10.551SYSTEMS ENGINEERING

Department of Chemical EngineeringMassachusetts institute of Technology

Spring 2011

Part-1:

Introduction to Systems Engineering

Section-1.1:

Objectives and Organization of 10.551

Course Objectives• Introduce the “Systems Approach” as a basic

paradigm for solving complex engineering problems.– Structured representation of engineering problems

• Objectives, Specifications, Constraints• Models, Solutions

– Integration of material from diverse sources• Cover a series of systems methodologies and

problem-solving procedures for typical classes of problems– Analysis, Synthesis, Diagnosis, Identification, Control,

Planning and Scheduling– Graphs, Simulation, Optimization, Model-Based

Control, Models from Data, etc.

Course OrganizationInstructors:Professors Richard Braatz, 66-372, braatz@mit.edu, and

George Stephanopoulos, 66-44, geosteph@mit.edu

Teaching Assistants:Adekunle Adeyemo (66-060) Tel. (617) 253-0285 (adeyemo@mit.edu)Matthew Stuber (66-363) Tel. (617) 253-6468 (stuber@mit.edu)

Time and Place of Lectures:Room: 66-110 Mondays and Wednesdays: 11:00 – 12:30 pm

Course Web Page:http://stellar.mit.edu/S/course/10/sp11/10.551/

Course Organization

Reading Material:Comprehensive notes and background articles will be distributed in

class. Students will be expected to read this material, and homework assignments will test material in these notes not covered in class.

Grade:Homework (individual effort) 45%Projects (group effort) 40%Class Participation 15%

Course SchedulePart-1: Introduction to Systems Engineering

- Systems and their origin.- Examples of problems in Systems Engineering- The 10.551 Course: Objectives, Syllabus, Organization.

Part-2: Foundations of Systems Engineering- Scope and Formulation of Engineering Problems - Goals, Objectives, Specifications and Constraints- Types of Models; Hierarchical decomposition of systems- Types of Problems: Forward solution and inversion of models

Part-3: Structural Analysis of Systems- Graphs and digraphs: Representation of systems- Partitioning and Precedence Ordering of systems- Structural analysis of modeling equations- Structural controllability and observability of systems- Applications to engineering problems

Part-4: Steady State Analysis of Systems- Formulating steady-state models and simulations- Degrees of freedom and design specifications- The Sequential-Modular Strategy - The Equation-Oriented Strategy- Applications to engineering problems

Course SchedulePart–5: Optimization of Systems: Theory and Algorithms- Basic concepts and definitions- Linear programming- Unconstrained nonlinear optimization- Nonlinear Programming- Combinatorial optimization- Applications to engineering problems

Part-6: Simulation of Dynamic Systems- Basic concepts: Systems described by ODEs and DAEs- Formulating dynamic simulations; consistent initialization- Numerical integration of ODEs and DAEs- Modeling-simulation of hybrid Discrete/Continuous systems- Applications to engineering systems

Part-7: Linear Systems Theory and Model-Based Process Control

- The nature of feedback control- The concept of model-based control systems- Design and analysis of model-based control systems applications

Part-8: Creating Models from Data- Types of models created from data- Linear and nonlinear regression- Experimental design- Clustering techniques

Schedule of AssignmentsAssignm. Date-out Date-due Subject

HW-1 February 2 February 14 Definition of systems and their characteristics

HW-2 February 14 February 21 Structural analysis of systems

Project-1 February 21 March 9 Sequential-modular Steady-State Simulation using ASPEN Plus

HW-3 March 9 March 28 Optimization

HW-4 March 28 April 6 Dynamic modeling

Project-2 April 6 April 20 Dynamic simulation using the Equation-Oriented Simulator JACOBIAN

Project-3 April 20 May 4 Model-Predictive Control

HW-5 April 4 May 11 Models from data

Personal Statement Regarding Homework Solutions

Personal StatementIn the spirit and practice of MIT’s long-held “Honor

System”, I state that, in preparing the solution for this problem set, I have not used material from the homework solutions of past students or copies of solutions provided by the instructor or the TAs in earlier semesters.

___________________________________ Name___________________________________ Signature

Attach signed copy of this statement with the submission of your homework.

Section 1.2:

What is Process Systems Engineering?

The Scope

The set of activities involved in the Engineering of Systemswith Physical, Chemical, Biological Processing Operations

What is Process Systems Engineering ?

Types of Processing Systems• Produce chemicals and materials• Provide therapeutic treatment of human diseases.• Produce energy.• Manufacture products that enhance quality of life• Ensure quality of the environmentThe Approach of Process Systems Engineering

• The interest is on the “behavior” of the system as a whole

• The emphasis is on studying how the components of the system and their interactions contribute to the overall “behavior” of the system

Processing Systems and Engineering ActivitiesSystems Engineering Activities

Chemical Processes Synthesis of processing schemes; Simulation and analysis of performance; Optimization of performance; Monitoring-Analysis-Diagnosis of operations; Control and Optimization of operations

Control and Safety Systems

Synthesis of control structures; synthesis of safety systems (ISIs; LOPAs); Synthesis of operating procedures; Monitoring and diagnosis of control and systems performance; Modeling and simulation of dynamic operations

Network of Batch Operations

(Batch Plants)

Synthesis of networks of batch operations; Planning and Scheduling (optimal) of batch operations into multi-purpose batch chemical plants; Monitoring-Analysis-Diagnosis of batch operations for equipment faults or/and performance degradation; Modeling and simulation of dynamic batch operations

Oil and Gas Production Systems

Identify fields with hydrocarbons; Identify geological structure of deposits and their amounts; Select optimal production strategy over the life of the field; Design production system; Inherently safe and operable production systems; Planning and scheduling production operations; Control and optimization of operations

Air Pollution Definition of system (Components; Interactions); Model Behavior; Simulate effects of various scenaria; Diagnose sources of increased pollution; Develop strategies for pollution control

Cardiovascular System

Model the entire cardiovascular system; Monitor-Analyze-Diagnose its performance; Control and/or redesign.

Molecules as Systems

Define molecules as systems (components; Interactions); Model physical and chemical behavior (structure-properties relationships; structure-reactivity relationships); Synthesize reactions; Generate Supra-molecular structures; Diagnose molecular failures

Reactions as Systems(Systems Chemistry)

Synthesis of chemical reaction networks (to achieve desired products); Select network of reactions to model chemical processes (e.g. combustion); Design self-replicating reaction networks; Identify networks of reactions as catalytic mechanisms

Biological Systems(Systems Biology)

Synthesis of metabolic networks; Identification of biological processes (signal transduction pathways; gene transcription system; gene regulation system; immunological activity; circadian rythms).

Products as Systems

Product Assembly of components Manufacturing of components Materials/chemicals of a component Production of materials/chemicals

Examples of Systems: Continuous Chemical Processes

The Hydrodealkylation of Toluene Process

Toluene

Make-up Hydrogen

Cooling Water

bank of coolers

Feed-effluentheat exchanger

Compressor

Furnace

Flash

Stab

ilizer

Benz

ene

Tolu

ene

WaterCooler

Fuel

Cooling Water

Cooling Water

Cooling Water

Steam

Steam

Steam

Quench

Purge

Steam

Toluene Recycle

Gas Recycle

Toluene + Hydrogen → Benzene + Methane2 Benzene → Diphenyl + Hydrogen

Feed-effluentheat exchanger Reactor

Furnace

bank of coolersFlash

Stab

ilizer

Design-Oriented Engineering Activities for Chemical Processes

1. Process Synthesis: Given a set of chemical reactions, synthesize an economically optimal process, i.e.

– Select the type of unit operations to be used; their sizes; and interconnections among units– Select the optimal sizes of unit operations and their optimal operating conditionsThat minimize the annual operating cost.

2. Process Analysis and Evaluation: Given a chemical process (type of unit operations and their sizes, the units’ interconnections) and its operating conditions (raw materials, heating and cooling resources, temperatures and pressures of all units), compute

– The characteristics of all streams (flows, compositions, temperatures, pressures), and– The total operating cost

Raw Materials (known)

Product (known)

By-Products (known)

Process?

Chemistry (known)

Raw Materials (known)

Processing Streams (?)

Performance (?) (Operating Cost; Operability; Safety; Environmental)

Process (known)

Process Synthesis

Purge (H2, CH4)I/O Plant

Energy, Q

Toluene

Hydrogen Product (B; 99%)12

34

Input-Output Plant

5 By-Product (D)

Toluene (T) + H2 Benzene + CH4

2Toluene Diphenyl (D) + H2

Toluene

Make-up Hydrogen

Cooling Water

bank of coolers

Feed-effluentheat exchanger

Compressor

Furnace

Reactor

Flash

Stab

ilizer

Benz

ene

Tolu

ene

WaterCooler

Fuel

Cooling Water

Cooling Water

Cooling Water

Steam

Steam

Steam

Quench

Purge

Steam

Toluene Recycle

Gas Recycle

Process Synthesis: The Methyl Acetate Process

Acetic Acid

Methanol

Catalyst

MethylAcetate

Water

HeaviesWater

Water

From: Siirola, 1996

Distillation

Liquid Extraction

Flash Column(Distillation)

AzeotropicDistillation

EntrainerRecovery Distillation

Solvent Recovery

(Distillation)

Extractive Distillation

Methanol Recovery

(Distillation)

Color Column (Distillation)

Inventing the Single Column Methyl Acetate Process

ExtractiveDistillation

Task F

DistillationTask G

ReactiveDistillation

Task E

ReactionTask A

ReactiveDistillation

Task B

DistillationTasks

C and D

Acetic Acid

Catalyst

Methanol

Methyl Acetate

Water(Agreda and Partin, 1979)

400,000,000 lb/yr

1/5 capital investment1/5 energy consumption

of conventional plants

Process Analysis and Evaluation (Simulators)

IPS PRO/IIInvensys Process Systems

Aspen Plus®Aspen HYSYS®

DESIGN II

Operations-Oriented Engineering Activities for Chemical Processes

1. At Early Stages of Process Design:– Inherent Safety– Avoidance of Effluents with Environmental Impact– Operable and Controllable designs

• Startup; Shut-down; Change-over.

2. At Later Stages of Engineering Design– Layout of Processing Units: Safety; Cost; Maintenance; Operability– Piping and Instrumentation diagram designs: Safety; Control;

Operability

3. During Operations:– Process Control– Monitoring, Analysis, Diagnosis of Process Operations:

– Identification of Faults; – Performance degradation: Catalyst decay; Fouling; Change of raw

materials, etc.– Optimization of Operations

Example of Process Synthesis: Hierarchical Synthesisof Hydro-dealkylation of Toluene Plant to produce Benzene

Purge (H2, CH4)I/O Plant

Energy, Q

Toluene

Hydrogen Product (B; 99%)12

34

Input-Output Plant

5 By-Product (D)

Toluene (T) + H2 Benzene + CH4

2Toluene Diphenyl (D) + H2

Recycle Structure

ReactionSection

SeparationSection

1

2

3

47

6

8

Gas Recycle (H2, T, CH4, B)

Liquid Recycle (T, B, D)

Toluene

Hydrogen

Purge

Product

5By-Product

1

2

3

4

ReactionSection

5QSteam-(b)

ProductRecovery

7

10 6

9

8

Generalized Phase Separation

F13

Hydrogen, Methane

Hydrogen

Toluene

Coolers

Exchanger

Compressor

FurnaceReactor

Flash

Sta

biliz

er

Ben

zene

Tolu

ene

PurgeGas

Recycle

Quench

BenzeneToluene

Diphenyl

The Complete Process Flowsheet

Examples of Systems: Control Structures

Steam

CW1

PI

SC

LI

CW2

PurgeA

FI

D

FI

E

FI

C

FI

FI

TI

TI

PI

TI

LI PI

FI

FI

JI

FI

FI

FI

TILI

Product

ANALYZER

XA

XB

XC

XD

XE

XF

ANALYZER

XA

XB

XC

XD

XE

XF

XG

XH

ANALYZER

XD

XE

XF

XG

XH

F1 (A, B)

F2 (D, B)

F3 (E, F)

F4 (A, B, C)

F6

F8

F5

F7

F10

F9

F11

TC

LC

LC

LC

PC

TI TC

x11,G , F11

CC

%A, %CControl

Short-horizonControl Strategies

Long-horizonControl Strategies

• What is the intention (purpose) of each control loop?

• How were they selected?

Control Loops for : Stabilization of Reactor Operation

Steam

CW1

PI

SC

LI

CW2

PurgeA

FI

D

FI

E

FI

C

FI

FI

TI

TI

PI

TI

PI

FI

FI

JI

FI

FI

FI

TI

Product

ANALYZER

XA

XB

XC

XD

XE

XF

ANALYZER

XA

XB

XC

XD

XE

XF

XG

XH

ANALYZER

XD

XE

XF

XG

XH

F1 (A, B)

F2 (D, B)

F3 (E, F)

F4 (A, B, C)

F6

F8

F5

F7

F10

F9

F11

TC

LC PC

Control Loops for : Material Inventory Control

Steam

CW1

SC

CW2

PurgeA

FI

D

FI

E

FI

C

FI

FI

TI

TI

PI

TI

LI PI

FI

FI

JI

FI

FI

LI

Product

ANALYZER

XA

XB

XC

XD

XE

XF

ANALYZER

XA

XB

XC

XD

XE

XF

XG

XH

ANALYZER

XD

XE

XF

XG

XH

F1 (A, B)

F2 (D, B)

F3 (E, F)

F4 (A, B, C)

F6

F8

F5

F7

F10

F9

F11

LC

LC

%A, %CControl

Control Loops for: Production Rate and Product Quality

Steam

CW1

CW2

PurgeA

FI

D

FI

E

FI

C

FI

FI

TI

PI

TI

PI

FI

FI

JI

FI

FI

FI

Product

ANALYZER

XA

XB

XC

XD

XE

XF

ANALYZER

XA

XB

XC

XD

XE

XF

XG

XH

ANALYZER

XD

XE

XF

XG

XH

F1 (A, B)

F2 (D, B)

F3 (E, F)

F4 (A, B, C)

F6

F8

F5

F7

F10

F11

TI

x11,G , F11

Long-horizonControl Strategies

Control Loops for: Minimization of Production Cost

Steam

CW1

SC

CW2

PurgeA

FI

D

FI

E

FI

C

FI

FI

TI

TI

PI

TI

PI

FI

FI

JI

FI

FI

FI

Product

ANALYZER

XA

XB

XC

XD

XE

XF

ANALYZER

XA

XB

XC

XD

XE

XF

XG

XH

ANALYZER

XD

XE

XF

XG

XH

F1 (A, B)

F2 (D, B)

F3 (E, F)

F4 (A, B, C)

F6

F8

F5

F7

F10

F11

TI

x11,G , F11

CC

Short-horizonControl Strategies

Long-horizonControl Strategies

TC

Missing Control Loops

Energy Inventory Control

Control loops ensuring that the operational constraints of the various equipment are satisfied.

Safety

Environmental Regulations Control

Operational Transition Control

Synthesis of Control Structures

• Given– Process with all its units, their sizes, and interconnections– Desired operating conditions, e.g.

• Minimize total operating cost,• Achieve desired product flowrate and composition,• Maintain operating conditions within safe ranges, etc.

• Synthesize a set of control systems, which achieve the desired objectives, i.e.– Select what variables to measure in order to monitor the desired

operating objectives,– Select what variables to manipulate in order to achieve the desired

operating objectives,– Select the interconnections between (measurements) and

(manipulations) in order to form the control loops,– Design the control laws, i.e. given the measurements, how much

should the manipulations change?

MPC Impact for 13 Ethylene Plants

2Starks and Arrieta, 2007

Broad Industrial Impact of MPC

3Qin and Badgwell, 2003

Examples of Systems: Safety Control Structures

Reactor Cooler

Temperature Measurements

(1-out-of-2)Safety Circuits

Gas Analysis Measurements

(2-out-of-3)

Shut-Down Valves

(1-out-of-2)

- Given a Process with all its units and desired safe operating ranges

- Select

- what variables to measure and the redundancy of measurements,

- what variables to manipulate and the redundancy of the manipulations

In order to ensure safe operation in the presence of various failures.

Risk Management and Process Integrity:Environmental Devastations and Industrial Accidents

3

WHEN WHERE WHAT FATALITIES

1955-80 Love Canal Health effects from toxic chemicals

1966 Feyzin, France LPG Bleve 181974 Flixborough, UK Cyclohexane 281979 Bantry Bay, Ireland Crude 501982 Ocean Ranger, Canada Platform 841984 Mexico LPG Bleve 600+1984 Bhopal, India Methyl isocyanate 20000+1986 Chernobyl, USSR Nuclear powerplant 100+1988 Piper Alpha Platform 1671988 Norco, USA Propane FCCU 71989 Pasadena TX, USA Ethylene/isobutane 23

Risk Management and Process Integrity

Love Canal, NY: 1955-80

800 families affected33% chromosomal damage56% of children born ‘74-’78 had birth defect

Flixborough, UKCyclohexane Plant

1974

Risk Management and Process Integrity

Piper Alpha, North Sea: 1988

167 killed

3,800 killed immediately

20,000+ over time.

Bhopal, India: 1984

Process Systems Engineering and Process Risk Management

From“React and Fix”

to“Predict/Detect and Prevent”

Inherently Safer Process Designs

IntegrateProcess Safety

AndControl Strategies

in early stages of design

Advanced Monitoring Diagnostic, and Mitigating

Systems

• SIS: Rational instrumentation • LOPAs: Rational protection• HAZOPs: Science-based• Risk Registers: Knowledge-based

Process Safety Management

ThroughContinuous Improvement

Culture

Work Processes

Management

Examples of Systems: Network of Batch Operations (Production of Intermediates for Pharmaceuticals)

- Synthesize a series of batch operations to convert TRIENONE to CARBINOL

- Allocate batch operations to a set of available equipment: Minimize total time

CH3MgBrTHF

H2O HOMgBr

CH3MgBr H2O HOMgBrCH4

HOMgBr

H2O

Mg++ Br-

H+

H2O

NaOAc

HOAc -OAcH2O

H2O/HOAc

(II)

(III)(II)

O (I) OMgBr

OMgBr OH

OH

M1:

M2:

Quench:

GelBreak:

SR:

Trienone(Primary raw

material)

Carbinol(Primary product)

By-Product

Decant

Mg+2

Br-

-OAcH2O

NaOAc

Trienone(I)

CH3MgBr/Et2O

Dissolve

Dissolve

THF

THF

H2O NaOAc

Dissolve

HOAc

Mix

M1

M2/Quench/

GelBreak/

SR

CoolCool

Flash

CH4(Et2O)(THF)

CrystallizeConcentrate Mix

Et2OTHF

Cyclohexane

Filter

III(II)

(THF)C6H12

IIDry

C6H12(THF)

Concentrate Mix

(Et2O)THFC6H12

Cyclohexane

V VL VL V

Condense Distill

THF

Et2OCH4

Condense Distill

THF

Et2O

DistillCondense Distill

C6H12

Et2O

THF

CondenseEvaporate

III(II)

THF

Distill

C6H12

THF

Distill

C6H12

CondenseEvaporate

H2OMg+2

Br-

-OAcNaOAc

Carbinol(Primary product)

Trienone(Primary raw

material)

Production-Related Operations

Ancillary Operations

Examples of Systems: Network of Batch Operations (Production of Intermediates for Pharmaceuticals)

Examples of Systems: Atmospheric Pollution

Activities

• Define system

• Components

• Interactions

• Model Behavior

• Diagnose, e.g.

• Sources of increased pollution

• Control pollution, etc.

Examples of Systems: Human Cardiovascular System

Activities

• Model

• Monitor

• Analyze

• Diagnose

• Control

• Redesign (?)

• other (?)

(6-amino-penicillianic acid)

Connected Components(functional groups through bonds)

Connected Components(atoms through bonds)

Examples of Systems: Molecules as Systems

Activities• Synthesize molecular structures• Model Behavior

• Physical Properties• Reactivity at various sites

• Diagnose molecular failures• Generate reactions

Examples of Systems: Molecules as Systems

Use Molecule’s structure to Compute physical properties or kinetic rates

(The Group-Contribution and LFER ideas)

C O

O

CC H

H

H

H

Physical Property =

= + + + correctionContribution from (C=C) Contribution from (C=O) Contribution from (O-H)

Examples of Systems: Molecules as Systems

Using Molecular Structural Components to Generate Reactions

C O

O

CC H

H

H

H

CCR

R

R

R CCR

R

C/O

H

These two inherit the same Reactivity around the C=C double bond as the “mother” group

CCR

R

O

H

This does not inherit the same Reactivity around the C=C double bond as

the “mother” group

Examples of Systems: Reaction Networks

System Components: MoleculesComponent Interconnections: Reactions

C2H6

CH3• H•C2H5•

C2H6

H2

C3H8

C2H4

CH4

Activities• Synthesize reaction pathways producing desired chemicals.

• Syntrhesize reaction network including reactions with substantial rates affecting the modeling of a chemical process (e.g. combustion)

• Model the behavior, e.g. composition of all reacting species in the network.

• Control the composition of reacting species in the network.

• Diagnose the failure of reacting networks

• other (?)

Examples of Systems: Generating Reaction Networks

Generate all reactions, which have substantial rates, and thus affect the modeling of a particular process

Rj(t) < Rmin(t) Rate-based termination rule

C2H6

CH3• H•C2H5•

C2H6

H2

C3H8

C2H4

CH4

.

.

.

Expanding Envelope of Reaction Set

Examples of Systems: Generating Reaction Pathways

• Generate all possible reaction pathways, which lead from given reagents to a desired product.

• Select the “optimum” reaction pathway for the development of a production process

.

.

.

.

.

.

.

.

.

. . . P (Desired Product)

.

R1

R2

Rn-1

Rn

R2,1

R2,2

R2,k-1

R2,k

R2,2,1

R2,2,2

R2,2,m-1

R2,2,mAvai

labl

e S

tarti

ng R

eage

nts

Examples of Reaction Systems: Identifying Catalytic Reaction Networks

C4 H10 C4 H8 + H2 (Overall reaction)

Elementary Reaction Steps:(1 ) C4 H10 C4 H8(m) + H2

( 1) C4 H8(m) + H2 C4 H10 + (m)(2 ) C4 H8(m) C4 H8 + (m)( 2) C4 H8 + (m) C4 H8(m)(3 ) C4 H8(m) C4 H6(m) + H2

( 3) C4 H6(m) + H2 C4 H8(m)(4 ) C4 H6(m) C4 H6 + (m)( 4) C4 H6 + (m) C4 H6(m)(5 ) C4 H10 + C4 H6 (m) + (m) 2C4 H8 (m)( 5) 2C4 H8 (m) C4 H10 + C4 H6 (m) + (m)

C4 H10C4 H10

C4 H8C4 H8

C4 H8(m)C4 H8(m)

H2H2

11

22

(m)(m)C4 H10

C4 H8

C4 H8(m)

H2

1

2

(m)C4 H10C4 H10

C4 H8C4 H8

C4 H8(m)C4 H8(m)

H2H2

11

22

(m)(m)

55

33

C4 H6(m)C4 H6(m)

C4 H10

C4 H8

C4 H8(m)

H2

1

2

(m)

5

3

C4 H6(m)

Select the most “Likely” using experimental data

C4 H10C4 H10

C4 H8C4 H8

C4 H8(m)C4 H8(m)

H2H2

11

22

(m)(m)

55

33

C4 H6(m)C4 H6(m)

C4 H10

C4 H8

C4 H8(m)

H2

1

2

(m)

5

3

C4 H6(m)

+

Other

Structures

Examples of Systems: Identifying Catalytic Reaction Networks

Combinatorial Generation of Feasible Reaction Networks for the Catalytic Dehydrogenation of Butane, using elementary steps in previous slide.

Emergence of the term “Systems Chemistry”

• Catalytic and autocatalytic reaction networks• Self-Replicating and self-reproducing chemical systems• Dynamic combinatorial chemistry• Emergent phenomena in molecular networks• Information processing by molecular networks• Complex dynamic and chaotic behavior of chemical

systems: bifurcation; chiral symmetry breaking• Bottom up approaches to synthetic biology and chemical

evolution• Chemical self-organization inspired by the problems of

the origin and synthesis of life• Self-assembly and formation of supramolecular

structures

Examples of Systems: Products as Systems

• DNA Sequencer, Batteries, Fuel Cells, OLEDs

• Example: OLED

Substrate (Glass, Plastic)Anode (ITO,other)

Hole Injection Layer

Hole Transmission Layer

Light-Emitting Layer

Hole Blocking Layer

Electron Transmission LayerCathode

OLED for Displays and Lighting

e -

p +

Light

Examples of Systems: Technology Supply Chain

Process Development / Manufacturing

Gene/Target Identification

Target Validation

LeadIdentification

Lead OPPreclinical Clinical

Trials

Commercial and PatientMgmt

Chips Proteomics Imaging Structure Predictive ADMET

CDU SNPFluidics

BiologyMarkers Computational Biology

Chemistry Chem GeneticsCompChemistry

Patho-pharmacology

Pharmaco-genomics

PatientManagement

Technology Supply Chain in the Development of Pharmaceuticals

Examples of Systems: Biological Systems (Emergence of a new field: “Systems Biology”)

DNA RNA Protein

Signaling Pathways

Metabolites

The “Cell” is among the most intricate and richest in diversity

systems we know

Examples of Biological Systems: DNA Transcription System

• Identification of system: components and interactions.

• What are the proteins triggering the expression?

• What part of the DNA (gene) regulates the onset of transcription?

• Modeling and analysis.

• Regulation and control of transcription.

• Diagnosis of failures in transcription.

• Coordination of transcription of many genes.

Examples of Biological Systems: Gene Expression Regulation Systems

• Identification of system: components and interactions.

• What are the proteins involved in gene regulation?

• What part of the DNA (gene) regulates the onset of gene expression?

• What is the structure of regulation?

• Feedback,Feedforward

• Cascade, Ratio, other

• Modeling and analysis.

• Interaction of control loops.

• Diagnosis of expression failures

• Coordination of expression of many genes.

Examples of Biological Systems: Functional Coupling of Gene Clusters

22light

2ifcA

7phbC

9citH

11ppsA

12glk

13pfkA

14pykF

15humG

16devB

17talB

3rbcR

18psbA2

8desB

30ackgap1 23

petApsbA1

28ndhndhdesCicd

4napA

10fumC

24accChumB

25ftrVgdh

19psbD1

20psbD2

26phaBpdhB

21nblA

6phaE 5

phaD327sll0phaD2gltAfbppsaApsbA3

31gap2ndhphaAftrCacnBppcpetBaccDglgAglgAglcErplAapcBnblArpl1

29atpAatpBacsicfAprkrbcLrbcSphaD1desAdesDpetFpdhAfabDbglglcDglcFenofdagpmBpfkApgipgkpykFtktApsaBapcAcpcAcpcBrpl2rps1

1pta

τ = 2

τ = 2

τ = 10τ = 1

τ = 2

τ = 6

τ = 5

τ = 2

Examples of Biological Systems: Metabolic Pathways

AllostericRegulation in the TCA

Examples of Biological Systems: Metabolic Pathways

Lysine Production: Over- and Under-Expressed Genes

Glucose/Lactose Results

Sequence L5G3 L5G3- 2 G5L3 G5L3- 2eno (CG) - 1.5827 - 1.60764 0.341567 0.517188fba (CG) - 1.05754 - 0.96981 0.091934 0.116375fba (CG- fu l l ) - 1.00681 - 0.9083 0.249736 0.012971gap (CG) - 2.4424 - 2.40659 1.546058 1.359307gap (CG- fu l l ) - 2.45508 - 2.46381 1.539526 1.3435gpi (CG) - 0.52108 - 0.59121 0.025475 - 0.04531gpm (CG) - 1.06974 - 1.06014 - 0.00774 0.161965pfk (CG) - 0.62438 - 0.64254 1.255223 0.636102pfk (CG- fu l l ) - 0.91885 - 0.79383 1.495258 1.261263pgk (CG) - 0.65385 - 0.34644 0.887281 0.832779pgk (CG- fu l l ) - 1.23935 - 0.91337 0.895475 1.226801pyk (CG) 0.8405 1.127788 0.312621 1.064184pyk (CG- ful l ) - 1.93227 - 1.94356 1.182092 1.11088tpi (CG) - 1.46836 - 1.07221 1.084423 1.642629tpi (CG- fu l l ) - 1.44374 - 1.11193 1.086573 1.356285

glucose-6-Ppgi

fructose-6-P

fructose-1,6-bisphosphate

pfk

3-phosphoglyceraldehyde dihydroxyacetonephosphate

fba

tpi1,3-bisphosphoglycerate

gap

pgk3-P-glycerate

gpm/Rv2419c/Rv3837c2-P-glycerate

enophosphoenolpyruvate

pykpyruvate

aceE/lpd/pdh/Rv0462acetyl-coA

citrate

glt/citEoxaloacetate

ketogluteratemalate

succinatefumarate

icd

suc/lpd

glyoxylate

aceA

aceB

sdh

fum

mdh

bioF bioA bioD bioBbiotin

pcappc

ask

glutamate

aspartate

aat/aspB

aspartate semialdehyde

asddapA dapB dapD dapE dapF lysE/G lysine

thrA

thrB

thrC

threonine

6-P-gluconatedevB/opcA/zwfgnd

ribulose-6-P

rpirpe

xylulose-5-P ribose-5-P

riboserbsK

tkt

sedoheptulose-7-P

tal

erythrose-4-P

tkt

Gene Chips: Monitor Gene expression levels

Chris Roberge; PhD thesis, 2005

Examples of Biological Systems: Metabolic Pathways

• Identify all the steps of a Metabolic Pathway of interest, e.g. production of poly-hydroxy-alkanoates.

• Estimate carbon fluxes through the metabolic pathway of interest and associated pathways.– Identify rate-limiting steps on pathway of interest– Identify yield-limiting steps on associated pathways

• Identify the allosteric regulation structures• Modify pathways to “optimize” performance

– Over-express “favorable” enzymes.– Knock-out “unfavorable” enzymes.

• Insert complete pathways from an other species

Examples of Biological Systems: Signaling Pathways

Receptor PTKReceptor PTK

Ras-GDPRas-GDP Ras-GTPRas-GTP

Growth FactorGrowth Factor

GRB2/SosGRB2/Sos

TFTFTFTF

MekMek MekMek PPPP

Receptor PTKReceptor PTK

PP

PP

PP

PP

PPMAPKMAPK MAPKMAPK

RafRaf

TranscriptionTranscription

PP

Receptor PTK

Ras-GDP Ras-GTP

Growth Factor

GRB2/Sos

TFTF

Mek Mek PP

Receptor PTK

P

P

P

P

PMAPK MAPK

Raf

Transcription

P

NucleusGene

induction

Receptor-Ligand binding

Signalingpathways

Examples of Biological Systems: Signaling Pathways

What is the structure of the signaling pathways?How is the information from a single ligandtransmitted to multiple targets?How do multiple ligands affect the expression of a single gene?How do different cell types or conditions influence signaling?How do differences in dynamics play a role in determining the “message”?

Examples of Biological Systems: Infection of a Cell with HIV

HIV is one of the most well-studied virus.

- Receptor mediated attachmentonto cell surface.

- Co-receptor mediated entry.- Release of mRNA.- mRNA translation.- Polyprotein expression.- Cleavage into protein.- mRNA replication.- Assembly of structural protein

and mRNA inclusion.- Exocytosis.

Interaction between HCV particle and cell receptoris critical for viral sensing system and vaccine study.

How does HCV attach to cell surface and internalize?

Example of Biomedical System: Targeted Delivery of Radionuclides to Tumors (From: Kelly Davis-Orcutt PhD Thesis)

excellent safety profile in humans

chelates trivalent cations (177Lu, 90Y, 86Y, 111In, 213Bi, 225Ac)

CEA binding

DOTA binding

Example of Biomedical System: Targeted Delivery of Radionuclides to Tumors (From: Kelly Davis-Orcutt PhD Thesis)

Does this design address effectively the problem ?

Clearing Agent A new design element

INTEGRATED SYSTEMS APPROACH

Product Design Selection of AntigenHaptenBispecific AntibodyClearing Agent

Therapeutic Process (Operation)Administration of Antibody; dose, timeAdministration of Clearing Agent; dose, timeAdministration of DOTA; dose, time

Examples of Systems: Information System for CIM

EXTERNALENVIRONMENT

MarketSupplier

DistributorGovernment

BUSINESS INFORMATION SYSTEM

Finance Marketing AccountingMaterials Supply

Decision Support , etc.

END USER FUNCTIONS

ManagementGeneral Planning

FinanceAccountingMarketing

SupplyDemand

Production PlanningManufacturing

Engineering

OFFICE AUTOMATION

Electronic Mail /File Schedules

PLANT PRODUCTION MANAGEMENTSYSTEM

Production Planning Production Evaluation, etc.

FIELD OPERATIONSLaboratory Process Utilities Storage Tanks Blending/Shipping

PROCESS MONITORING ,ANALYSISAND CONTROL

Distributed Control SystemAdvanced Control System

Information Flows

Example of Systems: Natural Gas and CO2

Supply Chain