modelling pharmaceutical manufacturing processes … · 2020. 10. 21. · pharmaceutical...

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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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