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Novelia Engineering Confidential
Novelia Engineering Confidential
System Engineering
for Continuous Productionof Pharmaceuticals & Fine Chemicals
Philippe CazeCPAC Rome - 22 mars 2011
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Outline
Pharma & Fine Chemicals Production
Continuous mode
System engineering
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Novelia Engineering Confidential
Pharma & Fine ChemicalsProduction
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Provides :
expected quality
within required delivery time at a defined cost
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Pharma & Fine Chemicals Production
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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 mainlydiscontinuous ( Batch)
Multipurpose environment
( Flexibility)
Significant use of external providersto source raw materials as well as
intermediates (Planning)
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Pharma & Fine Chemicals Production
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Measure, Manage & Optimize
Quality
Time Cost
Challenge
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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
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Solution
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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
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-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
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-3s -2s -1s 0 1s 2s 3s
95.4%
LSL USL
Process
Capability =
USL LSL
6s
= 0,67
Defect rate
= 4,6 %
= 46000 ppm
Normal Distribution
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-3s -2s -1s 0 1s 2s 3s
LSL USL
Process
Capability =
USL LSL
6s
= 1
Defect rate
= 0,27 %
= 2700 ppm
99.73%
Normal Distribution
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-3s -2s -1s 0 1s 2s 3s
LSL USL
Process
Capability =
USL LSL
6s
= 2
Defect rate< 1 ppm
-6s 6s
Normal Distribution
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Batch
Automotive
Pharma finaldelivery to
customer
Semiconductor
Benchmark
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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
Benchmark
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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 forflexibility 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
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For manufacturing of Pharma & Fine Chemicals,
99% operations are batch based
Batch variability is a main source of not achievingquality, 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
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Today process
Chinese selling price (6 steps) = European manufacturing cost (4 first steps)
Optimized process using Lean and Six Sigmamethodologies
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
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Continuous operations:
a solution for manufacturing ofPharma & fine Chemicals?
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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
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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 fewmillimeters)
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
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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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Pharma & Fine Chemicals Production
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Manufacturing
Operations
Intensification
Process
Intensification
Production facility
intensification
Maintenance of Business ++++ ++ +
New Products ++++ +++ ++
New Markets ++++ ++++ +++
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Quality
Time Cost
In order to Manage
and to Optimize.
what is required?
Continuous Production
of Pharmaceuticals & Fine Chemicals
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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
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Continuous Production
of Pharmaceuticals & Fine Chemicals
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System Engineering
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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 answeringcustomer specific needs
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Novelia Engineering
Products & Services
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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
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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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L
ean
Six
Sigma
Clients
Expe
rtise
Agile Chemical System Engineering
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Agile Chemical System Engineering
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Agile Chemical System Engineering
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Audit
AGILE SYSTEMS
Lean
SixSigma
AGILE CHEMICAL SYSTEM ENGINEERING
Agile
Functiona
lities
Ana
lysis
ContinuousF
low
Tec
hno
logy
Modeling
Simulation
Optimization
Continuous
FlowChemical
Engineerint
Audit
AGILE SYSTEMS
Lean
SixSigma
AGILE CHEMICAL SYSTEM ENGINEERING
Agile
Functiona
lities
Ana
lysis
ContinuousF
low
Tec
hno
logy
Modeling
Simulation
Optimization
Continuous
FlowChemical
Engineerint
Functionality Analysis
Continuous Flow Technology
L
ean
Six
Sigma
Clie
nts
Expe
rtise
Continuous Flow
Chemical Engineering
System
architecture
Modules
Interfaces
Automation
Agile Chemical System Engineering
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Audit
AGILE SYSTEMS
Lean
SixSigma
AGILE CHEMICAL SYSTEM ENGINEERING
Agile
Functiona
lities
Ana
lysis
ContinuousF
low
Tec
hno
logy
Modeling
Simulation
Optimization
Continuous
FlowChemical
Engineerint
Audit
AGILE SYSTEMS
Lean
SixSigma
AGILE CHEMICAL SYSTEM ENGINEERING
Agile
Functiona
lities
Ana
lysis
ContinuousF
low
Tec
hno
logy
Modeling
Simulation
Optimization
Continuous
FlowChemical
Engineerint
AGILE
Functionality Analysis
Continuous Flow Technology
L
ean
Six
Sigma
Clie
nts
Expe
rtise
Continuous Flow
Chemical Engineering
Mfg system:
Flexible,
scalable in capacity
Scalable in
functionnality
Funct ional i ty
analysis:
to take into accounts
new inputs orrequirements
Customer interact ion :
Transform knowledge
into data whenappropriate
Agile Chemical System Engineering
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Agile
Functiona
lities
Ana
lysis
ContinuousF
low
Tec
hno
logy
Audit
Lean
SixSigma
22/03/2011 33
Continuous
FlowChemical
Engineerint
Optimization
AGILE
Simulation
Functionality Analysis
Modeling
Continuous Flow Technology
L
ean
Six
Sigma
Clie
nts
Expe
rtise
Continuous Flow
Chemical Engineering
Agile Chemical System Engineering
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CPAC Rome 2010
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CPAC Rome 2010