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7/31/2014How has ACS Webinarsbenefited you? “I have learned a lot of what I aminterested in during the Drug DiscoverySeries. For example, I have obtained thenew information about the drug discoveryprocess from both academics andindustries.”Fan of the WeekZuping Xia, Ph.D.Research Associate Professor,and Director of NMR Core,College of Pharmacy, Washington State UniversityBe a featured fan on an upcoming webinar! Write to us @ binarsyoutube.com/acswebinars84
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7/31/2014 Upcoming ACS Webinarswww.acs.org/acswebinarsThursday, August 7, 2014“How to Write Abstracts that CaptureYour Audience”Celia Elliott, University of Illinois at Urbana-ChampaignPatricia Blum, University of Illinois at Urbana-ChampaignThursday, August 21, 2014“Forecasting Chemistry: PredictingTomorrow’s Cutting Edge Science, Today”Dr. Charles Twardy, SciCast Project Principal and Professorat George Mason UniversityContact ACS Webinars at acswebinars@acs.org11Did you miss the past recordingsin the Drug Discovery inars/drug-discovery-series-2014.html6
7/31/2014Next in the Drug Discovery Series!“Pharmacoeconomics and IP Strategiesin Drug Development”Thursday, September 25, 201413The Role of Chemistry in Clinical Trials:The Big Expense & Lessons LearnedDr. Graham JohnsonPresident, NuPharmAdvise LLCDr. John MorrisonSenior Research Investigator,Bristol-Myers SquibbDr. Jay SiscoFounder, JM Sisco Pharma Consulting LLCPast-President, AAPSRecordings will be available to ACS members after two weekswww.acswebinars.orgContact acswebinars@acs.org for a copy of today’s slides147
7/31/2014The Role of Chemistryin Clinical TrialsAn ACS Webinar Presented by:Dr. Graham Johnson – NuPharmAdvise, LLCDr. John M. “Jay” Sisco – JM Sisco Pharma Consulting, LLCModerated by Dr. John Morrison – Bristol-Myers SquibbOur Objective Create awareness and understanding of whathappens between lead candidate selection andNDA submission that translates into better drugdesign and lead candidate selection A small investment up front can translate intohuge savings later on8
7/31/2014Discovery to hToxicologyPhase 1Phase 2SafetyProof ofefficacyPhase 3RegistrationLarge safety andefficacyApprovalPostmarketingClinical Trials The sole objective of clinical trials are to definethe safety, tolerability/side effects, effectivenessand dose of a new drug and create theknowledge base on which the FDA can approveits use and sale. The “chemistry” of a new drug makes up acritical part of this knowledge base9
7/31/2014Drug Product Development Facilitation of repeated safe delivery of thecorrect quantity of active substance at thecorrect rate to the desired body compartment Guaranteed until the expiry dateEvery TimeChemistry, Manufacturing & Controls Chemical R&D: reliable, reproducible, scalable synthetic API process Pharmaceutical physicochemical properties of the API, drug productR&D:phase appropriate formulations – stable and deliver thecorrect dose Analytical R&D: analytical methodologies - release testing and stabilityevaluation of API and drug product. Quality:ensures compliance - regulations that govern themanufacture, analysis, packaging, labeling and shippingof API and drug product. Reg.CMC:author CMC section of submissions, interact withregulatory authorities on matters concerning CMC Supply Chain:manufacture, package, label and ship clinical trial material10
7/31/2014What is the Chemistry of a Drug To the FDA– A stable active pharmaceutical ingredient(API) that can be made in completely definedand controlled process that produces aproduct of consistent purity, chirality, stabilityand physical form To the Company– A compound that can be consistently made bya process that provides the greatest profitmargin or lowest “Cost of Goods”Bridging the Divide Medicinal chemistry - the interface of organic chemistrywith biological systems. The objective is the discovery ofnew drugs through the generation of structural diversityand understanding its relationship to biological activity Process chemistry - the interface of organic chemistrywith business. The objective is the manufacture of aspecific molecule and a defined form with a high degreeof quality both cost effectively and with lowenvironmental impact.11
7/31/2014Different Strokes for Different Folks To the Medicinal Chemist– The product is the driver! – how it is made and whatgoes on in the flask is of less importance To the Process Chemist– The process is the driver – understanding andcontrolling every facet of what goes on in the flask iscritical To the Formulation Chemist– The properties are the driver – creating an activeand commercially viable formulation depends on themOperating in Different WorldsDiscovery Chemistry– All reaction types, reagents and solvents are on thetable – if you can buy it you can use it!– Temperatures from -110 to 300 – no problem!– Reaction concentration – what is that?– Specialized equipment – high pressurehydrogenation, microwave reactors – absolutelywe’ve got that!– Purification – HPLC does the trick every time!– Safety – if I am not working with diazomethane orHF why do I need to worry?12
7/31/2014Operating in Different WorldsProcess Chemistry– Safety is a primary driver– Stability, toxicity, disposal and allowed residues limitchoices– Temperatures outside -20 to 120 C are a challenge– Most chemistry is bimolecular – concentrated reactionswork better and save on many levels– Chromatography is expensive - crystalline solids arethe workhorse of isolation and purification– Controlling crystallization is essential– Specialized equipment offer options to solve chemicalproblems – flow reactorsContinuous Flow Rectors – The Conceptpurificationflow reactorfeed tankspressure regulatoranalysisproduct tank13
7/31/2014Continuous Flow Reactors - ExpandingWhat is Possible Flow reactors permit smaller reaction vessels – unlimitedscalability Chemistry can be run 24hrs a day In line continuous analysis of conditions and product Safety is ensured by carefully controlled reactor crosssection and flow rates Fast and efficient mixing for rapid reactions Highly exothermic reactions become manageable Microwave heating, cooling, photolysis, increasedpressure are all possible Quality, reproducibility and safety are ensuredCase Study - Naproxcinod Collaboration between Nicox, DSM and Corning GlassConcern for exothermic breakdown of the productKey intermediate nitrated using 65% nitric acidReaction flow continues into quench and neutralization14
7/31/2014Scaling by Parallel Processing1mm reactionchannelsMultiplexed product delivery 14kg/hrDSM produced 25 metric tons of API undercGMP conditions!Crystal Form – Polymorphism“The ability of a solid material to exist in two or morecrystalline phases with different arrangements orconformations in the crystal s“poly” many“morph” formsCrystallineNon-crystallineHydrate/Solvate15
7/31/2014PolymorphismSame chemical structureMolecules arranged differently in the unit cell𝜸 - glycineα - glycineDifferent Physical & Chemical PropertiesPolymorphismEffects physicochemical and pharmaceuticalproperties of the APIPacking:DensityThermodynamic: SolubilityFree EnergyMelting PointSpectroscopic:Vibrational echanical:Pharmaceutical:HardnessTensile StrengthFlowabilityCompatibilityCompressabilityAPI & DP 16
7/31/2014Biopharmaceutics ClassificationSystem (BCS)High SolubilityLow Solubility10Class 2High SolubilityHigh PermeabilityLow SolubilityHigh PermeabilityClass 3Class 4High SolubilityLow PermeabilityLow SolubilityLow PermeabilityLowPermeability1Class 1HighPermeabilityPermeability (1x10-6 cm/s)1000.1110100100010000100000250Volume Required to Dissolve the Highest Dose(mL)Case StudyEffect of Polymorphism onthe ManufacturingProcess for the Drug ProductLamivudine (3TC): GSK17
7/31/2014Drug Product Processing - FlowLamivudine (3TC) – “Pseudopolymorphs”Class:nRTITreatment:HIV 1&2Hep B3TC – Form 1NoteScaleHabit:NeedlesMelting Point: 135ºCSolvate:Crystallization Solv’t: WaterSol’y Stable Form:Water & MeOH0.2 HydrateCrystal Class: OrthorhombicZ:2018
7/31/20143TC – Form 2NoteScaleHabit:bipyrimidsCrystallization Solv’t: IMS & iso-PrOHMelting Point:178ºCSol’y Stable Form:Solvate:non-solvatedEtOH, n-PrOH,iso-PrOH, n-BuOHCrystal Class: tetragonalsec-BuOH, EtOAcZ:ACN, Acetone8Case StudyPolymorphism Effect onBioavailabilityChloramphenicol Palmitate19
7/31/2014Chloramphenicol PalmitateProdrug of chloramphenicollipases3 Polymorphs: A (stable)B (metastable)C (unstable)Bioavailability of Polymorphic FormsComparison of mean blood serum levels of chloramphenicol after dosingsuspensions containing varying ratios of the A and B polymorphs of theprodrug chloramphenicol palmitate (expressed as %B polymorph).20
7/31/2014Case StudyPolymorphism Effect on SolubilityRitonavir: AbbottRitonavirProtease Inhibitor:HIV1&2Marketed by Abbott: 1996 Not bioavailable from the solid state Solution and capsule formulations:Soft-gel capsules: ritonavir in EtOH/water Single crystal form identified during development 240 lots of capsules manufactured No stability issues21
7/31/2014The Rest of the Story Mid-1998 batches of capsules failed dissolution Capsules analyzed by microscopy and XRD– New polymorph – Form II– Greatly reduced solubility Once seed crystals appeared - new polymorph everywhere Hydro-alcoholic capsule formulation:– Not saturated with respect to Form 1– 400% supersaturated with respect to Form II Formulation could no longer be manufactured Seriously threatened the supply of a life saving drugRitonavir PolymorphsForm IForm II22
7/31/2014Case StudyInsoluble and PermeabilityLimited AbsorptionTorcetrapib: PfizerTorcetrapibCholesteryl-ester transfer protein inhibtor (CETP-inhibitor)Combination product: torcetripib & atorvastatin"Second coming of Lipitor"Poorly solubility Highly liphophilic Log P 7.5 Absorption - highly variable Significant food effect 23
7/31/2014Torcetrapib/Atorvastatin Combination Development started in 1990- Torcetrapib SDD:torcetrapib: hydroxypropyl methylcellulose acetate-succinate(1:3 w/w)spray-dried from solution in acetonestable amorphous spray-dried dispersion- Torcetrapib SDD – CR:torcetrapib SDD in an osmotic-pump controlled-release tablet- Torcetrapib Drug Product:torcetrapib SDD – CR coated with IR layer of atorvastatinTorcetripib Clinical Program Clinical trials started in 1999 December, 2006 - Independent Data Safety Monitoring Board﹣ Recommended termination of a 15,000 patient Phase 3clinical study﹣ “Imbalance of mortality and cardiovascular events”patients taking torcetripib/atorvastatin experienced excessdeaths compared to those taking Lipitor alone. Early in 2007 development stopped on the “Prized Asset”24
7/31/2014The Result:One of Pharma’s Biggest FlopsGOOD: Developed a new area of formulation science:“Spray-Dried Dispersions”BAD:Took 9 years to get into the clinic with the SDDformulationBAD:Invested heavily - commercial manufacturing plant forAPI and SDD in IrelandBAD:Very late Phase 3 failureBAD:Estimated spend to failure 800 millionBAD:Two weeks after failure announced, 10,000 jobs cutCase StudyTime to Market:Amorphous vs Crystalline APIAtorvastatin Calcium: Parke-Davis/Pfizer25
7/31/2014Time to Market“For every day a drug is delayed coming to market,a million dollars of revenue may be lost.”? Thinking another way ?“How many life-hours are lost for every day a drugis delayed coming to market?”Atorvastatin Calcium – Lipitor Initial Development:– amorphous atorvastatin calcium Form B (later Form 23) No crystalline forms were known to exist Amorphous atorvastatin calcium– intrinsically unstable– can be stabilized through various additives to the formulation26
7/31/2014The Rest of the Story Crystallized: trihydrate form - during late stage clinical trialsCrystallineAmorphous Tablets were reformulated using crystalline API Extensive bioequivalence testing conducted:– Crystalline tablets – slower rate of absorption– However, the extent of absorption was the same FDA reviewed the clinical data relating to the two forms– Concluded that approval of the crystalline tablets was appropriateThe Moral of the StoryLipitor Peak Yearly Sales (2006): 13.7 billion1.5 Year Delay to MarketLost Revenue 20.6 billionNumber of life-hours lost:or 37.6 million/dayToday:? Indeterminate ?at least 47 known polymorphsvarious amorphous forms27
7/31/2014Final WordsSafePureEffectiveEvery TimeQualityFurther ReadingFlow ReactorsChemica Oggi/Chemistry Today 2011, 29, (3), 47-49Chemica Oggi/Chemistry Today 2012, 30, (4), 42-44Chemica Oggi/Chemistry Today 2012, 30, (4), 51-54Chemica Oggi/Chemistry Today 2009, 27, (1), 26-29C&E News 2009, 87, (11), 17-19C&E News 2014, 92, (21), 13-21Organic Process Research and Development 2011, 15, 1477-1453Organic Process Research and Development 2012, 16, 1069-108128
7/31/2014Further ReadingCrystalline & Amorphous Solids Jozwiakowski MJ, Nguyen, N-AT, Sisco JM, Spancake CW, “Solubility Behavior ofLamivudine Crystal Forms in Recrystallization Solvents,” J. Pharm. Sci., 85 (2): 193199, 1996. Lin, S-Y, “An Overview of Famotidine Polymorphs: Solid-State Characteristics,Thermodynamics, Polymorphic Transformation and Quality Control,” Pharm. Res.,31 (7): 1619 -1631, 2014. Ku S, “Use of the Biopharmaceutical Classification System in Early DrugDevelopment,” AAPS J., 10 (1): 208-212, 2008. Butler JM, Dressman JB, “The Developability Classification System: Application ofBiopharmaceutics Concepts to Formulation Development,” J. Pharm. Sci, 99 (12):4940-4954, 2010. Aguiar AJ, Krc J Jr, Kinkel AW, Samyn JC, “Effect of Polymorphism on the Absorptionof Chloramphenicol from Chloramphenicol Palmitate,” J. Pharm. Sci, 56 (7): 847853, 1967. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J, “Ritonavir: AnExtraordinary Example of Conformational Polymorphism,” Pharm. Res., 18 (6): 859866, 2001. Friesen DT, et al., “Hydroxypropyl Methylcellulose Acetate Succinate-Based SprayDried Dispersions: An Overview,” Mol. Pharm., 5 (6): 903-1444, 2008.The Role of Chemistry in Clinical Trials:The Big Expense & Lessons LearnedDr. Graham JohnsonPresident, NuPharmAdvise LLCDr. John MorrisonSenior Research Investigator,Bristol-Myers SquibbDr. Jay SiscoFounder, JM Sisco Pharma Consulting LLCPast-President, AAPSRecordings will be available to ACS members after two weekswww.acswebinars.orgContact acswebinars@acs.org for a copy of today’s slides5829
7/31/2014 Upcoming ACS Webinarswww.acs.org/acswebinarsThursday, August 7, 2014“How to Write Abstracts that CaptureYour Audience”Celia Elliott, University of Illinois at Urbana-ChampaignPatricia Blum, University of Illinois at Urbana-ChampaignThursday, August 21, 2014“Forecasting Chemistry: PredictingTomorrow’s Cutting Edge Science, Today”Dr. Charles Twardy, SciCast Project Principal and Professorat George Mason UniversityContact ACS Webinars at acswebinars@acs.org59The Role of Chemistry in Clinical Trials:The Big Expense & Lessons LearnedDr. Graham JohnsonPresident, NuPharmAdvise LLCDr. John MorrisonSenior Research Investigator,Bristol-Myers SquibbDr. Jay SiscoFounder, JM Sisco Pharma Consulting LLCPast President, AAPSRecordings will be available to ACS members after two weekswww.acswebinars.orgContact acswebinars@acs.org for a copy of today’s slides6030
7/31/2014Next in the Drug Discovery Series!“Pharmacoeconomics and IP Strategiesin Drug Development”Thursday, September 25, 201461How has ACS Webinarsbenefited you? “I have learned a lot of what I aminterested in during the Drug DiscoverySeries. For example, I have obtained thenew information about the drug discoveryprocess from both academics andindustries.”Fan of the WeekZuping Xia, Ph.D.Research Associate Professor,and Director of NMR Core,College of Pharmacy, Washington State UniversityBe a featured fan on an upcoming webinar! Write to us @ acswebinars@acs.org6231
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7/31/2014 ACS Webinars does not endorse any products orservices. The views expressed in this presentationare those of the presenter and do not necessarilyreflect the views or policies of the AmericanChemical Society.Contact ACS Webinars at acswebinars@acs.org65 Upcoming ACS Webinarswww.acs.org/acswebinarsThursday, August 7, 2014“How to Write Abstracts that CaptureYour Audience”Celia Elliott, University of Illinois at Urbana-ChampaignPatricia Blum, University of Illinois at Urbana-ChampaignThursday, August 21, 2014“Forecasting Chemistry: PredictingTomorrow’s Cutting Edge Science, Today”Dr. Charles Twardy, SciCast Project Principal and Professorat George Mason UniversityContact ACS Webinars at acswebinars@acs.org6633
Chemical & Engineering News (C&EN) The preeminent weekly news source. NEW! Free Access to ACS Presentations on Demand ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events. NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
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Presentation on DRAFT FY 2021 budget for discussion and consideration. Adoption in June meeting Jill Flygare, Chief Operating Officer 5. Strategic Business Plan Informational Presentation on DRAFT FY2020-FY2024 Strategic Business Plan Jack C. Hedge, Executive Director, UIPA Donald Ludlow, Vice President, CPCS Camille Wu, CPCS 6. Public Comments .
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