System Engineering for Continuous Production of Pharmaceuticals & Fine Chemicals Philippe Caze CPAC Rome - 22 mars 2011 Novelia NEonvegliian eEnegriinnege riCngo Cnofindfiedennttiiall Outline • Pharma & Fine Chemicals Production • Continuous mode • System engineering 22/03/2011 2 Novelia Engineering Confidential Pharma & Fine Chemicals Production Novelia NEonvegliian eEnegriinnege riCngo Cnofindfiedennttiiall Pharma & Fine Chemicals Production Provides : • expected quality • within required delivery time • at a defined cost 22/03/2011 4 Novelia Engineering Confidential Pharma & Fine Chemicals Production • A molecule is the output of a sequence made of 10 to 15 reactive and non-reactive steps (Complexity) • The Unit Operations are mainly discontinuous ( Batch) • Multipurpose environment ( Flexibility) • Significant use of external providers to source raw materials as well as intermediates (Planning) 22/03/2011 5 Novelia Engineering Confidential Challenge Measure, Manage & Optimize Quality Time Cost 22/03/2011 6 Novelia Engineering Confidential Solution Like other manufacturing sectors deploy • Lean Manufacturing – a systematic approach for continuous improvement (principles, concepts & techniques) – designed for a relentless pursuit in the identification and elimination of waste (non-value-added activities) – creating flow through the whole organization • Six Sigma methodology – a Management driven, scientific methodology for product and process improvement – which creates breakthroughs 22/03/2011 7 Novelia Engineering Confidential Limitations • Lean Management has very little impact in an environment with Unit Operations demonstrating variability – 10% defect rate increase process cycle time by 38% and the number of tasks by 54% (ASQ) • Six Sigma methodology require to have access to significant and multiple data – For Pharma and Fine chemicals accessing these data will be a challenge requiring: • Additional studies upstream (time & cost) • Operations modification (planning, loss of flexibility) 22/03/2011 8 Novelia Engineering Confidential Normal Distribution 99.73% Plot of each 95.4% batch yield, 68.3% or impurity level, or selectivity…. batch after batch -3s -2s -1s 0 1s 2s 3s 22/03/2011 9 Novelia Engineering Confidential Normal Distribution 95.4% Process Capability = Defect rate USL – LSL = 4,6 % 6s = 46000 ppm = 0,67 LSL USL -3s -2s -1s 0 1s 2s 3s 22/03/2011 10 Novelia Engineering Confidential Normal Distribution 99.73% Process Capability = Defect rate USL – LSL = 0,27 % 6s = 2700 ppm = 1 LSL USL -3s -2s -1s 0 1s 2s 3s 22/03/2011 11 Novelia Engineering Confidential Normal Distribution Process Capability = Defect rate USL – LSL < 1 ppm 6s = 2 LSL USL -6s -3s -2s -1s 0 1s 2s 3s 6s 22/03/2011 12 Novelia Engineering Confidential Benchmark Batch Automotive Pharma final delivery to customer Semiconductor 22/03/2011 13 Novelia Engineering Confidential Benchmark Batch This suggests the existence of a lot of non value added operations to meet the final objective Pharma final delivery to customer 22/03/2011 14 Novelia Engineering Confidential Impact • Batch process variability alone is responsible for: – 5% batch out of specifications (from 1 to 10%) – a cost of quality in the order of 20% due to heavy quality controls and rework operations – The inability most of the time to deploy Lean Manufacturing and get rid of the non value added operations • Batch process variability combined with need for flexibility in the production cycle is responsible for: – The inability to deploy Six Sigma due to lack of numerous and relevant data 22/03/2011 15 Novelia Engineering Confidential Conclusion • For manufacturing of Pharma & Fine Chemicals, 99% operations are batch based • Batch variability is a main source of not achieving quality, production cycle & cost objectives • Batch variability is the main barrier to deploy improvement methodologies like Lean Manufacturing and Six Sigma • Flexibility in production cycle is second 22/03/2011 16 Novelia Engineering Confidential Example • Today process Reaction 1 Reaction 2 Distillation 1 Distillation 2 Reaction 3 Reaction 4 Chinese selling price (6 steps) = European manufacturing cost (4 first steps) • Optimized process using Lean and Six Sigma methodologies Reaction 1 Reaction 2 Distillation Reaction 3 Reaction 4 Most of the economical gap could be removed Product variation after reaction 2 is now impacting yield of reaction 3 and 4 • Batch variability process is preventing further process improvement and is putting the whole manufacturing site under pressure 22/03/2011 17 Novelia Engineering Confidential Continuous operations: a solution for manufacturing of Pharma & fine Chemicals? Novelia NEonvegliian eEnegriinnege riCngo Cnofindfiedennttiiall Continuous mode production Switch from batch mode production to continuous mode production allows: • To significantly increase the process capability from 2 to 4 minimum (Six Sigma methodology) • To avoid non value added rework operations for out of specifications batch (Lean methodology) • To drastically reduce Quality control costs (Lean methodology) Manufacturing Operations Intensification 22/03/2011 19 Novelia Engineering Confidential Continuous mode production In addition to the continuous mode, operations could benefit from: • Process Intensification through characteristic dimensions reduction of the reactor (from meter to few millimeters) – Mass and Heat transfer Optimization in order to increase product quality, yields, safety and decrease environmental impact • Production facility intensification – Decrease of the footprint associated with production facility more compact, safer and cheaper 22/03/2011 20 Novelia Engineering Confidential Pharma & Fine Chemicals Production 1. Maintenance of Business – Manufacturing of existing & established molecules – Under significant pressure due to generics and eastern low cost producers – Batch variability is the main barrier to deploy improvement methodologies 2. New Products – Manufacturing of new molecules under development – Due to overcapacity, they will have to be produced in existing facility and equipment, – On top of the difficulties created by batch variability, scale up is even more difficult 3. New Markets – Manufacturing of future molecules and potential products – Combined difficulties from batch variation, scale up and innovation 22/03/2011 21 Novelia Engineering Confidential Continuous Production of Pharmaceuticals & Fine Chemicals Quality In order to Manage and to Optimize…. …what is required? Time Cost Manufacturing Process Production facility Operations Intensification intensification Intensification Maintenance of Business ++++ ++ + New Products ++++ +++ ++ New Markets ++++ ++++ +++ 22/03/2011 22 Novelia Engineering Confidential Continuous Production of Pharmaceuticals & Fine Chemicals The current productions of existing & established molecules under pressure of generics or low cost producers are the candidate # 1 for switching to continuous operations….. ….if we can maintain or increase the flexible and multipurpose nature of these manufacturing facility 22/03/2011 23 Novelia Engineering Confidential System Engineering Novelia NEonvegliian eEnegriinnege riCngo Cnofindfiedennttiiall Novelia Engineering Products & Services • Products – Production Systems • Scalable in term of capacity and functionality • Limited number (#15) to fit with the main production themes and problems in Pharma et Fine Chemistry • Made of generic modules, • Continuous or hybrid mode • Reactive and non reactive steps • Services – Customization of these Systems for a customer • In order to transform these systems into a unique solution answering customer specific needs 22/03/2011 25 Novelia Engineering Confidential Technology Agile Chemical System Engineering for Advanced Manufacturing Technologies: – Lean, Six Sigma, Agile methodologies, – Scientific and technical expertise for functionality analysis, Continuous Flow Technologies, modeling and simulation. 22/03/2011 26 Novelia Engineering Confidential Agile Method An iterative and incremental approach, which is led in a collaborative spirit, just with what it is necessary of formalism • Individuals and interactions over processes & tools • Working operational over comprehensive documentation • Customer collaboration over contract negotiation • Responding to change over following a plan 22/03/2011 27 Novelia Engineering Confidential Agile Chemical System Engineering a m n g a i e S L x i S e s s ’ i t t r n e e i p l x C E 22/03/2011 28 Novelia Engineering Confidential Agile Chemical System Engineering 22/03/2011 29 Novelia Engineering Confidential Agile Chemical System Engineering 22/03/2011 30 Novelia Engineering Confidential 2 2 / 0 3 / 2 0 1 1 A Client’s Audit Lean g i Expertise Six Sigma l e A A Lean G G C I I L L Six Sigma h E E C C e N H H o Agile m E E v e M M C l i a o C A A i I F I n C C E h Functiionalliitiies c u G G t C n e A A i n n g Anallysiis I I a m o c L L L L i u n n t i E E o e i c S S l o t u e i a Y Y n n S S r s l S i u a Y Y S S n Conttiinuous Fllow E F l o g T T S S i n y Technollogy t l u y o T E T E C g s w A E M E M o s i n F n n M M T e t l f Contiinuous a o e i e d E E l e w c S S e y Fllowr Chemiicall N N h i n s n n t m Engiineeriint i G G g i s a o l I I l N N o g E E y E E E Modeling R R n I I N N g G G a A Simulation i I r n u n M c S t t h e y o o e i s t m r d t e e f u e Oa ptiimiizatiion c a l c m r t t e e u i i s o s r n n e g 3 1 Agile Chemical System Engineering AGILE Mfg system: • Flexible, Functionality Analysis a •