 million+NH2CO2HNNOHNN NNFFNHOCH3OOOClONH2NNHOO-OH OH OFO2SNNHNONNNONNCF3SOOH2NThe Pharmaceutical R&D Process Discovery Stage Exploratory Development Stage Full Development Stage RegistrationIt all starts with an Idea to address a disease through an associated Therapeutic Target.Example – perhaps we can find a treatment for HIV-infected individualsif we could inhibit an enzyme which is crucial for replication of the virus. This leads to some questions…….. Can we design and chemically synthesize a small organic molecule (i.e., a drug) which can fit into the active site of the enzyme and inhibit its function? Can we find a way to administer this drug to humans? Is the drug safe for humans to take? Does the drug have the desired effect on a person’s health condition?The Discovery Stage The main goal of the Discovery Stage is to identify a single discrete organic molecule as a good candidate to become an effective, marketable drug.  The Discovery Stage can take up to 7 years, but rarely takes less than 3 years. The candidate compound then passes into the Exploratory Development Stage where the potential of that drug candidate to become a drug is evaluated. The Discovery PhaseThe Discovery PhaseThe Discovery StageThe Exploratory Development Stage Consists of Three Phases–Preclinical Phase - animal testing•Toxicity–Phase I - initial testing in healthy humans•Toxicity–Phase II - testing in humans with the disease•Toxicity•Establish dosing parameters•Initial indications of efficacyTherefore, the need for much larger quantities of the drug becomes acute. The drug must be chemically synthesized, usually in multi-kilogram amounts and the drug purity must be very high -- generally > 95%. The drug candidate will be given to a variety of animals andto a large number of human subjectsSuch large scale synthesis activities requires expertise in: synthetic organic chemistry chemical engineering analytical chemistryThe Exploratory Development StageOnce prepared, the drug substance must be formulated, i.e., preparedin such a way that it can easily enter living tissue and make its way to the site(s) of drug action.Exploratory Development StageExploratory Development StageThis generally requires that the drug substance be combined with other organic and inorganic compounds (called excipients) which are used to: Control the release of the drug substance in the human body Improve the assimilation process and bioavailability Enhance drug dissolution Extend the stability and shelf life of the drug substance Aid in the manufacturing process (e.g., production of tablets and capsules) Mask an unpleasant tasteOnce formulated the drug substance is called the drug product.Exploratory Development StageExploratory Development StageCommon ExcipientsMagnesium stearateLactoseStarchTalcSucroseSilicon dioxideTitanium dioxideCalcium phosphateEthylcelluloseGelatinExample: Prozac (an antidepressant drug) is formulated with starch, gelatin, silicone, titanium dioxide and iron oxide, among other excipients.Once it has been formulated, the drug product is ready for administration to animals and humans.Exploratory Development - SummaryExploratory Development - SummaryLarge scale organic synthesisis used to produce the drug substanceThe drug substance is combined with excipients to produce the formulateddrug product.The drug product is toxicity-testedin animals for safety.In Phase I clinical studies, the drug product is tested in humans to assess safety, and tolerability.In Phase II clinical studies, the drug product is tested in humans to determine the dose range and to collect information on efficacy.Success rates in Exploratory Development are low -- around 10 - 25%.The Full Development StageThe Full Development StageA drug candidate moves into Full Developmentafter enough information has been gathered which gives a strong indication that the candidate will be successful in treating the disease.Phase III clinical studies in humans are thenconducted to confirm the efficacy of the drug in a large population of patients.Many more activities must go on at this time to prepare to “launch” the drug.Pre-Launch ActivitiesDrug Substance – a large scale, inexpensive and robust manufacturing process for the drug substance must be developed.Drug Product – a large scale, inexpensive and robust formulation process for the drug product must be developed.The Key Terms here are “Large Scale” and “Process.”What is a “Process”?Process – a sequence of actions; in organic synthesis, those actionstaken in performing a chemical reaction or series of chemical reactions;may refer to a