Scale up optimization using simulation experiments

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Scale up optimization using simulation experiments
M. Bentolila, R.S. Kenett, S. Malca, R. Novoa, M.
Hasson, B.N. Yoskovich
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Perrigo IL Structure
names
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Intellectual Capital ChemAgis Israel
6 Days 3 shifts
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R D Organization Chart
Chemagis personnel constantly strive to develop
newtechnologies and processes that meet the
stringent scientific and regulatory demands and
challenges to support today's global markets.
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Our ProductsGeneric API Active Pharmaceutical
Ingredients

• production 30 products py

• Examples ofr our products
• Pentoxifylline
  Vasodilator
• Pramipexole Dihydrochloride Anti
  Parkinsonian
• Rocuronium Bromide
  Neuromuscular blocker
• Temozolomide
  Antineoplastic, alkylating agent
• Terbinafine Hydrochloride
  Antidermatophyte (fungal infections
• 
  of the nails)
• Tramadol Hydrochloride Analgesic
  
• Zonisamide
  Antiepileptic

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Scale Up Methodology (J.M. Berty. CEP, 1979)
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Scale Up Methodology (J.M. Berty. CEP, 1979)
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combined
2005 -
2001-2005
Before 2001
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Before 2001
The scale-up process columnar didnt use any
simulation tools
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Visimix and Dynochem
2001 - 2005
DOE Design Of Experiments
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Visimix Dynochem
2005 -
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The programs used for Modeling simulation and
optimization

• VisiMix Mixing simulation and calculation
  software.
• Mathematical modeling of mixing phenomena.
• Calculation of average and local characteristics
  of mixing flow and distribution of concentration.
• Simulation and calculation of real non perfect
  mixing.
• DynoChem Chemical dynamic simulation software.
• Fitting if chemical reaction models.
• Prediction of scale-up conditions.
• Optimization of laboratory and production
  results.
• Equipment characterization.
• Shows effects of scale dependent physical
  phenomena (mixing, heat transfer, mass transfer).
• Dynochem can be used for simulation of reactions
  performed in homogenous environment. When mixing
  is not ideal and the solution is not homogenous
  VisiMix is used for finding the required mixing
  conditions.

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TIme To market reduction via Statistical
Information Management Project No. GRD1
2000 - 25724
INTRASOFT (GR), London School of Economics (UK),
POLITECNICO DI TORINO (IT), Centre National de la
Recherche Scientifique CNRS (F), BLUE Engineering
Group (IT), EASi Europe (D), KPA Ltd (IL), SNECMA
(F), Israel Aircraft Industries Ltd IAI (IL)
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TEMO production Process

• Crude TEMO production - The crude production step
  contains two main operations the reaction and
  the precipitation.
• Crystallization This is the main purification
  step of the process.
• The reaction is described at these equations

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• Optimal reaction time yields maximum amount of
  TEMO and minimum amount of impurities (maximum
  yield).

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Model Fitting, Optimization and Simulationusing
Visimix and Dynochem
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Model Fitting, Optimization and Simulation
Where K Reaction Constant (m3/mol.s) and
(1/s) Ea Reaction Activation Energy
(kJ/mol) KLa Mass transfer coefficient (1/s)
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optimization

• 8 TEMO batches were produced at RC1 scale at the
  production conditions set according to the
  Visimix and DynoChem simulation and optimization
  results.
• The required impurities level is N.M.T 0.15 (for
  each impurity) at the final product.
• Impurity levels at production

At the end of crude step the impurity levels are
higher then spec We cant skip crystallization
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The experimental array
(Simulation experiments)
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(No Transcript)
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Process parameters vs. constraints
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Non ideal stirring non homogeneity

• When DynoChem simulation does not match
  experimental data we should suspect a stirring
  problem and non homogeneity conditions in the
  reaction solution.
• VisiMix software is used in order to find the
  required stirring characteristics.
• New conditions are applied on experiments before
  fitting a model at DynoChem software .
• For example The product XXXX is produced at a
  solid liquid reaction.
• The main reaction at this process is
• BBCM TA POCA ?XXXX
• POCA reagent properties
• Solid
• High particle size mean735mm
• High density 2300 kg/m3
• suspension must be achieved in order to fit a
  DynoChem model to the reaction.
• VisiMix was used for suspension calculation.

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Non ideal stirring non homogeneity

• Before performance of scale up experiments
  VisiMix simulation was used to check suspension
  at different Mini Pilot Reactors

Not all Mini Pilot reactor are capable of full
suspension of POCA.
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Financial aspects
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Adjusting the EOR time according to the financial
optimization saves about 4 of the material.
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Summary and Conclusions

• As part of the continuous professionals'
  formation policy of our company ours engineers
  and operative personal have to permanent learn
  about causes and consequences of changes present
  in scale-up, scale-down challenge .
• Using software package like VisiMix and Dynochem
  orient the eng during the process development to
  the best results.
• Scale-up (or down) is a very complex enterprise
  and, for to arrive an acceptable results, needs
  to be faced by an interdisciplinary team-work of
• Technicians
• Chemical process ENG
• Chemists
• Mathematical statistics experts,
• Computation ENG
• And others
• As a result of the team-work we arrive at the
  desired result and at the same time every
  participant and their collaborators update his
  knowledge in a large spectrum of related sciences
  and arts.

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Thank you for your attention