Don’t Feed the Trolls – Crazy Powders and Electrostatic Charge in Continuous Manufacturing

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Don’t feed the
trolls – crazy powders
and electrostatic charge in
continuous manufacturing
Michela Beretta, Theresa Hörmann-Kincses
15th of April, 2021

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Employees
150+
Turnover
€ 11.8 M
(FY 2019 / 2020)
Partners
150+
Papers
385
(Status 06.2020)
Patents
7
(Status 6.2020)
Key Facts
RCPE is a global leader in
pharmaceutical engineering
science.
By optimizing products and
processes, we help our partners to
develop and manufacture
advanced medicines - for patients
around the world.
Research Center for Pharmaceutical Engineering - RCPE

Our Areas
Turn-key solutions for the product
manufacturing of the future
Our combined areas and services
redefine current thinking in the field
of healthcare.
Rapidly designing new formulations,
products and the associated
manufacturing process is in our DNA.
Research Center for Pharmaceutical Engineering - RCPE
Modeling
and Prediction
Advanced
Products
and Delivery
Process and
Manufacturing
Science
Continuous
Flow Synthesis
and Processing

Agenda
1
2
3
The role of powder feeding in CM
Theresa Hörmann-Kincses
Analysis of powder feedability – data,
models and learnings
Theresa Hörmann-Kincses, Michela Beretta
Process-induced material changes –
the case of electrostatic charge
Michela Beretta
4
5
Make the powder (s)we(a)t –
a solution for electrostatics?
Michela Beretta
Conclusions and Q&A
Theresa Hörmann-Kincses,
Michela Beretta

The role of
powder feeding in
CM
P. Toson, RCPE.

The Challenges
Don’t feed the trolls – crazy powders and electrostatic charge in continuous manufacturing | 15.04.2021
8
Powder Feeding
Powders
aka “The Troll”
Powder hopper
GMP hammer
+
From:
Mehos,
Greg,
„Hopper
Design
Principles
for
Chemical
Engineers“
Which powder may become a troll at your site?

Feeding Performance as a Key to Final Product Quality
9
Powder Feeding
Element QTPP Target
Dosage form Tablet
Dosage design IR tablet
Route of Administration Oral
Dose strength xx mg
Pharmacokinetics IR enabling Tmax in 2.5 h or less;
Stability At least xx months shelf-life at RT
Drug product quality attribtues Physical attributes
Identification
Assay
Dosage uniformity
Dissolution
Degradation products
Residual solvents
Water content
Microbial limits
𝑐𝐴𝑃𝐼
𝑨𝒔𝒔𝒂𝒚
100%
105%
95%
ሶ
𝑚𝐸𝑥𝑐
ሶ
𝑚𝐴𝑃𝐼

Dispensing
Is the repeatable addition of a
specific, accurate amount of
material to a process within a
certain time
Batch vs Continuous Manufacturing
Powder Feeding
10
Feeding
Is the consistent, continuous
addition of powders to a process at
a specific rate and over a long
period of time
vs
New technology and performance demands
→ new critical material attributes to become relevant
Hsiao et al, 2020. Drug Discovery Today

Technology and Process Parameters
11
Powder Feeding
Twin-screw feeders in CM
 Large design variety
 Process control and optimization
− Control strategies:
gravimetric (based on LIW scale data) vs volumetric
− Hopper refilling strategies
Screws
Outlet screens
Agitators
Hopper types
Engish et al, 2015, J.Pharm.Innov., vol. 10.
Diverse range of feeder design available → effect of design parameters?

The Challenges
12
Powder Feeding
Unexpected Failures
Flow stagnation by settling of
powder on flat agitator
Feeding of milled APAP
Electrostatic effects at outlet
Feeding of micronized APAP
Feeding of
calcium stearate
Powder bridging
above agitator
 Unexpected feeding failures
− Bridging/ratholing/caking
− Electrostatic material build-up
− Feeder disturbances from
environment
Today‘s focus on predicting flow problems
& mechanisms behind electrostatic charging

Analysis of powder
feedability – data,
models and learnings
Theresa Hörmann-Kincses, Michela Beretta

To understand the final performance of a feeder,
the flow of material to be fed needs to be investigated
Convey – Measure – Control
15
The Basis for Successful Feeding
Tasks of a Feeder [from Vetter, 1998]
Even the most advanced gravimetric
controller requires successful flow
from hopper into the screw section
powder flow/
conveying
metering/
measurement
controlling
DOSING
Vetter (1998)

Slide 16
ECCPM 2.0 – Material Science Use Case
The RCPE approach
▪ Different powders (APIs and excipients)
and grades (separate chemical and
physical effects)
▪ Twin-screw feeders with different hopper
shapes and sizes, screw diameters and
screw pitches
▪ Volumetric feeding experiments under
controlled conditions
▪ Statistical correlation and models of
material properties, feeder attributes and
feeding performance indicators to extract
the most relevant factors
A
Material properties
B … N
2
Feeder descriptors
(screw, agitator, hopper)
…
1 n
Models for feeding
performance

Extensive material and process characterization
17
Materials and Methods
9 pharmaceutical powders relevant for DC (APIs, excipients, lubricant)
Mannitol
(FG M, M100, M200)
Cellulose
(PH101, PH102, PH200)
Acetaminophen
milled (PMIL), micronized (PMIC)
Kaerger et al., 2004.
Magnesium stearate
Morin, Briens, 2013.
(MgSt)
Material descriptors from powder characterization:
▪ Particle descriptors: particle size (x50, span), aspect ratio (a50), true density (𝜌𝑡𝑟), charge density (CD),…
▪ Bulk descriptors: bulk (BD) and tapped density (TD), compressibility, flowability (ffc, HR, C, AIF, BFE, SE, etc.),…
• Material conditioning essential to erase previous powder history
• Wide range of material descriptors to capture the complexity of powders

Extensive material and process characterization
18
Materials and Methods
Volumetric feeding experiments with 4 different feeders and 3 different
screws (where possible)
KT20
(KTron)
MT-S
(Brabender)
CF, CF_adp
(GEA)
ZD12FB
(ThreeTec)
Feeder descriptors
▪ Screw free volume
▪ Screw overlap
▪ Agitator frequency
▪ Hopper size
Process
parameters
▪ Screw speed
▪ Hopper fill level
• Simplified feeding experiments required for comparability of results
• Definition of feeder descriptors and process parameters essential

Impressions from the real world
19
Research Highlights
Hopper Emptying Test (Coarse Concave Screw)
M200 PMIC
MT-S not possible
MgSt
Wrong initial fill weight
KT20
ZD12FB
CF
CF_adp
MT-S
Mass
flow
[kg/h]
Mass
flow
[kg/h]
Mass
flow
[kg/h]
• M200 exhibiting basically constant flow rate across the entire hopper emptying run
• For poorly flowing PMIC almost immediate flow stagnation in small scale feeders
• Low end fill levels suggest stable performance in continuous feeding applications
End fill level
EFL

Approach
20
Statistical Modelling
Hopper emptying model
1. Enough material is flowing from
the hopper in the screw
→ no hopper flow stagnation
2. Screw conveying is accurate and
consistent
→ Mass flow well controlled by screws
Hopper
Screws
Feeding performance
Good feeding performance when...
Statistical approach
Mass flow model
Model able to predict the risk
of flow stagnation in the
hopper for different feeder and
screw geometries
Model able to predict the mass
flow at different screw speeds
for different feeder and screw
geometries
Models for the prediction of feeding performance of different materials in
combination with different feeder configurations and process parameters

Flow Stagnation Model – End Fill Level (EFL)
21
Statistical Models for Feeding Performance Prediction
Flow stagnation model
PLS model performance: R2X=0.668, R2Y=0.690,
Q2=0.631, 3 PCs
▪ Most correlated material
characteristics:
▪ angle of internal friction (AIF_E)
▪ Hausner ratio (HR)
▪ compressibility (CPS_0.5kPa)
▪ particle shape (a50)
▪ Most correlated feeder descriptor:
▪ filled hopper volume (VH,filled)
Screw
Hopper
Agitator
Material descriptor
Feeder descriptor
Feeding response
*normalized factors
Int. friction
Flowability
Compressibility
Shape
Charge density
Flow stability
Size
Flowability
Material descriptors most
relevant for EFL!

EFL Prediction Use-Cases - M200 vs PMIC
22
Statistical Models for Feeding Performance Prediction
0
20
40
60
80
100
EFL
in
%
Predicted EFL Observed EFL
CF CF_adp
M200 PMIC
100% 25%
50%
100% 25%
50%
100% 25%
50%
100% 25%
50%
PLS model performance: R2X=0.668, R2Y=0.690, Q2=0.631, 3 PCs
EFLcrit
EFLcrit
Agitated volume →
critical end fill level
M200 PMIC
CF
M200 PMIC
CF_adp
Distinction between critical and non-critical EFL ranges possible with statistical model

Process-induced
material changes –
the case of
electrostatic
charge
Michela Beretta

Overview of possible scenarios
24
Feeding-induced material changes
When feeding a powder...
• Particles can break leading to PSD changes
• Particles can interact with environmental conditions (especially for long term runs)
• Particles can acquire electrostatic charges
shear
segregation
Different packing,
higher inter-particle forces

As cats do not like electrostatic charges…
…also feeders dislike them…
Why are we interested in it?
Powder electrostatics
25
[1] Allenspach et al., Int. J. Pharm. (2021)
Electrostatic charge
build-up of HPMC [1]
Reduced powder flow
Alteration of trajectory
during free-fall motion
Agglomeration
Impeded use of screens
Bridging/Ratholing
Important to characterize at the early stage of product
development to avoid unexpected failures in the process!

What is it and which implications has it?
Tribo-charging
27
Charge transfer mechanism which occurs when two materials come into contact and are then separated.
+
+
+
+
- -
-
-
- -
-
-
Material 1
Material 2 Charge exchange
(electron, ion, material)
Acquired charge
Contact Separation
Feeder surface
Particle-wall
contacts
Pharmaceutical
particles
Charge exchange
Filled
hopper
Twin-screw
feeder
Particle-particle
contacts
Pharmaceutical
particles
Charge exchange
• Impact on mass flow accuracy and consistency
• Effect on down-steam operations such as blending
• Relevant for long processing times (refilling)

Aim of the study
28
Mannitol
(M100, M200)
Cellulose
(PH101, PH200)
Magnesium
stearate
(MgSt)
Paracetamol
(PMIC)
Powders
Powder
conditioning
Lab-scale charge
measurements
Determination of
feeding-induced charge
Beretta et al, 2020a. Int. J. Pharm 591
Goal, materials and methods
Can we estimate the charge developing in a process from lab-scale testing?

Analysis of the material charge propensity at lab-scale
29
• Controlled environmental conditions:
22 ± 2 °C and 53 ± 5 %RH
• Sample mass of 10 g
• Net charge determined after sliding in
contact with a stainless-steel surface
• All powders showed a negative charge polarity
• Charging propensity:
PMIC > PH101 > PH200 > M200 > M100 > MgSt
MCC MAN
GranuChargeTM
(GranuTools)
Different charging propensity observed for distinct material types
(API > excipients > lubricant)!
Lab-scale determinations

Controlled environmental conditions during volumetric feeding: 22 ± 2 °C and 53 ± 5 %RH.
Can we estimate the charging tendency during process
from lab-scale measurements?
30
• Similar charge trend compared to lab test for all material types
• Different magnitudes between the two experimental set-ups →
Difference in discharge pathways and adhesion in setups
• Different polarity for MgSt → Formation of a MgSt layer change
the contact from metal-particle to particle-particle
PH101 PH200 M100 M200 PMIC MgSt
-150
-145
-140
-10
-5
0
Surface
charge
density
(nC/m
2
)
Material
q1
qAF
Polarity
change
after feeding
lab-scale
MCC MAN
Ranking of powder charging tendency possible, however the different
inter-particle collisions lead to different magnitudes/polarity!

Statistical analysis (PCA)
Which factors govern tribo-electrification?
31
PC2:
Work
function,
moisture
content,
charge
PC1: Particle size distribution, shape, flow descriptors
• Powder frictional properties strongly related to the
tribo-charging behavior of the powders, however:
• Cluster of charge density and effective angle of
internal friction suggests inter-particle friction as one
of the main factors contributing to tribo-charging
• Absence of the wall friction angle in the cluster
indicates the minor relevance of this factor
• Inter-particle friction indicated as one of the main driver for tribo-charging
• Correlation between the charge density measured with the two
experimental set-ups statistically confirmed

Make the powder
(s)we(a)t – a solution
for electrostatics?
Michela Beretta

Solutions for electrostatic charging?
33
Charge
mitigation
strategies
Environmental
conditions
Material
characteristics
Equipment
conditions
Process
parameters
Speed
Configuration
Relative humidity
Temperature
Formulation
Particle engineering
Earthing system
Equipment materials
Is making the
powder (s)we(a)t
always a solution?
RH often increased
for charge
mitigation, but…

Effect of RH on powder tribo-charging
34
• MCC: charge density first increases from 23 to
53% RH and decreases thereafter at 75% RH
• MAN: consistent increase in charge density
with RH up to 75% RH
• APAP: charge density decreases from a high
to low level at elevated RH
• MgSt: slight decrease of charge density with
RH (minimal charge density)
MCC MAN APAP
Tribo-charging sensitivity to RH
The selection of an optimal RH level for charge mitigation should be
carefully considered based on the material selection

The role of water on material tribo-charging
Hyphothesis and findings
35
KT20 (RH 66%) MT-S (RH 33%) CF (RH 34%) CF_adH (RH 33%)
PMIC
For each material seems to exist a RH threshold for the formation of a conductive water
layer, from which the magnitude of the acquired charge is reduced
• MCC: increased conductivity of hygroscopic material only after formation of a thick
water layer on particle surface (>53% RH)
• APAP: thin water layer on non-hygroscopic material resulting in lubrication effect
(charge reduction caused by reduced friction)
• MAN: thin water layer resulting in particle agglomeration of non-hygroscopic powder,
binding water in inter-particle spaces, while contributing to the increase in charge
density (facilitated charge transfer via liquid bridges)

Does higher charge always result in higher adhesion?
36
M200 @ 53 %RH M200 @ 75 %RH
M200 @ 23 %RH
PMIC @ 53 %RH PMIC @ 75 %RH
PMIC @ 23 %RH
MAN APAP
Electrostatic charging is only the root cause for powder adhesion but
other material-dependent forces as VdW forces play a big role!
• Compared to the other powders, the increase of charge density observed for MAN does not
translate into a higher adhesion

Conclusions and Q&A
Michela Beretta, Theresa Hörmann-Kincses

• Simplified feeding experiments are required to ensure transferability of results
• Statistical models for predicting raw material feedability were presented and successfully used to
identify cases with high risk of flow stagnation
• A large range of particle and bulk properties were found to be relevant for feedability of powders
• Electrostatic charging can severely affect feeding performance, but can be estimated from lab-scale
testing in combination with material attributes
• Electrostatic charging is often blamed for powder adhesion, but it is only one of the root causes and
other material-dependent forces such as Van der Waal forces should also be considered
• Environmental conditions can affect powder bulk behavior and therefore can be specifically
adjusted to improve powder processability depending on material type (!)
Conclusions
38
Crazy powders and electrostatic charge in continuous manufacturing

39
Q&A

Michela Beretta
Scientist
RCPE GmbH
theresa.hoermann@rcpe.at michela.beretta@rcpe.at
Senior Scientist
RCPE GmbH
The vibrant M, Parteck® and Emprove® are trademarks of Merck KGaA, Darmstadt, Germany or
its affiliates. All other trademarks are the property of their respective owners. Detailed
information on trademarks is available via publicly accessible resources.
© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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Don’t Feed the Trolls – Crazy Powders and Electrostatic Charge in Continuous Manufacturing