modelling pharmaceutical manufacturing processes … · 2020. 10. 21. · pharmaceutical...
TRANSCRIPT
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MODELLING PHARMACEUTICAL MANUFACTURING PROCESSES USING PARTICLE SIMULATIONMikyung.Yang / Engineer / 2020.10.21
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Contents
• Context & challenges
• Introducing EDEM simulation technology
• Calibration tests for powders
• Pharmaceutical applications
• Powder mixing / blending
• Tablet coating
• Tablet breakage
• Die filling
• Granulation
• Milling
• Q&A
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Context & Challenges
• Over 75% of all pharmaceutical products are in solid dosage form
• Gain valuable insight into manufacturing processes otherwise difficult or sometimes
impossible to measure
• Drive product innovation & reduce need for physical testing
• Efficient handling and processing of particulates is critical to profitable manufacture of
pharmaceutical products
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Introducing EDEM technology
• Simulates behavior of bulk solids, granular
materials and particulates
• Powered by Discrete Element Method (DEM)
technology
• Used for virtual testing of equipment design
& process optimization
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The Discrete Element Method
Discrete Element Method – a way of simulating discrete matter
DEM captures the dual nature of granular media which behaves both like solid and
fluid-like material
The bulk behavior emerges from the collective interaction of each individual object
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How does EDEM work?
Bulk Solid Flow
Properties
XB, localParticle A
Particle BZA, local XA, local
YA, local
ZB, local
YB, localFnormal
Ftangential
kt
cn
kn
ct
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EDEM Workflow
Create materials,
particles, geometry and
physics models
Define run-time and simulation
settings and process the
simulation
Visualize your results, create
videos, graph the results and
export data
v
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Critical Calibration Tests for Powders
FT4 Powder Rheometer
Static Angle of Repose
• Dynamic Angle of Repose
• Compressibility tests
Shear cell test
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PHARMACEUTICAL APPLICATIONS OF EDEM
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Pharmaceutical Manufacturing Work-stream
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Common Applications
Granulation
Tablet Coating Tablet Breakage
Die Filling Milling
Powder Mixing
Tablet Compaction Powder Fluidization Wurster (Tablet) Coater
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How EDEM Can Help
• Gain key insight into manufacturing processes
• Optimize processes
• Drive product innovation
• Greater control over product quality
• Study effects of critical parameters
• Identify edge of process failure
• Experiment scale-down
• Evaluate control strategies
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POWDER MIXING & BLENDING
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Critical Role of Powder Mixing/Blending
Inefficient mixing results in:
• Losses due to failed batches
• Recalled products
• Added costs due to production delays
Mixing quality is important because:
• It affects operations that follow that step
such s granulation, milling and tabletting
• Poorly mixed materials adversely impact
final product quality
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Challenges in Powder Blending & EDEM Role
EDEM can help:
• Visualize internal flow
• Reduce risk of segregation
• Validate scale-up/down processes
• Identify areas prone to caking
• Test mixing efficiency based on fill level
Continuous Mixer
Ribbon Blender
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Powder Mixing/Blending
Study mixing mechanisms and
effect of material, equipment and
processing conditions on:
mixing/residence
times
shear
rate
final blend
quality
Bin blender
(Courtesy of Pfizer)
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Powder Mixing/Blending
Enhance process understanding
and minimize materials/time lost in
testing by exposing:
dead or low
velocity zones
high
shear
compaction
zones
Predicted Final State
Initial Condition
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Examples: Mixing processes
Mixing Process Optimization(Courtesy of University of Edinburgh)
Axial Mixing of Tablets in Pan Coater(Courtesy of RCPE)
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Example – Powder Mixing & Breakage in High Shear Granulator
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Example – Powder Mixing & Breakage in High Shear Granulator
(Courtesy of University of Edinburgh & CPI)
• Cohesive and non-cohesive powder
• Defined critical rate processing kernels
• Breakage experiments in screw elements
• Developed customised breakage model for PBM
• Implementation of a mechanistic modelling kernel
in gFORMULATE
• Estimation of residence time distribution using
EDEM
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TABLET COATING
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Importance of Coating Uniformity
Obtaining uniform coating depends on:
• good mixing of the tablets in the coating pan
• a uniform distribution of tablet orientations in the spray zone
process
inefficienciesvariability in
dissolution
performance
potential
batch failure
Significant variability in film-coating
thickness can lead to:
Purposes of coating:
Taste
masking
Humidity
protection
Gastric resistance
Modified
release
Active
coating
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Tablet Coating
Use EDEM to model inter- and intra-tablet coating variability
Study parameters that can affect inter-tablet coating:
• Tablet shape
• Pan speed
• Tablet load
• Spray zone size and location
Study parameters that can affect intra-tablet coating:
• Pan rotation speed
• Tablet load
• Effect of baffles
• Tablet form
• Fill volume Courtesy RCPE
Courtesy Pfizer
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Tablet Coating
EDEM simulation enables to extract
key process attributes:
Tablet velocities Residence
time
Intra-tablet coating
variability
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Tablet Coating example
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Tablet coating exampleCourtesy of University of Maribor
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Tablet Attrition During Coating
Predict and assess risk of tablet attrition based on:
• pan speed
• tablet volume
• fill level
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OTHER PROCESSES
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Tablet Breakage
• Investigate attrition and breakage of
pharmaceutical tablets during transportation
• Ensure no defective tablets are commercialized
to meet quality standards
Tablet damaging within tumbling drum
Powder compaction
Tablet compression
Courtesy of Technical University of Braunschweig
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Die Filling
Analyze:
• Fill variability between dies
• Feeder/screw performance
• Effect of various key parameters
• Understand micro-macro dynamics of particles inside
the feed frame
• Visualize segregation inside the feed frame & during
die filling
Capsule
Filling
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Die Filling example
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High Shear Wet Granulation
• Predict forces, stresses, velocities
• Determine effect of fill level, blade speed, material
properties
• Validate scale-up models
• Optimize granulation performance
Courtesy of Osaka Prefecture University
Courtesy of Tridiagonal Solutions
R
H
D
D
(a) (b)
(c)
25 deg
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Milling
• Test various impeller speeds
• Analyze effect of material properties and
operational conditions
• Get insight into breakage mechanism
• Predict mill performance: collisional energy, stress
magnitude and distribution
Courtesy of Rutgers University
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Summary
EDEM is a key predictive tool to optimize
pharmaceutical manufacturing processes such as
tablet coating and mixing.
EDEM can provide key insight leading to:
• optimized processes
• better product quality
• less physical prototyping
• cost savings
This technology is expected to be a key tool to help
transition from batch to continuous pharmaceutical
manufacturing.
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