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
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• 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)
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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
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95.4% Process Capability = Defect rate USL – LSL = 4,6 % 6s = 46000 ppm = 0,67
LSL USL
-3s -2s -1s 0 1s 2s 3s
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99.73%
Process Capability = Defect rate USL – LSL = 0,27 % 6s = 2700 ppm = 1
LSL USL
-3s -2s -1s 0 1s 2s 3s
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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
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Batch This suggests the existence of a lot of non value added operations to meet the final objective
Pharma final delivery to customer
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• 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
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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
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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 ++++ ++++ +++
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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
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