Continuous Manufacturing: Technologies and Economic Benefit 2 nd Symposium on Continuous Flow Reactor Technology for Industrial Applications Oct. 4, 2010, Paris Dr. B. Schenkel
API manufacturing in Pharmaceutical Industry Novartis Pharma AG: Chemical Manufacturing of API s in 800 stirred vessels with a total volume of 3000 m 3 in batch mode. Why? Copy of lab Flexibility in production capacity (number of batches) Flexibility to combine reaction with distillation and extraction Broad ranges of reaction parameter possible, e.g. exothermic reactions can be safely run in semibatch mode 2 initiatives in Novartis to challenge the situation and to shift to conti. manufacturing: Technology Platfom Conti. Manufacturing of API MIT/Novartis Project for Conti. Manufacturing 2 Oct. 4, 2010
-30 C... +200 C 0 bar.. 10 bar (40 bar) Continuous Manufacturing (CM): Which Equipment is available in Chemical Development of Novartis Installed are Microreactor/Flow reactor Units in different scale, different labs for Early Phase Supply and Development of Production Processes We are planning to implement in 2011 a multipurpose Pilot Plant CM under GMP, production capacity of 50 kg... 15 t/a. 15 g/ 10 h 150 g/ 10 h 1.5 kg/ 10 h 30 kg/ 10 h MIT Unit Early Phase Development Units Process Development Units Pilot Plant CM (planned) 3 Oct. 4, 2010
Continuous Manufacturing (CM): Which Equipment is available in Novartis Feed solutions Syringe pumps and micro gear pumps Autosampler 4 Oct. 4, 2010 Different types of Microreactors Standardized Flow Reactor Units in the labs: - Flexible equipment, design and size - Standardized control system
Successful Examples in Flow Lab: TEMPO Oxidation H + TEMPO + TBAB R N PG OH NaOCl + NaHCO 3 R H N PG H O Quench Na 2 S 2 O 3 Starting Material (red) Side Products (green) Product Starting Material Side Products Batch Improved selectivity because of reduced overoxidation to acid Micro Microreactor reactor Microreactor Product 5 Oct. 4, 2010
Successful Examples in Flow Lab: Nitro Michael Addition Highly energetic Nitroethylene used in Nitro Michael Addition step of a new API synthesis CM is enabling the new synthesis: continuous Nitroethylene production and consumption Successful process development in flow reactors of different scale: Reaction time: 60 min MIT microreactor/ ETFE tube 0,5mm x 100 m / static mixer 5mm x 5..20 m, Bo>300: identical yield and enantioselectivity as in batch, robust and safe continuous process N + O O + R O H Toluene Organ. Cat., acetic acid H O R O N + O Tube and Static Mixer Reactors in lab scale 6 Oct. 4, 2010
Successful Examples in Flow Lab: Coupling of Grignard-like Reagent Li Mg Cl + Ar Br Ar Mg - 3 Li +. LiCl ( ) n O N O Boc Ar ( )n H N Boc Consecutive (over reaction) and parallel formation of byproducts can be reduced in conti. mode by adding simultaneously the starting materials into the coupling reaction. Optimal concentration profiles achieved which are not possible in batch Yield can be increased by 6% compared to batch Significant reduction of raw material costs in production Cost savings justify to switch the current batch production on this step to continuous Conti. production process will be integrated in existing batch equipment at minor cost 7 Oct. 4, 2010
Successful Examples in Flow Lab: Transforming reactions into production scale For the above shown reactions Microreactors would be ideal reactors because of plug flow mixing power heat exchange low consumption of starting materials in development Ranges of Mixing Power Ranges of Heat Transfer 100000 100000 Mixing power [ W / L] 10000 1000 Heat transfer [ W / L K] 10000 1000 100 100 10 10 1 1 20*10-6... 0.4 Microreactor 0.1 Stirred Vessel 6000 Stirred Vessel Reactor Volume [Liter] 20*10-6... 0.4 Microreactor 0.1 Stirred Vessel 6000 Stirred Vessel Reactor Volume [Liter] 8 Oct. 4, 2010
Successful Examples in Flow Lab: Transforming reactions into production scale Cost [CHF] 1200000 1000000 800000 Stirred vessel Limitations of microreactors 600000 400000 200000 0 0 2000 4000 6000 Volume of Reactor [ L ] Reaction Column Microreactors (Volumes 90...360 ml) Microreactor costs at reaction times > 2.. 10 min get high In many cases the reactions in our portfolio cannot be shortened below 2..10min selectivity issue at higher temperatures Is CM limited to short reactions? There are cost efficient solutions for longer reaction times 9 Oct. 4, 2010
Transforming reactions into production scale Example Pd- catalyzed Reaction Sonogashira Coupling Reaction R Cl + R' Pd-Cat. CuCl R R' Side Reaction + R' R R' Terbinafin Product Byproduct R' Reaction time of Sonogashira Coupling Step reduced from 7h to 1 h for continuous processing Highly exothermic reaction (adiabatic heat increase 164 C), possible heat accumulation in batch reactor in case of inactive catalyst Situation at project start: large production capacity >100 t/a expected Identical selectivity in continuous mode, safe reaction conditions, economic equipment possible compared to batch manufacturing? 10 Oct. 4, 2010
Temperature [ C ] Transforming reactions into production scale Flow Reactors for longer reaction times Conversion [ - ] Temperature [ C ] N/S = (1/Se) [ - ] Conversion [ - ] Temperature [ C ] Conversion [ - ] Reactor variant: 1 Microreactor and 4 static mixer reactors in series Simulation of reaction Selection of optimal reactor design based on Semenov number 7 6 5 4 3 2 1 0 1 S [ - ] 10 61.8 61.3 60.8 Temperature / C Wall Temperature / C (T in pre-heating / C) conversion [ - ] Microreactor Reaction in 3 plates 0.10 0.09 0.08 0.07 0.06 100 90 80 70 60 Static Mixer Reactor 4 Moduls of different type/size 2.0 1.8 1.6 1.4 1.2 140 120 100 80 Static Mixer Fluitec Reactor 2 Moduls of different type/size 2.5 2.0 1.5 60.3 0.05 0.04 50 40 1.0 0.8 60 1.0 59.8 59.3 0.03 0.02 0.01 0.00 0 20 40 60 80 100 120 Reactor Volume [ml] 30 20 10 0 Temperature / C 0.6 Wall Temperature / C 0.4 Conversion / - 0.2 0.0 0 2000 4000 6000 8000 10000 12000 14000 Reactor Volume [ ml ] 40 20 0 Temperature / C Wall Temperature / C Conversion / - 0 2000 4000 6000 8000 Reactor Volume / ml 0.5 0.0 11 Oct. 4, 2010
Transforming reactions into production scale Flow Reactors for longer reaction times Temperature [ C] Yield. Reactor variant: Reaction Column Typical reaction times 0.5<tr<2 h Small reaction volumes in conti. mode Large production capacity 140 130 120 110 100 Simulation Pilotplant (two temperature levels) Temperature / [ C] Jacket temperature / [ C] Maximum yield of 95.3 % Yield 100% 90% 80% 70% 60% First simulations showed lower yield in reaction column: 91 % compared to batch: 96 % 90 80 70 60 50% 40% 30% 20% Lower yield in Reaction Column results from 12 Oct. 4, 2010 - High conversion rate at reactor entrance - Strong temperature increase - Increased byproduct formation 50 40 0% 0 5 10 15 20 25 Stirred Chambers Limit the reaction rate in the first reaction chambers Introduce 2 temperature levels along the column Max. yield in reaction column: 95.3% Simulation confirmed in lab and pilot experiments 10%
Transforming reactions into production scale Continuous Manufacturing Process for Terbinafin Continuous production process for Sonogashira Coupling Reaction Reaction Column Static Mixer Extraction Column M Waste Gas Water Mixer Settler HCl Falling Film Destillation Unit Work up steps focused on conti. extraction and conti. destillation waste O2 / N2 to recovery Cyclohexane Educts Sonogashira Step combined with precedent reaction step to a 2 step conti. process Solvents in both synthesis steps identical to avoid solvent switch between the steps No solid handling, no crystallization in conti. process chain Process piloted and basic engineering done Raw Product Continuous process reduces plant costs by 25% compared to new batch plant 13 Oct. 4, 2010
Conclusions from experiments and experience for Continuous API Processing Current state: 2..3 chemical steps in continuous mode are possible in API synthesis Yield improvement is possible for selected reaction steps by continuous manufacturing. Huge economic benefits can be achieved Continuous plant equipment can be 25% cheaper than corresponding batch equipment Reaction times have to be relatively short (e.g. <2 hours), work up steps have to be adapted to continuous, expensive solid handling has to be avoided 14 Oct. 4, 2010
Case study on economic impact of CM Economic impact of continuous manufacturing of full API syntheses was investigated in 3 case studies in Novartis Total continuous API syntheses (upstream) were combined with galenical production processes (downstream) Short summary on selected aspects with an emphasis on upstream 15 Oct. 4, 2010
Case study: applied approach in the study Step 1: Design of a conti. process starting from batch process without experimental verification, Process Flow Diagram, Material Balance Step 2: Equipment sizing Step 3: Estimation of equipment cost Step 4: Estimation of raw material cost Step 5: Total capital costs, Operational costs Step 8: Total production costs (TPC) Step 9: Study on parameter sensitivity 16 Oct. 4, 2010
Case study: PFD of 3 conti.steps of the selected 6-step-synthesis 17 Oct. 4, 2010 : reaction steps
Capital Costs of Batch and CM Plant for selected 6-step-synthesis Equipment Costs Calculation Total Equipment Costs = Sum of costs of equipment in final size + additional costs (Erection, Piping, Automation, Engineering) + building related costs Assumptions: 100 Tons / year DS, 335 working days / year Capital Costs for Upstream Plant 53% lower than batch Total Capital Cost [CHF/kg] 250 200 150 100 50 Upstream Downstream 18 Oct. 4, 2010 0 Conti. Process with Extrusion Batch Process with Extrusion
Operating Costs and Total Production Costs of selected 6 step synthesis Operating Costs - costs for raw materials, utilities, labor -Number of operators reduced by 50% Operating Costs for Upstream reduced by 15% compared to batch Total Production Costs TPC reduced by 25% for combined upstream & downstream CM process TPC reduced by 23% in upstream manufacturing Operating Cost [CHF/kg] 40 35 30 25 20 Upstream Downstream Total cost [CHF/kg] 600 500 400 300 Total Production Cost Total Operating Cost Total Capital Cost 15 10 5 0 19 Oct. 4, 2010 Conti. Process with Extrusion Batch Process with Extrusion 200 100 0 Conti. Process with Extrusion Batch Process with Extrusion
Fraction of Labor Cost in TPC Sensitivity Study: Impact of Labor on Total Production Cost 45.0% 40.0% Base Case 36.3% 39.9% 35.0% 32.4% Base case labor requirement: 10 full time workers per shift = 50% of batch operation 30.0% 25.0% 20.0% 15.0% 10.0% 13.0% 18.5% 23.6% 28.2% Fraction of Labor in TPC depends significantly on Labor Requirement 5.0% 0.0% 50% 75% 100% 125% 150% 175% 200% Fraction of Labor Requirement Opportunity for Continuous Manufacturing 20 Oct. 4, 2010
Sensitivity Study: Impact of Multipurpose vs. Dedicated Operation of Manufacturing Plants Number of Products per Line Plant Size Motivation: Batch Plants are used in manufacturing for more than one API/Drug. Difference in flexibility between batch and continuous manufacturing schemes Cost benefits of Multipurpose Plant: Capital cost divided between products Economies of scale Downside: Storage cost for API/Drug Setup and cleaning operations adding to operation cost 1 2 3 4 5 1 year 21 Oct. 4, 2010
T P C (C HF /kg ) Sensitivity Study: Impact of Multipurpose vs. Dedicated Operation of Manufacturing Plant 1400 1200 1000 1192 TPC per kg of Product C ontinuous B atch CM has lower TPC for each of the schemes 800 600 400 200 717 504 777 430 631 555 392 368 508 TPC decreases for multipurpose plants If CM is run in dedicated and Batch is run in multipurpose equipment Batch is cheaper 0 1 2 3 4 5 Number of P roduc ts per L ine 22 Oct. 4, 2010
Conclusions from Case Study Case studies on combined API/DP continuous manufacturing show TPC reduction up to 25 % in continuous compared to batch manufacturing Continuous Plants result in lower production costs (TPC) compared to batch Identical flexibility has to be achieved in conti. mode compared to batch mode Concepts for flexible multipurpose plants should be worked out. Operation Costs are dominated by raw material cost in upstream optimal synthesis regarding raw material cost and work up steps is key yield is key Capital cost and personnel cost are important and can be reduced by CM Equipment will be dominated in number and cost by work up equipment Efficiency and cost of purification processes are important Case study on economic impact of CM was based on assumptions which have to be further proven 23 Oct. 4, 2010
Novartis / MIT Center for Continuous Manufacturing Vision of Novartis and MIT to transform the current batch manufacturing of its drug substances and drug products to a fully continuous sequence of process steps for each drug substance and drug product New and enabling technologies will be developed within 10 years with significant economic advantages compared to batch manufacturing 24 Oct. 4, 2010
Acknowledgements Prof. T. Roeder, Dr. J. Hollmann, Dr. G. Paredes, Dr. F. Kollmer, M. Rentsch, Dr. L. Padeste, M. Aubry, Dr. H. Hirt, Dr.C. Fleury. U. Scholer, D. Plaziat, Dr. G. Penn, Dr. U. Beutler, Dr. B. Wietfeld, S. Bourne, Dr. B. Martin All external partners in numerous co-operations Students of MIT Practice School Programs Feb, June 2008, Prof. C. Lupis Novartis/MIT CM Team 25 Oct. 4, 2010