See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/332515731

Jet milling industrialization of sticky active pharmaceutical ingredient using

quality by design approach

Article in Pharmaceutical Development and Technology · April 2019

DOI: 10.1080/10837450.2019.1608449

CITATIONS READS

9 3,049

4 authors, including:

Nakach Mostafa jean-rene Authelin

École des Mines d'Albi-Carmaux Sanofi
16 PUBLICATIONS 163 CITATIONS 26 PUBLICATIONS 597 CITATIONS

SEE PROFILE SEE PROFILE

Giovanni Gianola
Gianola
2 PUBLICATIONS 9 CITATIONS

SEE PROFILE

All content following this page was uploaded by Giovanni Gianola on 30 June 2020.

The user has requested enhancement of the downloaded file.

         

 !"#$ %&!&'!$( %)    *++,,,- . -  ++/

)   * 0 .*  1 

       *2  3 *
 

4* .1 5) 6 78  599*:;;

   *         

 !"#$%&' (   ) * %  &'&+ ),)'&
** - %  .*% '/ &).01$! 2! 3 4! 35678 2 !"2!9 377"

1  *       

  !"# " "

$%% " & !   ! ! 

$
'(   ! ! )"#

*( # " %  + !"

$ %&  

 ,  "- ""

./ 0, !  ! 1"%%"! %"!(1 ! "

 "! 1 ! !% "% ! + !"2!1  " !3+ !", 4  
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
https://doi.org/10.1080/10837450.2019.1608449

RESEARCH ARTICLE

Jet milling industrialization of sticky active pharmaceutical ingredient using

quality-by-design approach
Mostafa Nakacha, Jean-Ren
e Authelina, Carlo Corsinib and Giovanni Gianolab
a
Sanofi R&D, Vitry sur Seine, France; bF.P.S. Food and Pharma Systems Srl, Como, Italy

ABSTRACT ARTICLE HISTORY

Jet milling is frequently used in pharmaceutical industry to achieve different objectives. It can be used as Received 1 December 2018
enabling technology to overcome poor water solubility linked to hydrophobic active of pharmaceutical Revised 23 February 2019
ingredient (API) by reducing the particle size and therefore increasing the dissolution rate. Alternatively, Accepted 11 April 2019
jet milling can be used either to enhance blending efficiency of API with excipient in case of formulation
KEYWORDS
at low dosage strength or to achieve the required particle size for inhalation therapy. In this study, devel- Jet milling; specific energy;
opment of commercial manufacturing process of sticky API and its industrialization are described. The scaling-up; QbD; risk
methodology used is based on quality-by-design approach to deliver safe, effective and robust manufac- assessment; design space
turing process. The study showed that the specific energy is a key factor that drives particle size during
jet milling and the scale-up from lab to industrial scale. After understanding the process, a design space
was built where different zones such as operating point, operating space (where the product is compliant
to specification despite variability of process parameters), and the knowledge space were outlined.
Finally, an industrial installation was proposed to deliver product with high productivity yield, compliant
with safety regulation, and cleanable in place.

1. Introduction The quality-by-design (QbD) approach (Snee et al. 2008) was

Particle size reduction is an important operation in pharmaceutical
industry as it fixes the final formulation of drug product and
thereby its biopharmaceutical performances. Jet milling technology
is the most commonly used in pharmaceutical industry as it pro-
vides the smallest particle with the highest specific surface, it is
mechanically simple (no rotary parts) and requires little or no main-
tenance. Jet milling is used to achieve (1) enhanced chemical
reactivity of intermediate active pharmaceutical ingredient (API)
due to the increase in specific surface area; (2) improved drug bio-
availability (Khadka et al. 2014) (i.e. increasing exposure) by dramat-
ically increasing the dissolution rate due to the increase of specific
surface area; (3) avoid segregation between API and excipients dur-
ing blending, conveying, and storage (Ticehurst and Marziano
2015). Segregation occurs whenever the mean particle size of free-
flowing particles of the minor component is less than one-third of
the mean size of particles of the major component that.
Manufacturing the major and minor components at the same par-
ticle size eliminates the probability for this type of segregation; and
(4) achieve optimal particle size distribution for inhalation therapy
(Lau et al. 2017) whose principal benefit is rapid onset of action.
The extent of deposition of the inhaled particles and the location
of the deposition largely depends on particle size (Yang et al.
2014). Particles <1 mm are likely to reach the peripheral airways
and alveoli or be exhaled, particles 1–5 mm will deposit in the large
and conducting airways, while particles >5 mm will predominately
deposit in the oropharynx (Newman 1985).
This report is intended to raise awareness among engineers
and scientists in the pharmaceutical industry of the fundamental
and applied complexity of commercial manufacturing process
related to jet milling of sticky API.
adopted for this study to deliver safe, effective, and reliable man-
ufacturing process. QbD uses scientific knowledge and appropri-
ate quality risk management to drastically reduce the process
impact on product quality attributes (QAs).
The methodology applied for the process development and
the design of the industrial installation begins by an initial risk
assessment (IRA) which is performed to identify risks linked to
process development and its scale-up. The IRA guides the study
design. The basic data required for process design and under-
standing are then acquired at lab scale, and the process is carried
out at pilot scale to determine the design space where the prod-
uct will be delivered with the appropriate QAs. The process was
designed to meet two key performance indicators (KPIs): high pro-
cess yield and compliance with environmental hygiene and safety
(EHS) regulations. Fine tuning the process was performed using
mock equipment that represented the intended scale for industri-
alization, and a cleaning in place (CIP) procedure was developed.
An industrial jet mill and its environment (delumper, feeder, cyc-
lone filter, micronized product recovery, and CIP skid) were pro-
posed for industrial implementation.
It is noteworthy that the proposed methodology for the devel-
opment of industrial jet milling process that includes the jet mill
itself, its peripheral equipment such as delumper, feeder, cyclone
filter etc. and their cleaning is scarcely reported in the literature.
2. Theoretical background
Spiral jet mill reduces particle size by using a high-speed jet of
compressed air or inert gas. Particles leaving the mill can be sepa-
rated from the gas stream by separation system that can be

CONTACT Mostafa Nakach mostafa.nakach@sanofi.com Sanofi R&D, 1, Impasse des ateliers, 94403, Vitry sur Seine, France
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 M. NAKACH ET AL.
cyclone, cartridge filters, or filter sleeve. A jet mill consists of cir-
cular milling chamber that can be flat or elliptic shaped.
Compressed gas is forced into the mill through nozzles tangent
to the cylinder wall, creating a vortex. The gas leaves the mill
through a tube along the axis of the cylinder (MacDonald et al.
2016) (see Figure 1).
Jet milling can be described by the energetic theory of milling
that was developed and reported in previous articles and origin-
ally proposed by Zao and Schur (Midoux et al. 1999). In this
approach, we correlate the specific energy of milling to the newly
created surface area.
Let us first describe the way the specific energy is calculated.
In a fluid jet mill, the energy input is due to the gas flow through
the nozzle (see Figure 2), the mechanical power is the flow of kin-
etic energy:
1
EC ¼  mg  U2g (1)
2
where Ec, mg, and Ug are the kinetic power (J/s), the gas flow (kg/
s), and Ug its velocity at the exit of the nozzle (m/s), respectively.
The theory of the flow through ideal nozzles is well known
since 1888 (Barre de Saint Venan (Chanson 2004)) for ideal noz-
zles assuming isentropic gas expansion. For a truncated nozzle, as
soon the inlet to outlet pressure ratio is above a critical value of:
Figure 1. Spiral jet mill description.
Figure 2. Grinding nozzle characteristics.
 k
Pi k þ 1 k1
¼ (2)
Po 2
where, Pi, Po, and k are the absolute inlet pressure, the absolute
outlet pressure, and the ratio of specific heats of the gas, respect-
ively. For a diatomic gas, k is equal to 7/5 and therefore the crit-
ical ratio (Pcrit) is equal to 1.89.
At the throat of the nozzle, the gas velocity reaches the vel-
ocity of sound. This regime is reached already for a milling pres-
sure of 0.89 bar over atmospheric pressure, therefore in practice,
jet milling almost always works in sonic regime.
Complete calculations (Midoux et al. 1999) show that the gas
mass flow (kg/s) in the ideal nozzle is given by (for P above Pcrit):
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Mw 2 ðkþ1
Þ Þ
k1

m g ¼ Pi  A  ð (3)
RT kþ1
where Pi, A, Mw, T, and R are the absolute pressure of the milling
gas (Pa), section of the nozzle at the throat (m2), molecular
weight (kg), absolute temperature (K), and ideal gas constant
(8.31 J/K), respectively.
After some manipulations, the ‘ideal’ mechanical power EC (W)
can be calculated as follows:
 3   3k1
P i  Mw k  R  Ti 2 2 2ðk1Þ
Ec ¼ 0:5  A    (4)
R  Ti Mw kþ1
We may observe that for a fixed nozzle section (A) working in
sonic conditions, both the gas flow and the power depend only
on the mill inlet pressure Pi and temperature Ti.
In a real nozzle, the gas flow and power at a given pressure
can be deduced from the ideal gas flow by a pressure orifice
coefficient Cor (Kayser and Shambaugh 1991).
mg ¼ Cor  mg and Ec ¼ Cor  EC (5)
Cor is determined experimentally by comparing at each pres-
sure the experimental gas flow from nozzles to the theoretical
flow from ideal nozzles having the same section. In our experi-
ments, we found that this coefficient varies from 0.25 (for badly
manufactured nozzles) to 0.95–0.97 for well manufactured nozzles.
We routinely use this coefficient as part of jet mill performance
requirements. Its determination is part of the operational
qualification.
The specific energy (Esp, J/kg) is the ratio of the power (J/s) of
the solid flow (Qsolid, kg/s). Interestingly, for a given mill configur-
ation, this ratio is proportional to the ratio of absolute pressure
and mass flow.
EC P
Esp ¼ / (6)
Qsolid Qsolid
From the above equation one can understood that for a given
jet mill, the critical process parameters are the grinding pressure
and the solid flow rate. In previous articles, we have shown the
existence of two distinct regimes (Nakach et al. 2004): (i) at low
energy input, a ‘fragmentation regime’, where the specific surface
area created increases approximately linearly with the specific
energy input. In this regime particles break in large fragments
and (ii) at high energy input, an ‘attrition regime’; where the
increase in surface area is low and small particles are chipped
from the surface. We often observed that surface amorphization
was associated with this regime (non-published data).
Furthermore, the surface area of the particles milled in ‘attrition
regime’, tends to decrease upon storage, as the solid surfaces
rearranges to lower its energy. Such unstable material is

undesirable for development; thus the attrition regime should be
avoided.
It is interesting to mention that we observed a similar behavior
for mechanical milling, where the specific energy is proportional
to the square value of mill tip speed (Nakach et al. 2004).
The scale-up approach of jet milling process is to keep the
grinding specific energy constant. It is, as described in Equation
(6), to keep the ratio of absolute pressure to mass flow rate con-
stant or ratio gas flow rate to solid flow rate constant. For homo-
thetic jet mills having same number of grinding nozzles, the gas
flow and solid flow rate are proportional to the square
diameter of nozzles and therefore to square jet mill diameter (see
Equation (7).
P Qgas
/ ¼ constant and Qgas / Qsolid / D2Jet
Qsolid Qsolid
Based on this theoretical approach, our experimental strategy
will be to first establish the correlation between the surface area
creation and the specific energy on a down scaled model, in par-
ticular to establish the limit of the fragmentation regime, and the
physical stability of the resulting material. The second step will be
to verify the scale-up rules, by conducting trials at larger scales.
To apply this methodology, we need to fully characterize the ori-
fice coefficient of various jet mills by measuring the mass flow
from the nozzles as a function of the grinding pressure, and com-
paring it to the ideal flow for nozzles of same throat diameter.
Figure 3. API crystal shape (A), API stickiness (B), ratholing effect during flow of API (C), and API drug release (D).
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 3
3. Materials and methods
3.1. Materials
3.1.1. Active pharmaceutical ingredient
The API (obtained from Sanofi) has a molecular mass of 464 g/
mol, and exhibits two crystalline forms with melting point of
155  C and 157  C. The API crystals are needle shaped (see Figure
3(A)), exhibit bad flowability (see Figure 3(B)), and ratholing dur-
ing flowing (see Figure 3(C)). The API apparent density and Carr
index are in the range of 0.3–0.35 g/ml and 34–36%, respectively.
In addition, the API contains aggregates with diameters higher
than 2 cm.
The API is classified as type 2 according the Biopharmaceutical
Classification System, its solubility in water at pH ¼ 2–12 is blow
1.2 mg/ml and its permeability (Caco2 cells) is about
(7)
mill
9.6  106 cms1.
Differential scanning calorimetry (DSC) analysis of the API DSC
under nitrogen with heating rate of 5  C/min indicated that the
decomposition temperature onset is 230  C and the enthalpy of
decomposition is 330 J/g.
Dust explosion characteristics showed that the minimum igni-
tion energy (MIE) of the API was in the range of 10–100 mJ indi-
cating high sensitivity of the API to ignition (Eckhoff 2002). The
rate of pressure rise (Kst) was found to be 283 barm/s. The API
is therefore classified as class 2 according to dust explosion classi-
fication (Bartknecht 2012), which means that the API can induce a
severe explosion. The electrical resistivity of API powder is about
4 M. NAKACH ET AL.
Table 1. Physical properties of the three cleaning agents used in this study.
RBS
Concentration of use (g/l) 10–20
pH 11.8
Surface tension mN/m at 10  C 28 at concentration of 15 g/l
Critical micellar concentration (g/l) 10
3.105 Xm indicating the proneness of the API to electrostatic
charges accumulation (Malliaris and Turner 1971). Only 1% of
accumulated electrostatic charges are dissipated in 1 h.
The API is formulated as tablet with low dosage strength for
oral administration. During early stage development, it was shown
that the API particle size reduction (jet milling) enhanced its con-
tent uniformity during blending and its dissolution profile (refer
to Figure 3(D)).
3.1.2. Cleaning agents
Three cleaning agents (RBS, lavorea, and Tega super) were eval-
uated: RBS was supplied by Chemical Products R. Borghgraef
Belgium, and Lavorea and Tega super were supplied by SODEVI
HE France. Their physical properties are summarized in Table 1.
3.2. IRA tool
Albus (1964) summarized different parameters that could impact
the physical quality of powders during jet milling. Overview of
these parameters is provided in Ishikawa’s diagram (Adam et al.
2011) (see Figure 4).
3.2.1. Identification of cause–effect relationships
Level of risk of each parameter on critical quality attributes (CQAs:
particle size and crystal structure) and on performance indicators
(KPIs; jet milling yield and compliance to EHS regulation) were
carried out. The impact (Table 2) and probability of occurrence
(Table 3) were considered to deliver a quantitative level of risk
(Table 4) for each parameter as follows:
 Impact
 Probability of occurrence
Combination of impact and probability of occurrence provided
overall rating as described in Table 4. The risk caption is described
as follows:
 For high risks (colored in red: score from 30 to 90), a mitiga-
tion action plan to lower the potential risks as much as pos-
sible was designed and executed as first priority.
 For medium risks (orange: score from 10 to 18), a mitigation
action plan to lower the potential risks as much as possible
was designed and executed as second priority.
 For low risks (green: score from 2 to 6), no mitigation action
plan was defined.
3.3. Equipment
3.3.1. Un-jet milled powder calibration
Two types of delumper were evaluated namely conical sieving
mill (see Figure 5(A)) and oscillating sieving mill (see Figure 5(B)).
A lab scale conical sieving mill (Quadro comill 193,
MEDELPHARM France) with sieve surface of 0.0014 m2 was tested.
Four sieves with screen mesh sizes of 600, 1000, 1400, and
2400 mm, were tested at 3550 rpm.
The oscillating sieving mill was tested using two scales: (1) a
lab scale mill (Erweka 5055, Frewitt (Fribourg Switzerland)) with
sieve surface of 0.067 m2, and four sieves with screen mesh size
Lavorea Tega super
2–3
11 Neutral
60 at concentration of 1.5 g/l 29 at concentration of 2 g/l
No micelles formation 0.08
of 315, 500, 630, and 800 mm, respectively. The milling tests were
performed at maximum oscillation speed (2m/s) and (2) and an
industrial scale mill (1MG 314, Frewitt (Fribourg Switzerland))
equipped with sieve surface of 0.5 m2 and screen mesh size of
800 mm. The milling tests were performed at maximum oscillation
speed (2 m/s).
3.3.2. Un-jet milled powder feeding
The un-jet milled powder feeding was evaluated using two
feeders: (1) a gravimetric weight feeder ML-D5-KT35 supplied by
K-tron France equipped with extension hopper having 50-l vol-
ume, three weigh bridges (3  K-SFT), vertical agitation to ensure
proper flowing during feeding, trough, horizontal agitation, and
twin screws; and (2) and a volumetric feeder K2-MV-T35 (K-tron,
France) having the same configuration as the gravimetric feeder
with the exception of weigh bridges.
Two twin screws were tested: namely auger and concave
screws. Both screws are frequently used for feeding poor flowing
material.
3.3.3. Powder jet milling
Lab, pilot, and industrial scale jet mills were supplied by FPS Food
Pharma systems (see Figure 6). Theirs characteristics are given in
Table 5.
3.3.4. Jet milled powder recovery
The recovery of jet milled material for the 1.5 inches was carried
using an antistatic polyester filter sleeve to separate the process
gas from the micronized product.
The recovery of jet milled material for 5 and 8 inches was car-
ried using two systems: (1) cartridges: polyurethane cartridge fil-
ters were adopted for the separation cyclone in its simplest
configuration. Cartridge de-clogging was obtained with a counter-
pulse of compressed air or nitrogen; and (2) filter sleeve: antistatic
polyester filter sleeve was adopted on the separation cyclone for
product-gas separation, with higher efficiency (recovery rate) and
less disturbance of the micronization during filter declogging.
The choice of the solids/gas separation system impacts the
classification of particles exiting the micronization chamber. The
gentler filter de-clogging assured by the octopus filter type grants
a better control of the pressure fluctuations on the jet mill
chamber.
Both 5- and 8-inch mills are fitted with a pressure compensa-
tion line, which connects the powder discharge zone from the
feeder to the separation cyclone top part. The pressure compen-
sation line separates the system from the installation room, which
has the following benefits: (1) avoid entrance of air from the
installation room. Especially when nitrogen is used as process gas,
introduction of ambient air may impact oxygen and humidity
content inside the jet mill chamber; (2) reducing noise of the sys-
tem; and (3) reducing dust generation in the room, especially
when blow back occurred.
3.3.5. Jet mills aerodynamic qualification
Spiral jet mill was used to achieve the target particle size
(2.6–4.4 mm). The experimental gas flow rate may be equal or
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 5

Figure 4. Ishikawa’s diagram highlighting different parameters that could impact physical quality of jet milled powder.

Table 2. Impact of parameters on CQA. and (2) gas flow rate for each nozzle was measured at different
Low 2 It is expected that this parameter and its variability may pressures using a mass flowmeter KOBOLD KES and 780 serial in
not impact quality attributes the gas exit of the jet mill (Figure 7). Since the nozzles are remov-
Moderate 6 It is expected that this parameter and its variability may able and a specific test apparatus for each nozzle was not avail-
impact quality attributes not beyond acceptable range
able, only the overall gas flow rate was measured and mean
High 18 It is expected that this parameter and its variability may
impact quality attributes beyond acceptable range value of pressure orifice coefficient was determined by connecting
the flow meter to the jet mill exit and measuring the overall
equipment flow. The overall gas flow rate and mean value of
pressure orifice coefficient are defined as follows:
Table 3. Probability of occurrence.
Low 1 In-house data are available with the same product (from
Qgas ¼ n  Qgas
th (8)
research or first experiments or previous process version) Qgas exp
Moderate 3 Literature data or in-house data with similar product are Cor ¼ (9)
Qgas th
available (prior knowledge)
High 5 No literature data nor product-related (or similar product) where Qgas_th, Qgas_exp, n, and Cor are the theoretical overall gas
data are available
flow rate through the jet mill, the experimental overall gas flow
rate, number of nozzles, and the pressure orifice coefficient,
respectively.
Table 4. Overall rating.
Impact 3.3.6. Cleaning in place
Probability of occurrence 2 6 18 For the selection of optimal cleaning agent, surface tension and
1 2 6 18 contact angle of cleaning agent were measured.
3 6 18 54 The surface tension (c) of cleaning agent was measured using
5 10 30 90 € K12V tensiometer (KRUSS
KRUSS
R
€ GmbH, Germany). The Wilhelmy
plate method (S. C. Biswas et al. 2001) was applied under quasi-
equilibrium conditions. The force required to detach the plate
below the theoretical one depending on the nozzles’ surface from the interface was accurately determined. The measurements
roughness, consequently, the gas energy needed for particle size were carried out at room temperature and repeated three times.
reduction can vary considerably. It is noteworthy, that the ratio The contact angle (Chander et al. 2007) was measured using a
between the ideal gas flow rate and the theoretical one corre- drop shape analysis system DSA 1000 IPS (supplied by KRUSS €
sponds to the pressure orifice coefficient Cor. Thus, it is important GmbH, Germany). About 20 ml of aqueous solution of cleaning
to know the diameter and pressure orifice coefficient of jet mill’s agent was placed on the surface of pure API tablet produced at
nozzles. The hydrodynamics characterization of the nozzles was 17 kN using Instron machine referenced 5567. The deposited drop
conducted as follows: (1) nozzles’ diameters were measured using contact angle depends on powder properties, liquid, and sur-
calibrated steel bars with diameter in the range of 1.25–1.7 mm rounding phase. In the case of complete wetting, the contact
6 M. NAKACH ET AL.

Figure 5. Conical and oscillating sieving mills.

Figure 6. Different jet mills used for manufacturing process development.

Table 5. Jet mill characteristics.

Jet mill scale Lab scale 1.5 inches Pilot scale 5 inches Pilot scale 8 inches ProMill-12 12 inches
Jet mill diameter (mm) 35 124 203 304
Jet mill configuration Elliptic Elliptic Elliptic Elliptic
Number of grinding nozzles 4 6 8 12
Diameter of grinding nozzles (mm) 0.40 1.25 1.50 3.0
Type of grinding nozzles Convergent Convergent Convergent Convergent
Grinding nozzles angle ( ) 52.5 53.0 53.0 52.2
Orifice coefficient of grinding nozzles 0.873 0.562 0.628 0.905
Injection nozzle diameter 0.75 1.75 2.50 3.00
Injection nozzle type Convergent Convergent Convergent Convergent
Classifier gap (mm) 1.0 3.8 5.2 8.0

angle is 0 . Between 0 and 90 , the solid is wettable and above
90 it is not wettable. In the case of ultrahydrophobic materials
with the so-called lotus effect, the contact angle approaches the
theoretical limit of 180 .
3.4. Powder characterization
3.4.1. Particle size analysis
Particles’ sizes were measured using laser diffraction (Malvern
Mastersizer 2000V). The equipment measures the angle of light
R
diffracted by the particles, which depends on the particle radius,
using Fraunhofer’s diffraction theory. This method can measure
the particle sizes down to 1 mm. For small particles, forward light
scattering is measured with the application of Mie Theory of light
scattering.
By combining the results obtained with light diffraction and
forward light scattering, particle size distributions can be meas-
ured in the range 0.02–0 mm (Swithenbank et al. 1976).
3.4.2. Apparent density, tap density, and Carr index measurement
The apparent and tapped densities were measured using
ENGELSMANN STAV 2003 tester supplied by J. Engelsmann AG

Figure 7. Principle of experimental design used for pressure orifice coefficient.
Germany. The tester was equipped with glass test tube of 250 ml.
A specified mass of powder was poured into a test tube and then
tapped against a hard surface for a specified number of times
(500 in our study). Tapping causes the particles to rearrange and
give denser packing. From bulk and tap densities, one can calcu-
late the Carr index as follows (McGlinchey 2008):
ðApparent density  Tapd densityÞ100
Carr index ¼ (10)
Tap density
When the Carr index is in the range of 5–15%, the material
exhibits a free-flowing behavior and can be assimilated to gran-
ules with excellent flow. When the Carr index is in the range of
12–16%, the material exhibits a good flowing. When the Carr
index is in the range of 18–21%, the material exhibits a fair pow-
dered granule flow. When the Carr index is in the range of
23–28%, the material exhibits an easily fluidisable powders having
poor flow. When the Carr index is in the range of 33–38%, the
material exhibits cohesive powders having very poor flow. When
the Carr index is in the range of 28–35%, the material exhibits
cohesive powders having poor flow, and when the Carr index is
higher than 40% the powder is cohesive with an extreme
poor flow.
3.4.3. Amorphization content
The amorphization content was evaluated using conventional DSC
(DSC 2920 TA Instruments, France). The typical sample size of
10 mg was placed into 40 ml aluminum pans and sealed with a
punched aluminum lid. Thermal curves were recorded with heat-
ing. A heating cycles with scanning rates of 5  C/min were
recorded from room temperature up to 250  C. Typical DCS profile
is described in Figure 8.
The amorphization content was calculated as follows:
Crystallization enthalpy
Amorphization content ¼  100 (11)
Melting enthalpy
3.4.4. Hopper indiciser
Hopper indiciser supplied by Johanson Innovations San Luis
Obispo, California, USA was used to measure the surface friction
of the powder at two predetermined compaction pressures in a
conical hopper. Two indexes were determined: Hopper Index (HI)
which represents the hopper angle required to initiate movement
along the walls of the hopper, and Chute Index (CI) which
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 7
represents the chute angle necessary to prevent material build up
on the solids impact areas (Marjanovic and Jones 1996).
In our study different material surfaces were used to determine
HI and CI: namely, polytetrafluoroethylene (PTFE), polyoxymethy-
lene, polyethylene terephthalate, polyethylene UHMW (PE 1000),
mirror polished stainless steel 316L, mechanically polished stain-
less steel 316L, and electro-polished stainless steel 316L.
4. Experimental section
In this section, we describe the outcome of IRA from which the
experimental plan was designed based on industrial user’s
requirements: that is, production of a jet milled API having mean
diameter (d50) 6 lm at the flow rate of 100 kg/h. The industrial
installation was designed with CIP system to achieve two KPs
namely milling yield higher than 99% and safe manufacturing
process designed for containment allowing dust emission below
100 mg/m3. The results of experimental trials are presented and
discussed. Then, a manufacturing process space in which produc-
tion parameters can vary without altering the quality of the final
product was designed and discussed. Finally, the layout of the
proposed industrial installation was proposed and discussed.
4.1. Initial risks assessment
4.1.1. IRA matrix
The IRA was applied to raw material attributes, operating parame-
ters, and geometrical configuration of equipment based on prior
know-how that includes data from product or product-like or lit-
erature. The matrix of the IRA is presented in supplementary
material. The scoring of each potential risk is presented in Figure
9(A,B,C). It outlines the potential critical parameters that could
potentially impact QAs and KPIs. One can observe from Figure
9(A) that the attributes of starting material such as particle size,
apparent density, flowability, crystal structure, surface charge, and
stickiness can significantly impact the QAs and/or KPIs. Also, the
operating parameters such as grinding gas type, grinding gas
pressure, injection gas pressure, and solid feed rate can impact
significantly the QAs and/or KPIs (see Figure 9(B)). With regard to
geometrical configuration of equipment, parameters such as jet
mill size, grinding nozzle type, grinding nozzle number, grinding
nozzle diameter, jet mill material, and micronized product recov-
ery can impact significantly the QAs and/or KPIs (see Figure 8(C)).
4.1.2. Study plan design
Based on the IRA, the mitigation study plan to overcome poten-
tial issues was defined and implemented as follows: (1) a safety,
hazards, and risk evaluation was conducted because the API is
classified as class 2 according to dust explosion classification
product; (2) the un-milled material needs to be de-agglomerated
prior to jet milling, to ensure high specific solid rate and limit the
degradation of the physical quality of product in terms of flow-
ability. For that purpose, two mills were evaluated (oscillating
sieve mill versus conical-sieve-mill); (3) gravimetric and volumetric
feeders were evaluated to ensure proper feeding and constant
feed rate; (4) jet mill that can lower adhesiveness of API was
selected. The goal is to overcome the stickiness of un-jet milled
and potential increase in inter-particle friction that can affect the
flowability of material; (5) characterization of aerodynamic behav-
ior of nozzles at the energy level to be used; (6) parametric study
to design the space where the API will be obtained with targeted
particle size without polymorphic change was carried out; (7) filter
sleeve and cartridges filters for micronized product recovery were
8 M. NAKACH ET AL.

Figure 8. DSC profile.

Figure 9. Impact of material attributes (A), operating parameters (B), and geometrical equipment on quality attributes (C).

evaluated; (8) a scale-up rule was defined and selection of the
mill scale was carried out according batch size to be processed;
and (9) design of sealed industrial installation that will make the
manufacturing process allow high containment and high efficient
recovery process was defined.
4.2. Experimental trials
Based on the API characteristics, a safety, hazards, and risk evalu-
ation was conducted to prevent release of dangerous substances,
and prevent sources of ignition.
4.2.1. Safety, hazards, and risk evaluation
The API is an insulating compound, that slowly dissipates its
charges, and airborne dust is sensitive to ignition (MIE
10–100 mJ). Any induced explosion will be violent as the API is
classified ST2 and its Pmax is close to 10 bars (absolute pressure).
Consequently, the hazards linked with the API airborne dust are
considered as important.
To protect the milling equipment from any electrical and non-
electrical explosion, the elimination or control of risks from explo-
sive atmospheres in the workplace was ensured by achieving the
following in order to be compliant with European directives for
controlling explosive atmospheres (ATEX) (Tommasini et al. 2013):
(1) the zoning plan where the milling equipment is placed was
defined according the hazardous zones requirements. Indeed, a
room classified as zone 20 (permanent explosive dust is present)
was selected; (2) the equipment category, T-class and explosion
group were defined according the ATEX Equipment Directive. In
the present case, the instrumentation probes were selected; (3)
the equipment was grounded and their equi-potentiality was veri-
fied; (4) during milling and jet milling, the operators were suited
with appropriate clothing that does not create the risk of an elec-
trostatic discharge igniting the explosive atmosphere; (5) the
micronization under nitrogen was selected and the operators
were protected from any anoxia. In fact, the micronization room
was equipped with oxygen meter and the operators were
equipped with hoods having breathable air; and (6) before run-
ning any milling or micronization, the overall explosion safety
measures were checked.
4.2.2. Delumping of un-jet milled API
4.2.2.1. Lab scale trials: The un-jet milled material contained large
lumps (up to 3 cm diameter) that could block or prevent the
proper feeding of the jet mill. To overcome this issue a compara-
tive calibration study was performed using oscillating sieving mill
Erweka 5055 and conical sieving mill Quadro comil 193. The
results of the study showed that the oscillating sieving mill leads
to higher specific calibration rate compared to conical sieving mill
(see Figure 10). Indeed, a specific calibration rate of 3800 kg/hm2
was observed when using the oscillating sieving mill with screen
size of 800 mm while, only 2000 kg/hm2 was obtained when using
conical sieving mill with larger screen size (2000 mm).
Furthermore, it should be noted that when using conical sieving
mill, smaller screen size than 1 mm could not be used due to
screen clogging.
For both delumpers, the apparent density and flow of the cali-
brated material were negatively impacted. Indeed, the apparent
density was decreased from 0.36 g/ml to approximatively
0.30–0.28 g/ml and the Carr index was increased from 31 to
approximatively 38–40.
4.2.2.2. Industrial trial: The industrial trial was conducted using
the oscillating sieving mill 1MG 314, equipped with sieve surface
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 9
Figure 10. Specific calibration rate as function of screen size.
of 0.5 m2 and screen mesh size of 800 mm. The processed batch
size was about 70 kg. The non-delumped API contained lumps
having particle size up to 3–4 cm diameter. The mill rotor was
oscillated at speed of 2 m/s. A specific calibration rate of 3500 kg/
hm2 was reached. The mean particle size, the apparent density,
and the Carr index of delumped API were found to be 21 mm,
0.27 g/ml, and 41%, respectively. The industrial trial confirms the
results obtained at lab scale in terms of productivity and physical
quality of delumped API.
4.2.3. Assessment of jet mill feeding
Midoux et al. (1999) demonstrated that jet milling is driven by the
specific energy (ratio of gas kinetic energy to slid feed rate)
applied during particle size reduction. Any variation of the feed
rate during the operation may have disproportionate impact on
the physical quality (particle size, apparent density, flowability,
and crystal structure) of the jet-milled material. Thus, the selection
of an appropriate feeding technology is important. A comparative
study was performed using a gravimetric and volumetric feeder.
The results of the study showed that the gravimetric feeder led to
accurate feed rate which was not the case for the volumetric
feeder. In fact, the deviation from the set feed rate was less than
1.4% whatever the used screw (augers or concaves) when the
gravimetric feeder is used (see Figure 11(A)) while, the deviation
from the set feed rate was higher than 105% in the case of volu-
metric feed rate (see Figure 11(B)). Based on the results of this
study the gravimetric feeder was selected to enable an efficient
jet milling process.
4.2.4. Selection of jet mill material
Adhesion between powders and surfaces plays an important role
in the handling and processing of pharmaceutical materials.
Different mechanisms that cause adhesion can be Van der Waal’s
forces, electrostatic forces, liquid bridges, or contact melting
(Booth and Newton 1987). Furthermore, it is already known that
small particle size and needlelike morphology can lead to bad
flowability and adhesion to surface (Leane et al. 2015) of jet mill
piping and filters which may result in bad jet milling yield and a
possible failure of the final QAs.
Adhesion between powders, either of the same or different
materials and between powders and surfaces, plays an important
role in the handling and processing of pharmaceutical materials.
To manage this processing risk, the flow functions of the
delumped API and jet milled one were carried out as function of
jet mill material using a hopper indiciser cell.
10 M. NAKACH ET AL.
Figure 11. Feeding performances of gravimetric (A) and volumetric (B) feeders.
Figure 12. Illustration of Hopper (A) and Chute (B) indexes.
An HI representing the hopper angle required to initiate move-
ment (Figure 12(A)) along the walls of the hopper is then calcu-
lated. A CI was also determined with this equipment. This index
recommends the chute angle necessary to prevent material build
up on the solids impact areas (Figure 12(B)).
The results gathered in Table 6 show that the lower HI and the
lower CI were obtained when using PTFE for both quality of API
(delumped and jet-milled). These results are in agreement with
data from literature indicating that PTFE is a well-known anti-adhe-
sive material (Lehmann et al. 2002) when in contact with powder.
4.2.5. Jet milling aerodynamic qualification
The flow rate as function of pressure was measured for each jet
mill and graphed as function of the theoretical flow rate from ideal
nozzles having the same section. All curves led to straight lines
(Figure 13) whose slopes allowed determination of orifice coeffi-
cients, which were found to be 0.9, 0.6, 0.6, and 0.9 for 1.5, 5, 8,
and 12 inches jet mill, respectively. The variability of orifice coeffi-
cient outlined the challenge of perfectly machining such small noz-
zles (0.4–3 mm diameter) and its dependence on the geometry
constraints due to the jet mill manufacture. In the rest of the study,
the orifice coefficient was used to calculate the real specific energy
applied during jet milling according to Equation (4).
4.2.6. Jet milling parametric study
A parametric study was carried out using three jet mills (1.5, 5,
and 8 inches) made from PTFE. Furthermore, an industrial trial
was performed (100 kg/h as solid feed rate jet milled at 200 kJ/kg)
using 12-inches jet mill also made from PTFE. The results covering
a large range of specific energy (0–800 kJ/kg) led to the following
observations: (1) the jet milling (created specific surface area as
function specific energy: Figure 14(A)) profile exhibits two
domains: a first domain is observed at low specific milling energy
where the created specific surface area increases dramatically
with specific energy. A second domain is observed at high specific
energy where the created specific surface area increases only
slightly with specific energy. Midoux et al. interpreted these
domains as driven by particle fragmentation for low specific
energy and by particle attrition for high specific energy; (2) the
specific energy approach seems to be a good scale-up marker.
Indeed, when the created specific surface area is graphed as func-
tion of specific energy, the milling profiles of different mills (1.5,
5, 8, and 12 inches) led to approximatively one master curve
(Figure 14(A)). It is noteworthy that the scale-up factor between
1.5 inches and 12 inches is about 143 (100 kg/h for 12 inches and
0.7 kg/h for 1.5 inches); (3) jet milling the API at specific energy
equal or lower to 200 kJ/kg does not induce any amorphization or
polymorphic transition. However, when applied specific energy is
equal or higher than 267 kJ/kg, amorphization of the API is
observed (Figure 14(B)); (4) jet-milled samples obtained at 200,
267, and 800 kJ/kg were stored at ambient temperature and dif-
ferent relative humidity. Monitoring the particle size over time of
these samples showed that the amorphous product exhibits a sig-
nificant crystal growth. As illustrated in Figure 14(C), it can be
seen that this phenomenon is even more pronounced for prod-
ucts containing high amorphous content and stored at high
humidity. However, the API that does not contain amorphous
component remains stable during storage; and (5) when the
diameter of 90% of particles (d90) was graphed as function of
mean diameter (d50), the obtained profile led to a unique master
curve (Figure 14(D)) outlining that the particle size distribution is
not affected by the used scale. The d90 versus d50 profile can be
considered as the milling pathway.
4.2.7. Jet milled product recovery
The jet-milled product recovery was evaluated using 8-inches jet
mill equipped either with filter sleeve or with cartridges filters.
The trials were performed at milling specific energy of 200 kJ/kg
(solid feed rate of 20 kg/h and grinding pressure of 9 bar). The

Table 6. Hopper and Chute indexes obtained for delumped and jet milled API.
Hopper index
Stainless steel 316L mirror polished
Stainless steel 316L electro-polished
Steel 316L mechanical polishing
Polyethylene terephthalate (PET)
Polyoxymethylene (POM-C)
Polyethylene UHMW (PE 1000)
Polytetrafluoroethylene (PTFE)
Figure 13. Experimental gas flow rate as function theoretical one.
recovery efficiency was found to be much higher when using the
filter sleeve. Indeed, the jet milling yield obtained with the filter
sleeve was about 98%, and when the cartridges filter was used,
the yield was found to be about 62%. The low yield obtained
when the cartridge filter was used is due to a high API build
observed within the product transport line and cyclone filter walls
(refer to Figure 15). It is noteworthy that this result was predicted
by adhesion evaluation of the API, which showed that the adhe-
sion is very high when API is in contact with stainless steel
material.
An industrial trial performed using 12-inch jet mill made from
PTFE, product transport line lined with PTFE and cyclone filter
equipped with filter sleeve led to jet milling yield of 99%.
4.2.8. Equipment cleaning
The industrial installation was intended to be used for jet milling
of different APIs. Based on concepts of good manufacturing prac-
tices, such as multiple usage is satisfactory provided that the
equipment is properly designed to be cleanable and the degree
of the cleaning is validated. The cleaning of industrial installation
was considered as critical for the following reasons: (1) potential
residue of same API adhering to the installation wall can be car-
ried over successive batches. Such carryover can adversely alter
the purity profile of the API; and (2) jet milling of different APIs,
should be conducted in a manner that prevents cross contamin-
ation between different APIs.
For that purpose, it was decided to clean the installation
between batches of the considered API. When switching from jet
milling one API to another API, the installation was cleaned
according to a validated cleaning process where the residues are
systematically verified.
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 11
Delumped API Jet milled API
Chute index Hopper index Chute index
0 90 0 90
0 90 0 90
0 90 0 90
4 90 0 90
0 90 3 81
1 90 0 90
9 84 44 72
Cleaning of API can be ensured using organic solvent, alkaline,
acid, or aqueous surfactant solution. For the present case study,
our choice was oriented towards the use of aqueous surfactant
solutions for the following reasons: (1) avoiding design of installa-
tion compliant with use of organic solvent and (2) solvent recov-
ery due to environmental requirement and potential cross-
contamination due to reuse of recovered solvent.
Three cleaning agents were screened for cleaning evaluation:
Tega, super RBS, and Lavorea. Each surfactant was used at the
concentration recommended by the supplier (refer to Table 1).
The screening was based on acquisition of basic data that are in
relationship with wetting characteristics: surface tension, contact
angle, and sinking time method which is by far the simplest (but
qualitative) method for assessment of wettability of a powder by
a surfactant solution. The selected surfactant was used for clean-
ing trial followed by analytical verification.
4.2.8.1. Surfactant screening.
4.2.8.1.1. Surface tension. The surface tension at the recom-
mended concentration was measured at 20  C. The obtained
results are 28, 29, and 50 mN/m for Tega super, RBS, and Lavorea,
respectively. From these results, one can observe that Lavorea sur-
factant has the higher surface tension, and may not be efficient
for removal of any API residue.
4.2.8.1.2. Contact angle. The contact angle at the recommended
concentration was measured at 20  C. The obtained results are 40,
46, and 70 for Tega super, RBS, and Lavorea, respectively. From
these results, one can observe that Tega super has the lowest
contact angle, and may potentially be efficient in removal of any
API residue. In contrast, Lavorea surfactant has a higher contact
angle, and may not be efficient for removal of any API residue.
4.2.8.1.3. Sinking time. About 100 mg of API was incorporated in
an aqueous solution containing 2% of surfactant. The time for
which a powder floats on the surface of a liquid before sinking
into the liquid is measured for different surfactant solutions. From
experimental trials, it was found that the API powder sank instant-
aneously into the liquid when Tega super surfactant was used.
The sinking time for RBS surfactant was found to be about 3 min.
However, in the case of Lavorea surfactant the API particles
remained floating at the surface of the aqueous solution (see
Figure 16).
Based on the results described above, the Tega super surfac-
tant was selected for further investigation (cleaning trial).
4.2.8.2. Cleaning trial. The cleaning trial was performed on 8-
inchs jet mill after jet milling of 20 kg of API. The trial was con-
ducted using an external cleaning skid composed of 50-l vessel
that was filled with 18 l of aqueous solution containing 2% of
Tega super, centrifugal pump, and feeding and recycling pipe.
The skid was connected to different spray balls distributed as fol-
lows: one on the lid of feeder, one on product transport line, one
12 M. NAKACH ET AL.
Figure 14. Created specific surface area as function of specific energy (A), amorphous content as function specific energy (B), evolving of d50 during storage (C), and
d90 versus d50 (D).
on the balance line, three on the top of the cyclone filter, and
three on the bottom of the cyclone filter. The surfactant solution
was recirculated through the skid at the flow rate of 1600 l/h
(recycling frequency: 89 h-1) for 1 h (89 cycles) at ambient
temperature.
After cleaning, the installation was dried using air from the
feeder, grinding nozzles, and injection nozzle at the flow rate of
100 m3/h for 1 h.
The visual inspection showed that all installation pieces were
perfectly clean except the filter sleeve where some API traces
were observed. The following recommendations can be provided
based on this trial’s results: Tega super is a better surfactant for
CIP. In fact, the surfactant ensures effective cleaning; it is classified
as food grade and its residue can be easily quantified using
atomic adsorption spectrophotometry.
In the final cleaning procedure, the sleeve filter should be
removed from the top part for separate washing.
4.2.9. Graphical construction of process design space
A different approach based on the use of the design space con-
cept can be used to design manufacturing jet mill process for a
given API. According to ‘ICH Q8 Pharmaceutical Development
Guideline’ 29 (Guideline 2009) a design space is the multidimen-
sional combination of input variables and process parameters that
have been demonstrated to provide assurance of quality. The
design space can be useful as it provides not only the best recipe,
but also gives information about the effect of the operating
conditions.
Graphical construction: In our study the design space was con-
structed based on the following considerations: (1) from bio-
pharmaceutical properties the d50 has to be lower than 6 mm (6/
d50 > 1 mm1); (2) the minimum specific energy to get particle size
within specification is 95 kJ/kg; (3) the maximum specific energy to
get particle size within specification without amorphization is
250 kJ/kg; (4) the critical operating process parameters for constant
geometrical configuration of jet mill and for constant temperature
are grinding pressure and solid flow rate; (5) the sonic regime is
obtained when the absolute pressure is higher than 2 bar (Midoux
et al. 1999); (6) the maximum absolute pressure to be used is
13 bar (maximum operating pressure for the jet mill); (7) the min-
imum solid flow rate to get particle size reduction for 12-inch jet
mill is 4.46 kg/h. The data were extrapolated from observed experi-
mental data using 5-inch jet mill. The solid flow rate was consid-
ered to be proportional to square of jet mill diameter as described
in Equation (7); (8) the maximum flow rate to get proper function-
ing of 12-inch jet mill is 350/h. At higher solid flow rate the jet mill-
ing is unstable resulting in a discontinuous output of the product
and large fluctuations in particle size. The data were extrapolated
from observed experimental data using 5-inch jet mill; (9) the
industrial requirements for commercial process are fixed in terms of
solid flow rate at 120 ± 10 kg/h, grinding pressure at 6 ± 0.5 bar, and
jet mill to be used is 12-inch jet mill equipped with 12 nozzles

Figure 15. Stickiness of API on cyclone walls and product transport line.
Figure 16. API wettability using sinking time.
with 3 mm diameter should be used; (10) nozzle orifice coefficient
of the jet mill is 0.9; specific energy for nominal process conditions
(120 kg/h, 6 bar) is about 159 kJ/kg; and (11) the specific energy is
proportional to the ratio of absolute grinding pressure to solid flow
rate according to Equation (6).
 
P tions, and assures effective cleaning during washing operations
ESP ¼ k  (12)
Q  Cyclone filter equipped with filter sleeve. The filter sleeve
where, ESP, k, P, and Q are the specific energy, constant, absolute
grinding pressure, and solid flow rate, respectively. Knowing the
orifice coefficient, the ESP is calculated and graphed as function
of P/Q ratio (see Figure 17(A)).
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 13
Figure 17(B) outlines the graphical construction of the process
design space which includes different zones: (1) knowledge space
where the manufacturing process is investigated and well-under-
stood. (2) Proven acceptance range which is the space where any
variation of critical process parameters (i.e. grinding pressure, solid
flow rate) will not led to product out of the specification; (3) nor-
mal operating range that taking in account the accuracy of instru-
mentation controlling the critical process parameters; and (4)
operating point based on set points of critical process parameters.
4.2.10. Industrial design
A preliminary sketch of the proposed industrial installation is illus-
trated in Figure 18. It is rated for zone 20 according to ATEX
requirements. The installation is composed of:
 Oscillating mill (using 630 mm grid size) equipped with PTFE-
lined hopper discharge to limit API adherence. The lid of the mill
and hopper discharge were equipped with rotating spray balls
 Lifting column for drum handling
 Gravimetric feeder equipped with 250 l hopper (vertical and
horizontal agitation). The lid of the feeder hopper was fitted
with a rotating spray ball
 12-inch jet mill in a vertical position to avoid any elbow con-
nection between the jet mill and product transportation line
 The jet mill was connected to PTFE-lined pipe for product trans-
portation. The product transport line was fitted with retractable
nozzles: this assures flush surface during micronization opera-
needs to be removed from the top part for separate washing.
The separation cyclone was fitted with three rotating spray
balls at 120 from each other, fitted on the cylindrical body
(top part), and three fixed sprinklers on the lower cone at 120
from each other. Spray balls and sprinklers were positioned to
14 M. NAKACH ET AL.

Figure 17. Grinding specific energy as function of ratio pressure to solid feed rate (A) and graphical construction of design space for jet milling process (B).

Figure 18. Sketch proposed industrial installation.


obtain complete wetting of the surfaces in contact with the
product. The use of the proper detergent assures good dissol-
ution of the product in the water-detergent solution and
mechanical removal of product residuals in the sticking areas
 Separation cyclone cone is PTFE-lined and has an angle <30
relative to vertical line to reduce adherence of API and
improve its flowability
 Exhaust fan whose rotation speed is controlled to ensure a
proper pressure within the cyclone filter. The exhaust fan is
complete with prefilter and high efficiency particulate air fil-
ter weighing station for drums weight measurement
 CIP skid that is composed of recycling vessel centrifugal pump,
temperature control, and connection to different spray balls
 A programable logic controller for the control of the manu-
facturing process.
5. Conclusion
Using QbD approach and engineering scientific best practices, a
commercial manufacturing process of jet milling of sticky API was
developed to ensure the required particle size for pharmaceutical
processing (mixing of API at low dosage strength) and for increased
dissolution rate. In addition, the manufacturing process was devel-
oped taking into account two industrial KPIs. The process was
designed to deliver jet milled API with high throughput (100 kg/h)
and compliant with safety regulation. For that purpose, a sealed
industrial installation was designed for the overall value chain that
includes the jet mill itself, its peripheral equipment such as
delumper, feeder, cyclone filter, etc. and their cleaning process. A
design space in terms of manufacture procedure was constructed.
It outlines different zones such as the operating point that may be
used for routine batch manufacturing, the operating space in which
the product is compliant to specification (even for highly variable
process parameters) and the knowledge space about the overall
manufacturing process.
Acknowledgements
The authors acknowledge Dr Abdessadek Lachagr, Dr Marc-
Antoine Fabre, and Dr Harivardhan-Reddy Lakkireddy for their
contribution to pre-review this paper.
Disclosure statement
The authors declare that they have no conflicts of interest to disclose.
References
Adam S, Suzzi D, Radeke C, Khinast JG. 2011. An integrated qual-
ity by design (QbD) approach towards design space definition
of a bending unit operation by discrete element method (DEM)
simulation. Eur J Pharm Sci. 42:106–115.
Albus F. 1964. The modern fluid energy mill. Chem Eng Progr. 60:
102–106.
Bartknecht W. 2012. Explosions: course, prevention, protection.
Berlin, Heidelberg: Springer Science & Business Media.
Biswas SC, Dubreil L, Marion D. 2001. Interfacial behavior of wheat
puroindolines: study of adsorption at the air–water interface
from surface tension measurement using Wilhelmy plate
method. J Colloid Interface Sci. 244:245–253.
Booth S, Newton J. 1987. Experimental investigation of adhesion
between powders and surfaces. J Pharm Pharmacol. 39:679–684.
View publication stats
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 15
Chander S, Hogg R, Fuerstenau DW. 2007. Characterization of the
wetting and dewetting behavior of powders. Kona. 25:56–75.
Chanson H. 2004. Hydraulics of open channel flow. Oxford (UK):
Elsevier.
Eckhoff R. 2002. Minimum ignition energy (MIE) – a basic ignition
sensitivity parameter in design of intrinsically safe electrical
apparatus for explosive dust clouds. J Loss Prev Process Ind. 15:
305–310.
Guideline I. 2009. Pharmaceutical development. Q8 Current
Step. 4.
Kayser JC, Shambaugh RL. 1991. Discharge coefficients for com-
pressible flow through small-diameter orifices and convergent
nozzles. Chem Eng Sci. 46:1697–1711.
Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J.
2014. Pharmaceutical particle technologies: an approach to
improve drug solubility, dissolution and bioavailability. Asian J
Pharm Sci. 9:304–316.
Lau M, Young PM, Traini D. 2017. Co-milled API-lactose systems
for inhalation therapy: impact of magnesium stearate on phys-
ico-chemical stability and aerosolization performance. Drug Dev
Ind Pharm. 43:980–988.
Leane M, Pitt K, Reynolds G, Manufacturing Classification System
(MCS) Working Group. 2015. A proposal for a drug product
manufacturing classification system (MCS) for oral solid dosage
forms. Pharm Dev Technol. 20:12–21.
Lehmann D, Hupfer B, Lappan U, Pompe G, H€außler L, Jehnichen
D, Janke A, Geißler U, Reinhardt R, Lunkwitz K, et al. 2002. New
PTFE-polyamide compounds. Des Monomers Polym. 5:317–324.
MacDonald R, Rowe D, Martin E, Gorringe L. 2016. The spiral jet
mill cut size equation. Powder Technol. 299:26–40.
Malliaris A, Turner D. 1971. Influence of particle size on the elec-
trical resistivity of compacted mixtures of polymeric and metal-
lic powders. J Appl Phys. 42:614–618.
Marjanovic P, Jones M. 1996. Assessment of a new technique for
measuring flow properties of powdered materials stored in
hoppers. Proc Inst Mech Eng Part E J Process Mech Eng. 210:
1–8.
McGlinchey D. 2008. Bulk solids handling. Hoboken (NJ): Wiley-
Blackwell.
Midoux N, Hosek P, Pailleres L, Authelin J. 1999. Micronization of
pharmaceutical substances in a spiral jet mill. Powder Technol.
104:113–120.
Nakach M, Authelin J-R, Chamayou A, Dodds J. 2004. Comparison
of various milling technologies for grinding pharmaceutical
powders. Int J Miner Process. 74:S173–S181.
Newman SP. 1985. Aerosol deposition considerations in inhalation
therapy. Chest. 88:152S–160S.
Snee R, Cini P, Kamm J, Meyers C. 2008. Quality by design – short-
ening the path to acceptance. Pharm Process. 25:20–24.
Swithenbank JJ, Taylor DS, Abbot D, McCreath GC. 1976. A laser
diagnostic technique for the measurement of droplet and par-
ticle size distribution. 14th Aerospace Sciences Meeting. p. 69.
Ticehurst MD, Marziano I. 2015. Integration of active pharmaceut-
ical ingredient solid form selection and particle engineering
into drug product design. J Pharm Pharmacol. 67:782–802.
Tommasini R, Pons E, Palamara F. 2013. Area classification for
explosive atmospheres: comparison between European and
North American approaches. Industry Applications Society 60th
Annual Petroleum and Chemical Industry Conference. IEEE,
p. 1–7.
Yang MY, Chan JGY, Chan H-K. 2014. Pulmonary drug delivery by
powder aerosols. J Control Release. 193:228–240.