Streamline Mixing Analysis

and Enable QbD Using ANSYS

Workbench

Marc Horner, Ph.D.

Sravankumar Nallamothu
ANSYS, Inc.
1 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential
 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

2 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

3 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Our Focus
ANSYS is dedicated exclusively to engineering simulation and is the
world's leading software provider. Product innovators in the most
demanding markets have trusted us for over 40 years.

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We’re passionate about developing world-class engineering software
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ANSYS

4 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Our Technology
Our technology enables you to predict with confidence that your
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 Our Support and Services
Our technology and people bring clarity and insight to your most
complex phenomena through fast, accurate and reliable simulation.

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6 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Our Strengths
Focused
This is all we do.
Leading product technologies in all physics areas
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Capable
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ANSYS Confidential
 Our Balance
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 Top Health Care Companies
Rely on ANSYS Simulation

9 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Health Care Industry Statistics
Global ANSYS Health Care Customer Base
• 80% of top 50 largest health care companies (and all top 10)
• Top 10 biomedical device companies
• 90% of top 25 biomedical companies
• 9 of top 10/17 of top 20 pharmaceutical companies
• Overwhelming CFD choice for respiratory drug delivery analysts
• Preferred choice for hemodynamic analysis
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• Pharmaceutical mixing modeling revenue exceeds the sum of all other competitors’ revenue
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“The ability to evaluate different designs with simulation without building

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Dr. Ron Kurnik
Cygnus Therapeutic Systems

10 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Products Overview
Leaders in the Field
Systems and Multiphysics

ANSYS Simplorer ANSYS Workbench ANSYS HPC

ANSYS Engineering Knowledge Manager ANSYS DesignXplorer

Structural Mechanics Fluid Dynamics Electromagnetics

ANSYS Mechanical
ANSYS FLUENT ANSYS HFSS
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ANSYS POLYFLOW ANSYS Q3D
ANSYS nCode
ANSYS Icepak ANSYS Designer
ANSYS Acoustics

11 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

12 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 CFD in the Pharmaceutical and
Biopharmaceutical Industries
ANSYS provides the broadest range of CAE solutions for:
• Drug Manufacture
• Separation Processes
• Materials Handling
• Drug Delivery
• Packaging and Distribution

13 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 What is CFD?

Flow simulation, or Computational Fluid Dynamics (CFD), is the science of

predicting fluid flow, heat transfer, mass transfer, chemical reactions, and
related phenomena by solving the mathematical equations which govern
these processes using a numerical process (that is, on a computer).
The result is detailed information about all flow variables in the system, for
example:
– Flow patterns
– Species concentrations
– Turbulence levels
– Local rates of mixing

• To understand how it works, let’s look in more detail at the CFD process

14 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 The CFD Process

• Flow in the stirred tank is The calculation

calculated using the finite volume domain is a 2000L,
baffled vessel
method with 2 A315
Impellers
– The calculation domain is discretized into a
finite set of control volumes or cells.
– General conservation (transport) equations Fluid region of tank
for mass, momentum, energy, etc., discretized into
 finite set of control

t V
dV   V  dA     dA   S dV volumes (mesh).
A A V

unsteady convection diffusion generation

are discretized into algebraic equations.
A Single
– All equations are solved to render flow field. Control
Volume
Eqn. 
continuity 1
x-mom. u
y-mom. v
energy h
15 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential
 Drug Manufacture

Mixing
Scale up
Gas sparging
Mass transfer
Macro mixing structures, colored by vorticity
Reacting flows contours, in a mixing tank with a 6-bladed Rushton
impeller
Crystallization
Distribution of product molecular Short circuiting
Mechanical stability weight in an LDPE reactor at baffles

Solid suspension
Shaft vibration

Picture

Velocity vectors (left) and gas distribution

16 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential (right) calculated in a tall fermentor
 Separation Processes

Chromatography
Spray drying
Centrifugation
Cyclone/Hydro-Cyclone
Liquid-liquid separation in
Freeze drying batch centrifugal separator

Absorption
Extraction

CFD results illustrating

d=25.5um d=210.5um the vortex core and
Effect of particle diameter (d) on flow velocity at various
17 © 2014 ANSYS, Inc. February 9, 2018 spray
ANSYSdryer performance
Confidential axial planes
 Materials Handling

Blending Volume fraction of larger particles at first 4 s

Milling
Granulation
Powder coating
1S 4S
Pneumatic conveying
Solid blending in a cone blender
Tablet compaction

Contours of granules (x1) Contours of granules (x9)

Distribution of von Mises and shear stresses in a tablet after Different sized particles in kinetically controlled
compaction granulation
18 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential
 Drug Delivery

Drug dissolution
Inhalers
Catheters
Drug-eluting stents
Particles flowing through the drug
Syringes blister of the TWINCER inhaler
(Pathlines colored by velocity)
Needle-free delivery

Instantaneous contour plot of the gas velocity and

low diffusivity drug high diffusivity drug
particle trajectories for a silenced configuration,
taken 120 ms after diaphragm rupture
drug delivery from a stent platform
19 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential
 Packaging and Distribution
Blowing pressure
Blister thermoforming
Sealing
Picture
Blow molding
Film/Sheet extrusion blow molding a tray

Cold chain

shear rate in a film seal

20 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

21 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 QbD and Design Space

Role of CFD in mixing analysis is

well established (and
validated)
Extend current efforts to include
parametric and statistical
Velocity vectors in an unbaffled reactor
analyses as outlined in ICH Q8,
Q9, and Q10
Including Design of Experiments
(DOE) and Response Surfaces
will yield significant additional
benefits

Isosurface of gas volume fraction near impeller

22 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Bioreactor: Geometry

Geometry:
Working volume: 1072L
• Impellers:2
– Rushton turbine
– LA-310 (downward pumping)
• Baffles: 4
• Straight sparger

Mesh:
• Tetragonal elements
• Number of cells:~ 725K

23 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Bioreactor: Mesh Details

Geometry:
Working volume: 1072L
• Impellers:2
– Rushton turbine
– LA-310 (downward pumping)
• Baffles: 4
• Straight sparger

Mesh:
• Tetragonal elements
• Number of cells:~ 725K

24 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Bioreactor: Physical Models & Operating
Conditions
Physical Models:
• For resolving turbulence, Realizable K-epsilon turbulence model is used
• Coupled DPM Model is employed for gas sparging simulation and tracking gas
bubbles in the tank.
Operating Conditions:
• Angular velocity: 120 rpm
• Water
– Density (): 998.2 kg/m^3
– Viscosity (m): 0.001003 Pa-sec
• Gas
– Density is calculated based on the mean pressure head in the tank using ideal gas
law.
– Mass flow rate: 2e-3 kg/s
– Bubble diameter: 3 mm

25 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Bioreactor: Parameters
Input parameters
• Geometry parameters
• Top Impeller offset (P1) P4

• Bottom impeller offset (P2)

P1
• Baffle offset (P3)
• Liquid level (P4)
• Length of the sparging area (P5)
P2
• Simulation parameters
P3
• Angular velocity
• Gas mass flow rate
• Bubble diameter
Output parameter
• Average overall mass transfer coefficient P5
(kLa-hr)

26 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

27 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
• Effect of impeller placement on mass gas distribution and mass transfer
Conclusions

28 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Variation of kLa-hr with gap between
impellers: Design Space

Study of design space using

DesignXplorer software
• Design of Experiments
– Custom type DOE method is
selected to generate design
points
– Input parameters used
• Bottom impeller offset
Design of Experiments (DOE) table
• Gap between the for this study
impellers

29 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Velocity vectors comparison on center plane
Top impeller
offset 30” 35” 40”

Bottom
impeller offset

14”

Kla = 81.96 hr-1 Kla = 70.46 hr-1 Kla = 70.05 hr-1

18”

Kla = 65.56 hr-1 Kla = 67.13 hr-1 Kla = 78.47 hr-1

30 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Gas volume fraction contour comparison on
Top impeller
center plane
offset 30” 35” 40”

Bottom
impeller offset

14”

Kla = 81.96 hr-1 Kla = 70.46 hr-1 Kla = 70.05 hr-1

18”

Kla = 65.56 hr-1 Kla = 67.13 hr-1 Kla = 78.47 hr-1

At bottom impeller offset of 18”, gas distribution became more uniform with increase in the gap between the impellers. For 14”, the
31 trend isANSYS,
© 2014 opposite.
Inc. February 9, 2018 ANSYS Confidential
 Comparison of gas volume fraction
Top impeller
distribution in the tank
offset 30” 35” 40”

Bottom
impeller offset

14”

Kla = 81.96 hr-1 Kla = 70.46 hr-1 Kla = 70.05 hr-1

18”

Kla = 65.56 hr-1 Kla = 67.13 hr-1 Kla = 78.47 hr-1

At bottom impeller offset of 18”, gas distribution became more uniform with increase in the gap between the impellers. For 14”, the
32 trend isANSYS,
© 2014 opposite.
Inc. February 9, 2018 ANSYS Confidential
 Mass transfer coefficient (kLa-hr)
comparison
Bottom Gap Length Gas
Liquid Baffle Angular Bubble Volume
Design impeller between of mass
level offset velocity diameter averaged
point offset impellers sparging flow rate
(in) (in) (rpm) (m) kLa-hr
(in) (in) area (in) (kg/s)

DP0 55 14 16 10 6 120 2e-3 0.003 81.96

DP1 55 14 21 10 6 120 2e-3 0.003 70.46

DP2 55 14 26 10 6 120 2e-3 0.003 70.05

DP3 55 18 12 10 6 120 2e-3 0.003 65.56

DP4 55 18 17 10 6 120 2e-3 0.003 67.13

DP5 55 18 22 10 6 120 2e-3 0.003 78.47

DP6 55 22 13 10 6 120 2e-3 0.003 75.85

DP7 55 22 18 10 6 120 2e-3 0.003 73.07

DP8 55 22 23 10 6 120 2e-3 0.003 81.80

Position of the impellers has significant effect on mass transfer coefficient.

33 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Variation of kLa-hr with gap between
impellers

• At bottom impeller offset of 18” and 22”, kla has

increasing trend with increase in gap between
impellers.
• At bottom impeller offset of 14”, kla has decreasing
trend with increase in gap between the impellers.

Observation: When the bottom impeller is close to sparger, the gap

between the impellers needs to be small in order to obtain higher kla
whereas when the bottom impeller is farther from sparger, the gap
between the impellers needs to be higher in order to obtain higher kla.

34 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Variation of kLa-hr with gap between impellers:
Design Space

Study of design space using

DesignXplorer software
• Response surface generated
using the design points
– Non-parametric regression
– Input variables:
• Bottom impeller offset, gap between
bottom impeller and top impeller
– Output variable
• Average kla-hr
Response surface for kla-hr

Observation: When the bottom impeller is close to sparger, the gap

between the impellers needs to be small in order to obtain higher kla
whereas when the bottom impeller is farther from sparger, the gap
between the impellers needs to be higher in order to obtain higher kla.

35 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Agenda

Introduction to ANSYS
ANSYS tools for pharma/biopharma
• What is CFD?
• Applications
Design exploration of a bioreactor
• Geometry & Mesh
• Physical Models & Operating Conditions
• Parameters
• Demo of simulation workflow
Results comparison
Conclusions

36 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Conclusions

In the example considered, the design space of a bioreactor is studied to

understand the sensitivity of mass transfer with impeller position using
parametric analysis and design exploration.
Position of the impellers in the tank has significant effect on mass transfer
coefficient since it effects the flow patterns and hence the gas
distribution in the tank.
• When the bottom impeller is close to sparger, the gap between the impellers
needs to be small in order to obtain higher kla whereas when the bottom
impeller is farther from sparger, the gap between the impellers needs to be
higher in order to obtain higher kla.
Similar study can be performed to evaluate the mass transfer /other
characteristics of the bioreactor by varying the parameters of interest.

37 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Conclusions

Simulation with CFD

• is an established method in pharmaceutical process design
Combination of CFD simulation, parametric capability and design exploration
• provides a simplified way of exploring design space of the reactor
• will lead process team towards improvement in process understanding
needed to reduce variability, increase process predictability and achieve
Quality by Design

38 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential

 Contact Information

Please contact your local account manager or the webinar speakers for more
information:
Marc Horner, Ph.D.
Technical Lead, Healthcare NA
marc.horner@ansys.com

Sravankumar Nallamothu
Technology Specialist, Support and Services
sravankumar.nallamothu@ansys.com

Shital Joshi
Sr. Regional Support and Services Manager
shital.joshi@ansys.com

THANK YOU FOR YOUR ATTENTION

39 © 2014 ANSYS, Inc. February 9, 2018 ANSYS Confidential