9 - Caze 110322 SAL CPAC Rome 2011.pdf

8/12/2019 9 - Caze 110322 SAL CPAC Rome 2011.pdf

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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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Pharma & Fine ChemicalsProduction


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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 mainlydiscontinuous ( Batch)

Multipurpose environment

( Flexibility)

Significant use of external providersto source raw materials as well as

intermediates (Planning)

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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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Novelia Engineering ConfidentialNovelia Engineering Confidential

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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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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Novelia Engineering ConfidentialNovelia Engineering Confidential

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



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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

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



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Audit

AGILE SYSTEMS

Lean

SixSigma


Agile

Functiona

lities

Ana

lysis

ContinuousF

low

Tec

hno

logy

Modeling

Simulation

Optimization

Continuous

FlowChemical

Engineerint

Audit

AGILE SYSTEMS

Lean

SixSigma


Agile

Functiona

lities

Ana

lysis

ContinuousF

low

Tec

hno

logy

Modeling

Simulation

Optimization

Continuous

FlowChemical

Engineerint

AGILE



L

ean

Six

Sigma

Clie

nts

Expe

rtise

Continuous Flow


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



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Agile

Functiona

lities

Ana

lysis

ContinuousF

low

Tec

hno

logy

Audit

Lean

SixSigma

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Continuous

FlowChemical

Engineerint

Optimization

AGILE

Simulation


Modeling


L

ean

Six

Sigma

Clie

nts

Expe

rtise

Continuous Flow




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CPAC Rome 2010


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CPAC Rome 2010

Documents

9 - Caze 110322 SAL CPAC Rome 2011.pdf