SIMULATION TOOLS FOR
FINE CHEMICAL
INDUSTRY
Moshe Bentolila
Contents
• Common Questions
• The Goal
• Pharmaceuticals Industry – Quality By Design
• Typical Mixing Parameters
• Data and Results Management
• Data Base Motivation
• R&D, Design, QbD and Process Safety Examples
Common Questions
�Did we cover the main parameters during the process
development?
�Will our facilities will be appropriate for the developed process?
�Does the equipment offer is good for the process?
�What about safety and runaway scenario?
�Do our process is robust?
�Does the operational range parameters are large enough for
the manufacture facilities?
The Goal Once the Science of the process (Chemestry, Biology or physics) is
known well, a common situation during the process transfer from lab to
production or from site to site is the gap between the old and new
results.
�Our first goal is to develop a process that will run properly in the
first trial on a new scale or site, similar to our successful results in the
lab or in the old facility.
In order to achieve this, we need to evaluate the process with the same
conditions we will have in the production phase.
�The main parameters we change are the hydrodynamics of the
system. If we are able to identify and control these parameters we
will be able to achieve to the available and optimal solution.
Pharmaceutical Industry
• Active Pharmaceutical Ingredient (API)
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Pharmaceutical Quality by Design• This FDA imperative is best outlined in its report
“Pharmaceutical Quality for the 21st Century: A Risk-Based
Approach.”[*]
• In the past few years, the Agency has made significant
progress in implementing the concepts of "Quality by
Design" (QbD) into its pre-market processes.
• The focus of this concept is that quality should be built into a
product with a thorough understanding of the product and
proceess by which it is developed and manufactured along
with a knowledge of the risks involved in manufacturing the
product and how best to mitigate those risks.
• This is a successor to the "quality by QC" (or "quality after
design") approach that the companies have taken up until
1990s.* Pharmaceutical Quality for the 21st Century: A Risk-Based Approach http://www.fda.gov/oc/cgmp/report0507.html
QbD activities within FDAOverall implementation of QbD:
•In FDA’s Office of New Drug Quality Assessment (ONDQA), a
new risk-based pharmaceutical quality assessment system
(PQAS) was established based on the application of product and
process understanding.
•Implementation of QbD for a Biologic License Application (BLA)
is progressing.
While QbD will provide better design predictions, there is also a
strong recognition that industrial scale-up and commercial
manufacturing experience provides new and very important
knowledge about the process and the raw materials used
therein. This vigilant and nimble approach is explained by FDA to
be essential to best protect the consumer (patient).
http://en.wikipedia.org/wiki/Quality_by_Design
API Batch Process Simulation – Scale Up Methodology. Roberto Novoa and Moshe Bentolila
QUALITY BY
DESIGN
Establish:
Critical
Quality
Attributes
Determine:
Critical
Process
Parameters
Define:
Design
Space
Set:
Control
Strategy
Quality by Design – Statistical Challenges
Yi Tsong,.
CDER, FDA 2007 FDA/Industry Statistics Workshop
Typical Mixing ParametersReview of the Main Mathematical Models Used in VisiMix – www.visimix.com
Mixing Simulation Software
R&D
Production
Design
QbD
Data and Results Management
Data Base Motivation
o The need for maximizing efficiency of a mixing process by compiling all its elements into a common database.
o The need for better understanding between the mixing process and its impact on the entire process and a simple solution to achieve this
o The need to create a common language within the company in order to achieve better communication with regards to these processes.
Integration of DataBase and Language
How does it work?
Equipment Data
New Process
VisiMix
VisiMix
Create Project for Equipment Data
Excel File Data
Equipment DataBase
Create Project for Process
Excel File Data
Process Knowledge DataBase
VisiXcel
VisiXcel
Common Language
Designing Engineer
PilotEngineer
ProductionEngineer
QA
DevelopmentChemist
Equipment “Database”
Process Knowledge “Database”
Common Language
Data Base Typical Spreadsheets
R&D - Example This example is based on a practical case application of VisiMixTurbulent by one of our clients. It is related to development of a new process of organic synthesis in a chemical plant that belongs to one of the big international pharmaceutical corporations.
One of the stages of this synthesis - a relatively fast chemical reaction between two reactants accompanied with a side reaction.
Schematically: the main reaction as A + B > C with the side reaction as B+B > D.
On the development stage, a low quantity of by-product and acceptable degree of purity of the main product was obtained in a batch pilot reactor (total volume - about 2 liter).
The process was transferred to a production glass lined 1230 liter reactor.
Scaling-up was based on reproduction of mixing time value. However, a significant deterioration of the product purity and increase of by-product concentration occurred.
R&D - Example
R&D - Example
R&D - Example
R&D - Example
• Semibatch Operation
R&D - Example
Example Conclusion:
�Reagent B was not well distribute in the
reactor.
�Macromixing time was not enough to avoid
to malfunction in the production reactor.
�A semibatch operation was adopted and gave
positive results.
Design Example
CRYSTALLIZER. SCALING-UP•The process rate and particle size distribution in crystallization and precipitation processes are dependent on chemical composition and physico-chemical properties of the system.
•In the same time they can be substantially dependent also on some phenomena that are functions of mixing conditions – for example, on primary and secondary nucleation, attrition and breakage of crystals, distribution of solid phase and liquid-solid mass transfer.
•The following example is related to a particular case when the crystallization is controlled mainly by these parameters, and scaling-up conditions include reproduction of these phenomena.
•The corresponding parameters selected from the list of VisiMix outputs and used below for crystallization scale-up are presented in the Table.
This example is based essentially on the article ‘Optimizing Crystallizer Scaleup’ by Wayne
J. Genk , Chem. Engng. Progress, June 2003, pp. 36-44
For calculation of the Mass transfer coefficient, it is
necessary to enter a number of additional initial data,
including the Diffusivity of the solute. In our case the
problem consists not in prediction, but in reproduction
of the same value of the Mass transfer coefficient.
Reactor Configurations
Pilot Production Design
Results
Methodology (J.M. Berty, CEP, 1979)(J.M. Berty, CEP, 1979)
LABORATORY(R&D)
PILOT(Pilot)
Demo – Simulation (Visimix, Dynochem,CFD)
PLANT (Production)
BENCH SCALE
(RC1,Mini Pilot)
LABORATORY(R&D)
PILOT(Mini Pilot)
PLANT (Pilot,Production)
BENCH SCALE
(RC1, HEL)
Scale Down
Final Disign
Build
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QbD
Lab and Prod
Calculations
Moshe Bentolila, Roberto Novoa, and Wayne Genck, Michal Hasson, Efrat Manoff, "Computer Aided Process
Engineering at Chemagis" , PHARMACEUTICAL ENGINEERING July/August 2011. 30-38
Non ideal stirring – non homogeneity• Before performance of scale up experiments
VisiMix simulation was used to check
suspension at different Mini Pilot Reactors:
Reactor 7603 7605 7605 7607 Volume, L 10 25 25 50 RPM 500 (Max) 400 500 (Max) 150 (Max)
Main Characteristic
Liquid – Solid Mixing
Solid suspension quality
Complete suspension is questionable.
Partial settling of solid phase may
occur.
Complete suspension is
expected.
Complete suspension is
expected.
Complete suspension is questionable.
Partial settling of solid phase may
occur. Max. degree of non uniformity of solid
distribution
AXIAL, % 22.3 10.3 29.1 132 RADIAL, % 65.7 34.3 76.3 90.8
Not all Mini Pilot reactor are capable of
full suspension of POCA.
Process parameters vs. constraints
Case Target Function Yield EOR [hr] Stirrer [rpm] TEMP [0C]
AHigh demand to the product and the reactor. Yield →max, EOR≤8
98.1 8 546 26
BThe price of the product equals 10 times the value of reactor availability. (10·yield-EOR)→max
98.4 8.3 623 25
C
High demand of the product with low availability of reactors. One hour of available reactor equals 10 times yield. (1·yield-10·EOR)→max
95.2 1.5 483 39
DHigh availability of reactors, High cost of impurity purification. (10·yield-10·IMAM-1·EOR)→max
98.9 14.4 637 20
Bentolila, M., Kennet, R., “Scale-up Optimization Using Simulation Experiments,”
presented at the American Institute of Chemical Engineers (AIChE), Palm Springs
California, 11-16 June 2006.
SECOND ORDER EXOTHERMAL REACTION IN A BATCH
REACTOR
•This example shows how to simulate 2nd order
exothermal reaction carried out in a stirred batch
reactor.
•VisiMix performs simulation of exothermal reaction
based on the analysis of the equipment and process
parameters, and helps avoid runaway reaction that
may take place when the energy generated by the
reaction is greater than the energy removed from the
reactor.
Process Safety
Example
Problem description: A second order irreversible reaction is carried out in a stirred batch reactor. This reaction is run according to the stoichiometry A + B C → The equation for the reaction rate is: r = k CA CB where
r is reaction rate, moles of A/(L⋅sec);
k is reaction rate constant, L/(mole⋅sec); CA is concentration of reactant A, mole/L; CB is concentration of reactant B, mole/L. The reaction rate constant is a function of the system temperature and is given by k = k0 e -E/RT where
k0 is Arrhenius constant, L/(mole⋅sec); E is energy of activation, kJ/mole;
R is gas law constant, J/(mole⋅K);
T is absolute temperature, K.
Results
Before Cooling Operation After Cooling Operation
Conclusion
�� VisiMix Product and VisiMix Product and Data base allows you Data base allows you
to manage your equipment and projects to manage your equipment and projects
together with a relevant parameterstogether with a relevant parameters
�� Common language for all the company Common language for all the company
involves in the new process runninginvolves in the new process running
�� Present a wide view and platform for a Present a wide view and platform for a
well QbD (quality by Design) study.well QbD (quality by Design) study.
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