Lonza 'Factory of Tomorrow' for Flow Processes ... - Chemspec Events

Pharma&BiotechLonza ‘Factory of Tomorrow’ for Flow Processesand MicroReactorsPractical Continuous Flow Technology, Munich, GermanyDominique Roberge / Lonza Ltd, 3930 Visp / 5 June 2013© Lonza

Re-design the Chemical Routes withthe Concept of Flash Chemistry in FlowRaw materials fromfine chemicalsSolventReagentSolventReagentSolventReagentInt. 1 Int. 2 Int. 3 APIStep 1Flash chemistry*Step 2 Step 3 Step 4• Flow Processes / Microreactors lead to drastic improvements• Excellent heat transfer & mixing• Exact control of residence time• Segregation of feeds, small volume, robust (pressure) etc.• Inherently Safer Design from the high level of confinement= Intensified Mini-Plant Concept* Flash chemistry concept see: Yoshida, J.-I. et al.,Chemistry – A European Journal 2008 (14) 74502Mai-13

Reaction Classification &AdvantagesType A reactions• Very fast (< 1 s)• Controlled by the mixing process• Increase yield through better mixing/heat exchangeType B reactions• Rapid reaction (10 s to 30 min)• Predominantly kinetically controlled• Avoid overcooking and increase yieldType C reactions• Slow reaction (> 30 min)• Batch processes with thermal hazard• Enhance safety• Need intensification3Mai-13

Microreactors Are at the Heart of aDramatic Shift in API ProductionIt enables continuous processes based on plug flow reactors withminimal volume of reagents, rapid dynamic responses androbustness, good temperature control, efficient mixing, etc.outlet coolinginlet coolingdelayloopoutlet productinlet fluid 1inlet fluid 2outlet coolinginlet cooling1 – 600 mL/min4May-13

Video of a Gas-liquid Type AReaction in the FlowPlate ® MicroReactor5May-13

Agenda• Reactor design for scale-up• Parallelization / Numbering-up illusionProcess intensification• Impact on production unit >> Factory of Tomorrow• Example 1. Organometallic reaction• Example 2. Azide chemistry6Mai-13

Grignard Reaction as a Test Reaction forManifold & Heat Exchange PerformancesOOOOOODimethyl oxalateCN 16543MW 118.09+Mg ClEthylmagnesium chlorideCN 38038MW 88.82OMg ClOO2-MOBCN 32182MW 116.12+OHO2-MOB_enolCN 32759MW 116.12RRT 1.17Feed-1: Dimethyloxalate (15 wt%), rest DMEFeed-2: Grignard (19 wt%), rest THFTemperature: -15°C, all feeds pre-cooledStoichiometry: Grignard / Dimethyloxalate = 1.15Flow rate: 40 g/min in total with1 or 4 injection points (Grignard)Roberge et al., Chem. Eng. Technol. 2008 (31) 1155 Barthe et al., Chem. Eng. Technol. 2008 (31) 11467May-13

Yield in area%Limitation of Pressure Driven Systems –Avoid Manifold / Parallelization10095908580Average = 84.4%Standard deviation = 0.13%Average = 84.0%Standard deviation = 0.09%7570656055With ManifoldWith Pumps and Flow ControllersAverage = 76.0%Standard deviation = 4.8%At ca 1.15 mol/mol500 10 20 30 40 50 60 70Time on stream [min]8May-13

Plate Size to DriveScale-up: FlowPlate ® MicroReactorsDevelopment Reactor• View the chemistry• Chemical systems aremetastable!• Test different structures• Ensure stoichiometryProduction Reactors• Design as a key ingredient toscale-up• Avoid parallelization• Enable Clean in Place• Multi-purpose & ready for cGMPFlowPlate ® LabChannel structurePlate Size: A6Plate Size: A5Roberge et al., Chemistry Today 2009 (27) 89Mai-13

As Small as Needed and Use“Micro” Where UsefulMulti-scale design to maximizeheat transfer and optimize mixingbut allowing variable residencetime modules > gain volume• Up to several hundreds of mL• seconds to minutes• Variable channel depth• to limit pressure dropCan be coupled with residencetime modules• Several liters• up to 30 minutesFlow rate from 15 to 600 mL/minNo internal parallelizationMicro dimension = 500 µmLarger dimension = 2 mm10Mai-13

Scale-up StrategyConventional Technology versus MRTMMRSInterfaceModulesMMRSApparatuses used at the early stage of processdevelopment need to have the potential for furtherscale-up.Production ScaleModules11May-13

Typical Projects in our PipelineProjects Formula P[bar]Test new technological approaches• Hydrogenation, Electro-dialysis, membranes, ozonolysis…T[°C]Project 1 Aggressive chemistry (corrosion!) 85 250Project 2 Organo-lithium reactions Normal -30Project 3 Fischer-Indole synthesis 20 170Project 4 Acid-catalyzed cyclization Normal -40Project 5 Nucleophilic substitution (Cl) 20 22012Mai-13

Example 1: FlowPlate ® MicroReactor toControl Reaction Heat2-Step Synthesis: Lithiation and Coupling+ +R1 H ( a c i d i c )Li R1 LiR1LiR3R2+ +OR1OR2R3LiSome Disadvantages• Plugging = Lonza patent applied Ultrasonic De-plugging SystemFirst reaction: Type A, highly exothermic (ΔTad > 75°C)• MicroreactorSecond reaction: Type B, exothermic (ΔTad < 25°C)• Static mixer under adiabatic conditions13Mai-13

Ultrasonic De-Plugging System• Optimize to use with theFlowPlate ® MicroReactors• Ultrasonic System to enablestable operations over days /weeks• Ultrasound is generated in theliquid > to create truecavitation• Optimal for spot plugging likein the mixing zone or exit• Imperative for organometallicreactions with BuLi14Mai-13

Microreactor Technology Leads toDramatic Process IntensificationsProcess intensification to enable inherently safer processesleading to a production paradigm• Lower reactor investment• Less manpower• Higher flexibility• Enhance safety• Faster change-over“Factory of tomorrow”250mL250L15Mai-13

Earlier Pilot Plant using MicroreactorTechnologyKey Features• Multi-purpose system• Modular• Hastelloy• T = -80 to +180°C• ATEX standards• Qualifiable for cGMP production• 3 dosage lines• 1 - 8 bar• 5 - 500 g/min (per line)Track record2 tons of isolated product20 m 3 processed fluid16Mai-13

Example 2: Azide Chemistry in MicroreactorsAzide-Nitrile Addition to make Tetrazole DerivativesTypical Type C reaction requiring several hoursThe mixture was heated under a N2 atmosphere at 100-105°C for 50 h• Segregation of Feeds: NaN 3 prepared in a special containment andprecisely mixed in the reactor avoiding batch bulk handling• Volume Minimization & Robustness: Reaction in flow performed in10 min at 220°CGutmann et al., Angewandte Chemie International Edition 2010, DOI:10.100217Mai-13

The Future of Flow Processes:Full Integration of MRT in Production UnitsIn the past conventional means all batch processesProtection Li exchange Coupling Hydrolysis Extraction DistillationCentrifugeDryerCurrently the MR is used to increase reaction yield & safetyValue-addedin terms of YieldProtection Hydrolysis Extraction DistillationCentrifugeDryerFuture will lead to fully integrated flow processes: MR and more…Value-addedin terms of YieldProtectionflow reactorHydrolysisflow reactorContinuousextractionContinuousdistillationContinuousCentrifugeContinuousdryer18May-13

Reaction and Work UpIntegrated in One Flow UnitMini-Plant concept to enable New Processesand extend the design space of how weperform chemistryKey Features• Microreactor for a flash reaction• CSTR for precipitation• High pressure valve• Filter to removal salt• Wiped film evaporator• Fraction collectorThroughput• More than 1 kg/day ofproduct;distillation is limiting19Mai-13

Lonza “Factory of Tomorrow” forContinuous Flow / MRTAim: huge process intensification via flowCabin concept to enable high flexibility• Use of various equipment: microreactors, static mixers,extraction column, distillation (thin-wiped film, etc.)• Various flow rates, high pressures &temperature• Up to several tons• 100 bar – 300°C > hydrogenationThroughput• 900 mL 10 kg/day• 3600 mL 40 kg/dayFaster Scale-up and change-over• Non ATEX• New concept for cGMP qualification>> Overall goal is to reduce drasticallythe costs of goods20Mai-13

“Factory of Tomorrow”Head TanksBunkerAreaCabin for theintensified processAirlockTechnicalroomProduct21May-13

Economical Gain: Batch Versus FlowExample 1: Process development in clinical trials / kg scaleBatch ProcessFlow ProcessReactor volume = 250 LReactor volume = 250 mLFaster change over & cleaningManufacturing gain = up to 30%Example 2: Commercial manufacturing / ton scaleBatch ProcessFlow ProcessReaction time = 10 - 14 hReaction time = 0.2 hReactor volume = 10 m 3 Reactor volume = 0.03 m 3Cycle time = 21 hProductivity = 764 kg/dNeed bunker to cover the 10 m 3 Investment =4 MCHF for a bunker infrastructureCycle time = 16 hProductivity = 977 kg/dLower assets usage; specialconfinement

Infrastructure OverviewFlowPlate®A6 A5 A4A++Portable skid mountedunits anywhere• Visp FCC• Nansha, China• Our customersLaboratory SystemFactory of TomorrowCommercial ManufacturingFlow labs fully integratedwith kg-LabsPiloting at lower costsModular, flexible on skid mountedunits1-150 g/minFew g to tens of kg150-600 g/min0.1–5 tons campaigns0.6- 5 kg/min5–80 tons campaigns- Your green andsustainable process oftomorrow- Plugging issues solved- Fully automated- Scale-up concept tested- Fit for any scale- Streamlined and simplified processes- Drastic reduction in costs of goods23May-13

ConclusionsFlow technologies are the heart of a quantum leap inpharmaceutical manufacturing leading to greener processes atlower costs• Design new chemical routesLonza is a leading manufacturer of chemicals using flowprocesses and advanced technologies• The central part of the lab development is the microreactorAcknowledgments & Contacts• N. Kockmann, R. Forbert, and O. Kappe (external)• dominique.roberge@lonza.com24Mai-13