System Engineering for Continuous Production of...

Novelia Engineering ConfidentialNovelia Engineering Confidential

System Engineering for Continuous Production

of Pharmaceuticals & Fine Chemicals

Philippe Caze

CPAC Rome - 22 mars 2011

Novelia Engineering Confidential

Outline

• Pharma & Fine Chemicals Production

• Continuous mode

• System engineering

22/03/2011 2


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)

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Novelia Engineering Confidential22/03/2011 6

Measure, Manage & Optimize

Quality

Time Cost

Challenge


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

Solution


• 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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Limitations


-3s -2s -1s 0 1s 2s 3s

68.3%

95.4%

99.73%

Plot of each batch yield, or impurity

level, or selectivity….batch after

batch

Normal Distribution


-3s -2s -1s 0 1s 2s 3s

95.4%

LSL USL

Process Capability =

USL – LSL6s

= 0,67

Defect rate= 4,6 %

= 46000 ppm

Normal Distribution


-3s -2s -1s 0 1s 2s 3s

LSL USL


USL – LSL6s= 1

Defect rate= 0,27 %

= 2700 ppm

99.73%

Normal Distribution


-3s -2s -1s 0 1s 2s 3s

LSL USL


USL – LSL6s= 2

Defect rate< 1 ppm

-6s 6s

Normal Distribution


Batch

Automotive

Pharma final delivery to customer

Semiconductor

Benchmark


Batch This suggests the existence of a lot of non value added operations to meet the final objective

Pharma final delivery to customer

Benchmark


• 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

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Impact


• 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

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Conclusion


• Today process

Chinese selling price (6 steps) = European manufacturing cost (4 first steps)

• Optimized process using Lean and Six Sigma methodologies

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

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Reaction 1 Reaction 2 Distillation 1 Distillation 2 Reaction 3 Reaction 4

Reaction 1 Reaction 2 Distillation Reaction 3 Reaction 4

Example


Continuous operations:

a solution for manufacturing of Pharma & fine Chemicals?


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

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

Continuous mode 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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ManufacturingOperations

Intensification

ProcessIntensification

Production facility intensification

Maintenance of Business ++++ ++ +

New Products ++++ +++ ++

New Markets ++++ ++++ +++

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Quality

Time Cost

In order to Manageand to Optimize….

…what is required?

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

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Continuous Production of Pharmaceuticals & Fine Chemicals


System Engineering


• 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

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Novelia EngineeringProducts & Services


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.

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Technology


An iterative and incremental approach,which is led in a collaborative spirit,

just with what it is necessary of formalism

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Agile Method

• 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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Agile Chemical System Engineering






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AGILE SYSTEMS

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AGILE CHEMICAL SYSTEM ENGINEERING

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Functionality Analysis

Continuous Flow Technology

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Continuous Flow Chemical Engineering

System architecture

ModulesInterfaces

Automation



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AGILE



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Mfg system:• Flexible, • scalable in capacity• Scalable in

functionnality

Functionalityanalysis: to take into accountsnew inputs or requirements

Customer interaction:Transform knowledgeinto data whenappropriate



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AGILE

Simulation


Modeling


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CPAC Rome 2010


CPAC Rome 2010

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