AAPS Workshop on

QbD-based Drug Development & Manufacturing

Baltimore, 27 April 2009

Model-Based Innovation
in Process Development and Design Costas Pantelides
Centre for Process Systems Engineering Imperial College London Managing Director Process Systems Enterprise Ltd.

2009ProcessSystemsEnterpriseLimited

Overview

Model-based Innovation Technological basis of Model-Based Innovation Model-Based Innovation in Practice Concluding remarks

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Model-Based Innovation
Innovation, risk and modeling

2009 Process Systems Enterprise Limited

Whymodel?

Competitive advantage
Higher risks

Impediments Innovation

New equipment & process designs New chemistry & catalysts New materials of construction .........................

Effective risk management Speed

(time-to-market)

Limited scope for evaluation of alternatives

Modelling

Imperatives
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Model-Based Innovation is
the use of validated, predictive models for
Quantified uncertainty in the model predictions Quantitative prediction of the effects of design & operating decisions on KPIs, within the accuracy necessary to achieve the business objectives

2. the quantification of the technological risk involved in model-based decisions 3. the effective targeting of experimental R&D towards minimization of this risk
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1. the optimization of process design & operation via comprehensive exploration of the space of alternatives

Innovation,risk&modelling

Competitive advantage
Impediments Innovation Higher risks Effective risk management Speed
(time-to-market)

Integrated experimental & modelling methodologies

Limited scope for evaluation of alternatives

Modelling

Imperatives
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Innovation,risk&modelling

Competitive advantage
Impediments Innovation

Model Based Innovation

Speed
(time-to-market)

management innovation Limited scope for evaluation of alternatives

Integrated Higher experimental risks & Effective management modelling of technology risk in Effective risk methodologies

Modelling

Imperatives
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Technological Basis for Model-Based Innovation

2009 Process Systems Enterprise Limited

Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

2009ProcessSystemsEnterpriseLimited

Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

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Modeling of processing equipment

Significant progress in understanding & quantification of basic physics and chemistry

large proportion of key unit operations can be described in terms of detailed fundamental mathematical models models predictive over wide ranges of conditions

Greatly increased ability to model transient systems which are distributed with respect to 2 or more dimensions

spatial and non-spatial distributions

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Modelingofdistributedunitoperations
Crystallization Particle size
n (1,2 ) t Mcat = Fincat nin (1,2 ) Fout cat n (1,2 ) Mcat Mcat G1 (1 ) n (1,2 ) 1 G2 (1,2 ) n (1,2 ) 2

Molecular weights MW1 + MW2 Co-polymerization

Coking+Temperature

Gasification

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Some key unit operations in pharma

Reactions

Filtration Milling/Grinding Granulation Drying/Freeze Drying Coating

homogeneous heterogeneous

Separations

Solution crystallization

cooling evaporative precipitation

Chromatography .................

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Solids transportation ................

Detailed modeling of solution crystallization

Size-dependent kinetics for nucleation, growth, attrition Mass & energy balances

multiple liquid-phase species multiple solid phases different polymorphs, enantiomers, chemical species

Population balance(s)

Accuracy of prediction ?

nV nG = V + fV ,in nin fV ,out nout + ( B D)V L t

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Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

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Model identification & validation

Most equipment models contain parameters that are not known a priori

Karamertzanis et al., J. Chem. Theo. Comput., accepted for publication, 2009)

thermodynamics heat & mass transfer kinetics multiscale modeling experimental data

Need to be estimated from

Experimentation often the bottleneck in terms of time & cost Need carefully targeted experiments

Brix Sensor K-Patents Process Instruments Inc.

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Typical experimentation in solution crystallization

Experiment types

production scale (~ m3) lab scale crystallizer (~ dm3) DSC

Online Particle Size Analysis with Ultrasonic Extinction (OPUS Sympatec GmbH)

Measured quantities

pressure, temperature liquid phase concentration: UV, IR, solid concentration: turbidity, particle size distribution: laser diffraction, sieving, acoustic attenuation, chord length distribution: laser backscattering (FBRM), Focus Beam Reflectance Measurement (FBRM, Mettler Toledo)

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The Model Validation Cycle

Model-based Model-targeted experimentation

Statistical significance analysis:

Is the model valid in principle?

Model of experimental rig

Experimental rig

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Successive refinement of solution crystallization model

WR = 331

account for measurement bias

WR = 301

WR = 43

replace traditional power law growth kinetics with combined description of mass transfer and surface integration

Parameters accurate enough?

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The Model Validation Cycle

Model-based Model-targeted experimentation

Model of experimental rig

Experimental rig

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Model-Based Experiment Design

Minimize (estimated) error in parameter values following nth experiment

taking account of previous experiments 1n-1 initial conditions for experiment controls during the experiment sampling times

Determine optimal

A complex optimization problem, but

Parameter Error (%)

random design human expert designer optimal design Experiment Number

can be solved routinely leads to significant benefits

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The Model Validation Cycle

Model-based Model-targeted experimentation

Model of experimental rig

Experimental rig

Accurate model parameters

of quantified uncertainty with minimum experimentation
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Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

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Example #1:

Optimization of batch crystallization recipe

Objective

minimize batch time; or minimize width of PSD; or temperature at end of batch growth rate during entire batch average size at end of batch width of PSD at end of batch amount and PSD of added seeds seed addition time cooling profile
Large space of time-varying decisions subject to many constraints Need formal mathematical techniques to search it

Constraints

1 mm

Decision variables

Dynamic Optimization
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Example #1:

Optimization of cooling crystallization profile

Original Recipe Optimal Recipe

New temperature profile

growth rate now below 0.01 m/s at all times

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Example #2:

Batch-to-continuous process conversion

Objective: maximize production rate while maintaining product quality
Model tracking ~10,000,000 polymeric species Kinetics extensively validated against batch pilot plant experiments

35% improvement in throughput; product quality at least as good

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Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

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Equipment scale-up

Key challenge: predict interactions between

detailed equipment geometry and design fluid flow/mixing [Equipment-scale dependent] other key phenomena [Equipment-scale independent]

chemical reaction homogeneous/heterogeneous mass transfer nucleation, crystal growth heat transfer

Scale-up may be difficult even in smaller equipment

depending on desired degree of control on product quality

A systematic approach to scale-up is needed

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Hybrid gPROMS/CFD equipment modeling

Concept: combine different descriptions of processing equipment within single, fully coupled model

Computational Fluid Dynamics (CFD) Fluid mechanics (single/multiphase) Mixing

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gPROMS Heterogeneous reaction Heat & mass transfer Nucleation & growth Electrochemistry

Hybrid gPROMS multizonal/CFD models

Urban & Liberis (1999), Bezzo, Macchietto & Pantelides (2000, 2004)

CFD model (Fluent)

total mass conservation momentum conservation

Multizonal model (gPROMS)

zone population balances growth, nucleation/attrition kinetics network mass/energy balances

CFD Multizonal phase mass fluxes between zones volume-averaged zone energy dissipation rate
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Multizonal CFD zone density/viscosity

Standardized, routine technology

Example

Detailed design of gas/liquid/solid reactors

O H3C OH O OH

H3C

HO

p-xylene
O

4-CBA

PTA
O H3C O CH3

H3C OH

0.5 O2
O

k3

CO2

H2O

CH3 H3C O Metyl acetate

4.5O2

3CO2

+ 3H2O

O CH3 H3C O Metyl acetate

3O 2

3CO

+ 3H2O

CH3

+ 10.5 O2

k5

8CO2

5H2O

Model accurate enough to identify improvements of <1%

confirmed by actual plant implementation
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CH3

CH3

+ 6.5 O2
CH3

K4

8CO

+ 5H2O

Technological basis of Model-Based Innovation

1. Modeling of complex unit operations 2. Model validation 3. Model-based optimization 4. Model-based scale-up 5. Quantification of risk in model-based decisions

2009ProcessSystemsEnterpriseLimited

The Model Validation Cycle

Model-based Model-targeted experimentation

Model of experimental rig

How accurate is accurate enough

Experimental rig

Accurate model parameters

of quantified uncertainty with minimum experimentation
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Model-based technological risk management

Three key questions

Given a certain level of model accuracy, what is the resulting uncertainty in the key performance indicators (KPIs) of a process designed using this model? If the risk associated with this uncertainty is unacceptable, which are the critical model aspects on which further R&D needs to focus? If the risk is, in principle, acceptable, then what is the best design that can deal with the residual model uncertainty?

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Quantification & management of technological risk

Determine critical uncertain parameters
[based on global sensitivity measures for KPIs]
No

Risk acceptable ? Determine KPI probability distributions

[Low-Discrepancy Sequence sampling techniques]

Yes

Process Optimization
[scenario-based]

R. Blanco-Gutierrez, PhD Thesis, Imperial College London, 2007

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Model-Based Innovation in Practice

Success or Failure?

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Model-Based Innovation

Case Studies

Energy & environment

Chemistry

Fuel cells & fuel cell systems Polysilicon production Waste gasification LNG storage Gas-to-Liquids conversion Safety analysis ...................

High-value polymers New partial oxidation processes New homogeneous catalytic routes ..........................

Health & Lifestyle

Pharmaceutical & fine chemicals crystallization Granulation Suppression of impurities in APIs Fermentation .....................

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Model-Based Innovation in Practice: Success or Failure?

1. What is the business objective?

What benefit(s) are we expecting? What payback period are we looking for? How much are we prepared/able to change current operations or designs to achieve this objective?

3. What modeling technologies/ tools can deliver this project?

Functionality: can the tool deliver in principle? Complexity: can the tool deliver in practice?

2.

Can modeling help us achieve this objective?

4. Can we use these tools to deliver this project?

What degree of modeling accuracy will be necessary? What level of modeling detail will be needed to deliver this accuracy? Do we understand the physics/ chemistry to the necessary extent? Do we have sufficient experimental measurements and/or capability to quantitatively characterize these physics/chemistry?

Skills? Time frame? Quality of delivery?

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Concluding remarks

2009 Process Systems Enterprise Limited

Model-Based Innovation

In summary
The Objective The Technology
1. 2. 3. 4. 5. Modeling of complex unit operations Model validation Model-based optimization Model-based scale-up Quantification of risk in model-based decisions

R&D productivity not R&D investment

is the real challenge for global innovation
Michael Schrage, MIT Media Lab
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Thank you for your attention

c.pantelides@psenterprise.com

Mark Matzopoulos Chief Operating Officer

2009ProcessSystemsEnterpriseLimited