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Wissenschaft und Technik
Originale
Quality by Design: Concept for the
Proof-of-Principle Testing Regarding
Automated Microdosing
1
2
Robert Bosch GmbH, Business Unit Packaging Technology, Waiblingen, Germany
University of Applied Sciences of Albstadt-Sigmaringen, Faculty of Life Sciences,
Pharmaceutical Engineering, Sigmaringen, Germany
Corresponding author: Dr. Elke Sternberger-Rützel, Robert Bosch GmbH,
Stuttgarter Straße 130, 71332 Waiblingen, Germany,
email: [email protected]
ABSTRACT
More and more capsules have to be filled with a low volume
of highly active pharmaceutical ingredients, which can cause
difficulties in fulfilling the given release specifications, such as
content uniformity.
Quality by Design (QbD) was used in order to define a process
window for dosing low quantities of a typical inhalation
product in order to launch new high-speed microdosing
equipment for the process of microdosing powders into capsules. QbD is a well-known tool used by the pharmaceutical
industry for formulation or process optimization as a scientific, risk-based, holistic, systematic, and proactive approach
to product testing.
The test plan was created by statistical software. The described QbD trials were then tested and analyzed according to
different parameters such as quality of lactose, fill volume,
applied vacuum, different vacuum dosing wheels, and fill
amounts. The results were examined by macroscopic evaluation, fill weight, particle size distribution, rheological powder
properties and their statistical analysis.
The analysis of variance investigated the main effects and
interactions that influence the fill weight and particle size distribution.
It was the aim of this paper to gain results on the influence of
equipment and process parameters on fill weight and particle
size distribution as insight for further similar projects.
Z U S A M M E N FA S S U N G
Quality by Design: Beweis der technischen Möglichkeiten
der Mikrodosierung
Immer häufiger werden Kapseln mit niedrigdosierten, hochpotenten Wirkstoffen hergestellt. Dies kann zu Schwierigkeiten
führen in der Einhaltung der in den Zulassungsdokumenten
festgelegten Spezifikationen, wie der Gleichförmigkeit des
Gehalts.
Um grundsätzliche Untersuchungen an einer Hochgeschwindigkeitsanlage für Mikrodosierung von Pulvern durchzuführen,
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
© ECV · Editio Cantor Verlag, Aulendorf (Germany)
wurde in dieser Publikation ein Quality by Design (QbD)Ansatz gewählt, um den Einfluss von kritischen Parametern
auf den Abfüllprozess zu identifizieren und quantifizieren.
QbD ist eine in der pharmazeutischen Industrie bekannte wissenschaftliche Methodik, die in der Prozessentwicklung und
-optimierung eingesetzt wird.
Nachdem ein Testplan auf einer statistischen Basis erstellt
wurde, wurden unterschiedliche Qualitäten von Laktose, Füllgewichte, angelegtes Vakuum, Dosierwalzen und Füllvolumen
als kritische Parameter betrachtet und getestet. Die Befüllungsergebnisse wurden evaluiert anhand der makroskopischen
Betrachtung, der Kontrolle des Füllgewichts, der Partikelgrößenverteilung, pulverrheologischen Eigenschaften und derer
statistischer Auswertung.
Die Varianzanalyse detektierte die Hauptfaktoren und die
Interaktionen, die das Füllgewicht und die Partikelgrößenverteilung beeinflussen.
Ziel dieser Publikation war es, den Einfluss von Geräte- und
Verfahrensparametern zu eruieren, um Erfahrungswerte für
vergleichbare zukünftige Projekte zu sammeln.
1. Introduction
Quality by design (QbD) is a well-known tool used by the
pharmaceutical industry for formulation or process optimization as a scientific and risk-based approach that is
required by the regulatory authorities.
The U.S. Food and Drug
KEY WORDS
Administration (FDA) as
well as the European au. Adjustable and fixed vacuum
thorities put an emphasis
dosing wheel
on QbD strategies during
. Automated microdosing
the development and
. Filling weight statistics
manufacturing of medi. Particle size distribution
cinal products. In the
. Powder rheology
FDA’s “Guidance for InPharm. Ind. 74, Nr. 1, 145–154 (2012)
dustry: Quality Systems
Sternberger-Rützel et al. · Quality by Design
145
Nur für den privaten oder firmeninternen Gebrauch / For private or internal corporate use only
Elke Sternberger-Rützel1, Werner Runft1, Melanie Beck1, Elke Weber2, Martina Kleiner2,
Brigitte Gumpinger2, Ingrid Müller2
Originale
2. Mat e r ials a nd meth ods
2.1 Equipment
A GKF 2500 capsule filler, developed and manufactured by Robert Bosch
GmbH, was used for the experiments. It was modified with a special
filling unit for microdosing – a vacuum dosing wheel, which is commercially available. The working principle of the vacuum dosing wheel is as
follows:
a) The powder flows out of the hopper by gravity into the powder
chamber where a stirrer is located. Dosing into the bores of the
vacuum wheel (the top of the wheel = 0°) is guided by vacuum (e. g.
146
–450 or –600 Pa). Therefore, the density of the powder is increased
during the transfer.
b) The vacuum dosing wheel rotates and the dosed fill volume of
powder is held by vacuum during rotation (0–180°).
c) At the bottom of the wheel (180°) the transfer of single doses of
powder into the capsules takes place via compressed air.
d) At the last station (270°), the integrated filter of the vacuum dosing
wheel is cleaned by a compressed air blast.
An identical equipment parameter set-up was chosen for all trials with
different lactose qualities and therefore, it effected the filling results of
the single trials in a non-optimized way. The filling results could be
optimized by adjusting the equipment parameters to the individual
lactose qualities. In order to compare the main effects and their interactions (lactose quality, fixed/adjustable vacuum dosing wheel, low/high
fill weight, low/high transfer vacuum) some of the equipment parameters had to be fixed (Table 1).
Tab l e 1
Overview of fixed machine parameters.
Fixed Parameters
Equipment (GKF 2500)
Scraper
Use of one type of filter
8-108-013-619
Speed
140 cycles/min
Transfer pressure
0.6 bar and 18 ms
Inner cleaning parameters
(vacuum and pressure)
1.0 bar and 30 ms
Outer cleaning parameters
(vacuum and pressure)
0.6 bar and 30 ms
Stirrer
double wire stirrer
Stirrer rotation and movement:
2/min, direction to the left
2.2 Statistical evaluation
For the design of the experiments the software Minitab® 15.1.30.0 by
Minitab Inc., State College, Pennsylvania, USA, was used (see 3.2). A
general full factorial set of experiments was chosen.
The performance of the statistical evaluation such as variance analyses was performed with Minitab, as well as the creation of diagrams.
2.3 Analytical procedure
2.3.1 Weighing
The weighing was manually performed on an analytical balance, type
“Kern 770-80”. A differential net-weighing process was used in order to
eliminate any additional failures. The capsules were fully weighed (incl.
powder), emptied incl. cleaned, and then weighed again.
Each trial ran 5 min, resulting in roughly 12,500 capsules, of which 30
were randomly sampled.
2.3.2 Particle size distribution (PSD)
The measurement of the PSD was performed by laser diffraction (Mastersizer 2000, Malvern Instr., Herrenberg, Germany) at the laboratory of
the University of Applied Sciences of Albstadt-Sigmaringen, Pharmaceutical Engineering.
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
Approach to Pharmaceutical cGMP Regulations” it is explained that “Quality by Design means designing and developing a product and associated manufacturing processes
that will be used during product development to ensure that
the product consistently contains a predefined quality atthe
end of the manufacturing process…” [1]. The International
Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH)
has developed the ICH Q 8 “Pharmaceutical Development”
[2], Q 9 “Quality Risk Management” [3] and Q 10 “Pharmaceutical Quality Systems” [4] guidelines, which deal, among
others, with the implementation of QbD strategies into the
development of products and processes. Additionally, they
put an emphasis on a risk-based approach. Especially the
ICH Q 8 guideline, which is adopted by the European Union,
includes information about development processes.
With the QbD tool one can get a full understanding of
how product attributes and process parameters are related to the product performance. Especially during a
development process, it is the target to understand each
operation unit and which process parameter affects critical quality attributes (CQAs). Furthermore, with QbD,
risk analysis can be conducted and critical process parameters and material attributes can be identified. So a
risk reduction strategy and an appropriate control
strategy can be established to minimize effects of variability on CQAs and to evaluate risks in terms of severity,
likelihood, and detectability.
The performance of the trials was divided into four
steps:
1. Identification of the critical parameters regarding the
microdosing process
2. Calculation of the test plan by the means of statistical
software with the target of reducing the quantity of
tests and in parallel to gain statistically significant
results.
3. Performance of the filling process and analysis of the
following parameters:
a) filled powder’s appearance
b) powder flowability
c) weight
d) particle size distribution before and after the filling
process
4. Evaluation of the results using statistical methods.
Parameter of analysis:
Laser obscuration: 3-17 %
Air pressure: 1 bar (1 000 Pa) (analog method development)
All trials were repeated (n=3) for statistical reasons.
2.3.3 Flowability and density of untreated lactose
qualities by a Ring Shear Tester
2.4 Materials
During the trials pure lactose was filled without pre-processing. Therefore, no addition of flowability enhancers or similar additives was made.
Furthermore, no active pharmaceutical ingredient (API) was added because the influence of APIs differs strongly. API can act as a roller bearing
and improve flowability strongly or it can lower the flowability of the
lactose significantly by e. g. changing the surface charge of the particles.
The following lactose qualities were chosen in order to represent a
broad spectrum of different quality attributes such as particle size
(coarse vs. fine), PSD (broad vs. narrow), flowability (good vs. bad),
and manufacturing methods (milled vs. sieved). These four different
qualities represent an overview of products on the market.
InhaLac® 120
InhaLac 120 by Meggle is a sieved crystalline lactose quality with an
excellent flowability, well defined particle surfaces, and physico-chemical stability. It has a smooth particle surface, narrow PSD, and no amorphous lactose [5].
Batch no. 9521 with the following characteristics was used for the
trials:
d10 = 72 μm
d50 = 126 μm
d90 = 178 μm
Hausner ratio = 1.14 (very good flowability)
Flowability = 13 ( free flowing)
GranuLac® 200
GranuLac 200 by Meggle is milled lactose with limited flowability. The
PSD is pretty broad as expected [6].
Although this lactose quality is not a typical inhalation product, it was
chosen because of its characteristics ( flowability and PSD)
trials:
d10 = 5 μm
d50 = 32 μm
d90 = 105 μm
Hausner ratio = 1.42 (bad flowability)
Flowability = 2.0 (very cohesive)
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
Lactohale 201 is special inhalation lactose by Friesland Foods Domo for
adhesive mixtures with coarse and fine lactose particles. It is hard milled
lactose with a pretty broad PSD in order to satisfy the active surfaces of
the coarse lactose with very fine lactose particles. With this approach the
theoretical added API in the formulation could occupy low energy sites
and the needed energy for dispersion during inhalation is lower [7].
trials:
d10 = 3 μm
d50 = 24 μm
d90 = 61 μm
Respitose® ML006
Respitose ML006 by DMV-Fonterra Excipients is fine milled inhalation
grade lactose with a narrow PSD [8, 9].
Just before use of ML006 two batches of 10540717 and 10418456 were
mixed together, resulting in the following characteristics:
d10 = 3 μm
d50 = 20 μm
d90 = 51 μm
3 . R e sul t s
3.1 Setup of the critical parameters regarding the
capsule filling process
Based on previous experiences, the parameters that influence the capsule filling process were defined. The quality of the powder, the type of vacuum dosing wheel, the fill
volume, and the applied vacuum were identified as critical parameters and therefore named as variable parameters. Table 2 gives an overview of these variable parameters.
Within the parameter of “fill volume” the two different
vacuum dosing wheels are integrated. They are shown
below, with the continuous value of 12 mm³ for the fixed
vacuum dosing wheel, 18 mm³ for the low volume of the
adjustable vacuum dosing wheel, and 24 mm³ for the high
volume used with the adjustable vacuum dosing wheel.
3.2 Calculation of the test plan
Minitab was used to set up the test plan (Table 3).
Due to the fact that all parameters were described as
continuous parameters, except for the quality of lactose,
which is a discrete parameter, no response surface design
diagram could be created. Additionally, no calculation of
the optimized parameters can be performed by applying
one discrete parameter.
3.3 Results of the filling tests
3.3.1 Macroscopic evaluation
A picture of every trial was taken in order to compare the
appearance of the filled capsules with the untreated
147
The analyses were performed at the laboratory of the University of
Applied Sciences of Albstadt-Sigmaringen, Pharmaceutical Engineering,
with a Ring Shear Tester RST-XS (Dietmar Schulze Schüttgutmesstechnik, Wolfenbüttel).
Sample volume: 30 ml (of unprocessed lactose)
Yield locus test: preshear σpre: 2000 Pa,
shear to failure σsh,1: 300 Pa, shear to failure σsh,2: 950 Pa,
shear to failure σsh,3: 1600 Pa, σsh< σpre
Time yield locus test: preshear σpre: 2000 Pa, based on the shear tests
the consolidation stress is determined for each product.
After preshearing at σpre = 2000 Pa, every powder is consolidated
during a period of time of t = 1 min, and t = 10 min with the corresponding . Afterwards the shear to failure
σsh,2 = 950 Pa is applied.
Lactohale® 201
Originale
Tab le 2
Overview of variable parameters.
Variable parameters
Quality of lactose
. InhaLac 120
. GranuLac 200
. Lactohale 201
. Respitose ML006
Vacuum ( for filling of bores and transport)
. –450 Pa
. –600 Pa
material. In Fig. 1 only one capsule – representing all six
trials for the identical lactose quality – is displayed because there is no macroscopic difference between the
results of the filling process.
Tab le 3
Setup of full factorial design with the adjustable and fixed vacuum dosing level.
Trial no.
148
Lactose quality
Fill volume
Vacuum [mbar]
Vacuum dosing wheel
1
InhaLac 120
High/24 mm³
–450
adjustable
2
InhaLac 120
Low/18 mm³
–450
3
InhaLac 120
Low/18 mm³
–600
4
InhaLac 120
High/24 mm³
–600
5
GranuLac 200
High/24 mm³
–600
6
GranuLac 200
High/24 mm³
–450
7
GranuLac 200
Low/18 mm³
–600
8
GranuLac 200
Low/18 mm³
–450
9
Lactohale 201
High/24 mm³
–600
10
Lactohale 201
Low/18 mm³
–600
11
Lactohale 201
Low/18 mm³
–450
12
Lactohale 201
High/24 mm³
–450
13
Respitose ML006
Low/18 mm³
–450
14
Respitose ML006
Low/18 mm³
–600
15
Respitose ML006
High/24 mm³
–600
16
Respitose ML006
High/24 mm³
–450
17
Respitose ML006
Fixed/12 mm³
–450
18
Respitose ML006
Fixed/12 mm³
–600
19
Lactohale 201
Fixed/12 mm³
–450
20
Lactohale 201
Fixed/12 mm³
–600
21
GranuLac 200
Fixed/12 mm³
–450
22
GranuLac 200
Fixed/12 mm³
–600
23
InhaLac 120
Fixed/12 mm³
–450
24
InhaLac 120
Fixed/12 mm³
–600
fixed
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
Different vacuum dosing wheels, combined with different fill volumes:
. fixed vacuum dosing wheel with fill volume of 12 mm³
. adjustable vacuum dosing wheel
– low fill volume of 18 mm³
– high fill volume of 24 mm³
3.3.2 Weighing
When using the vacuum dosing wheel, the fill weight
(Fig. 2, the trial setup is explained in Table 3) – as the
most prominent result – did not fluctuate too much.
Fourteen out of 16 trials for the adjustable vacuum dosing
wheel resulted in a relative standard deviation (RSD)
< 2 %, which complies perfectly with the target of < 3 %.
Two trials (no. 1 and no. 4, both with InhaLac 120) resulted in RSD > 5 %, which does not comply with the
target. The free-flowing characteristic of InhaLac 120 is
the reason for the non-compliance in combination with
the equipment parameters used. When changing the
setup of the parameters (e. g. use of low fill volume), like
in trial no. 2 and 3, the flowability of the lactose does not
affect the fill weight RSD as much anymore and the results are compliant.
Fig. 2 is divided into three parts: The top (between 15
and 19 mg) describes the capsule weights of trials performed with the adjustable vacuum dosing wheel and
high filling volume, resulting in high average weight (appr.
16-18 mg average, incl. the two trials with failed RSD). The
middle portion (11-13 mg) shows the adjustable vacuum
Originale
b)
c)
d)
Fig. 1: Pictures of filled capsules with different lactose qualities: a) Filled capsule with InhaLac 120, b) GranuLac 200, c) Lactohale 201
and d) Respitose ML006, which did not change visually. InhaLac represents the only free flowing quality, which can be confirmed
visually. (All pictures are Bosch property.)
dosing wheel with low fill volume and the bottom portion
(7-9 mg) shows the fixed vacuum dosing wheel.
Outliers of fill weight RSD were expected to a certain
extent because InhaLac 120 is lactose with free-flowing
properties and the others are very cohesive. Therefore, in
certain constellations lactose qualities with poor flow
properties can be filled more easily, when considering uni-
formity of weight compared to free-flowing lactose qualities. The reason must be a certain extent of fluctuation in
vacuum during movement based on filter characteristics,
to which the adjustable vacuum wheel is more sensitive.
When calculating an average RSD of the 16 trials with
the adjustable vacuum dosing wheel, it results in 2.11 %,
compared to the average of 1.92 % for the fixed vacuum
Weight variation of different lactose qualities into
hardgelatine capsules on GKF2500
trial no. 1
trial no.2
trial no. 3
trial no. 4
19
trial no. 5
trial no. 6
trial no. 7
17
trial no. 8
weight [mg]
trial no. 9
trial no. 10
15
trial no. 11
trial no. 12
13
trial no. 13
trial no. 14
trial no. 15
11
trial no. 16
trial no. 17
trial no. 18
9
trial no. 19
trial no. 20
trial no. 21
7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
capsule no.
trial no. 22
trial no. 23
trial no. 24
Fig. 2: Weight variation of different lactose qualities during filling.
150
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
a)
dosing wheel. The slightly higher RSD for the adjustable
vacuum dosing wheel was expected as well because of
mechanical reasons. Vacuum fluctuations may theoretically occur, especially when using high fill volumes, based
on the design of the bores. This could influence the uniformity of weight, which was slightly plausible.
When performing a yield locus test, the flowability , the
bulk density of the unconfined yield strength, and the
consolidation stress are determined.
The time yield locus test gives quantitative information about whether consolidation occurs during storage.
3.3.3 Particle size distribution (PSD)
The PSD was analyzed before and after filling the powders
into the capsules in order to detect any influences of the
process, such as agglomeration or exhaustion of fine particles.
Fig. 3 shows the results of the PSD of the different
lactose qualities. The PSD did not change significantly
in any case during filling. The PSD was very stable when
comparing the untreated material with the processed
material (powder filled into capsules). This means that
no agglomeration, segregation, tendency of baking, or
similar effects are notable and furthermore, no exhaustion of fine particles occurred.
3.3.4.1 Yield locus tests
InhaLac 120, with a flowability ( ffc) of 13, is a free-flowing
material, whereas GranuLac® 200, Lactohale 201, and
Respitose ML006 show very poor flow properties with
values between 1.9 and 2.0, as shown in Table 4. The
flowability ( ffc) is the ratio of consolidation stress to unconfined yield strength. Therefore, low unconfined yield
strength refers to a good flowability.
3.3.4 Results of the flow properties testing for the
different lactose qualities
The different lactose types were analyzed to characterize
their flowability characteristics.
Two sets of tests were performed: Yield locus tests and
time yield locus tests.
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
3.3.4.2 Time yield locus tests
Table 5 shows the differences between the testing times of
unconfined yield strengths for GranuLac 200, Lactohale
201, and Respitose ML006. These lactose qualities do not
have a tendency for time consolidation, thus they do not
differ in their properties when stored with additional
strengths.
InhaLac 120 acts differently, as it changes it’s behavior
over time. It’s free-flowing properties change to good
flowing properties. The values decrease from 12.71 to 8.44
after 1 min and to 9.42 after 10 min.
151
Fig. 3: Change of particle size distribution of different lactose qualities during filling with adjustable vacuum dosing wheel.
Originale
Order” diagram shows a
randomly distributed picResults of Ring Shear Tester for different lactose qualities for yield locus.
ture of the residuals, meaning that there is no inConsolidation
Unconfined yield
Bulk density ρB Flowability
Material
fluence by the order of
[kg/m³]
ƒƒc results
stress σ1 [Pa]
strength ƒc [Pa]
the trials. Therefore, no
GranuLac 200
671
2.0
4272
2096
systematic error is demInhaLac 120
723
13
3727
293
onstrated.
Resulting
correlation
Lactohale 201
597
1.9
4231
2226
equation for the model fit:
Respitose ML006
488
1.9
4217
2245
S = 0.109403 R-Sq = 99.98 %
R-Sq(adj) = 99.91 %
Tab le 5
When checking the R-Value describing the fit of the
Flowability results in conjunction with time con- model, R² of 99.98 % and. R²(adj) of 99.91 %, the model fits
very well.
solidation.
The statistical evaluation of the results was performed
by calculating the p-values with an analysis of variance.
Flowability
Material
When calculating the analysis of variance, the p-values
ƒƒc results
are the most interesting parameters in this case. For
t=0
t=1 min
t=10 min
interpretation it is common to compare every p-value
GranuLac 200
2.03
1.96
2.08
to the α-level of 0.05. If the results are less than or equal
InhaLac 120
12.71
8.44
9.42
to 0.05, one can conclude that the effect is statistically
significant and vice versa: if the p-value is greater than α,
Lactohale 201
1.90
1.81
1.93
the effect is not significant.
Respitose ML006
1.88
1.94
1.89
The lactose quality, the fill volume, the vacuum, and
the interaction between lactose quality and fill volume are
stastically significant influences on the filling process.
The interaction between fill volume and vacuum or between lactose quality and vacuum does not influence the
3.4 Calculation of linear models for the adjustable filling process according to the above mentioned p-values
(Table 7).
and the fixed vacuum dosing wheel
Table 8 shows the results of the analysis of variance for
Table 6 describes the parameters that are used for calcuthe particle size distribution
lation by the statistical program.
The resulting correlation equation for the model fit:
The Gaussian distribution has to be confirmed as a
S = 0.181769 R-Sq = 100.00 % R-Sq(adj) = 100.00 %
pre-requisite for calculation of a variance analysis.
The p-values prove the statistically significant inIn Fig. 4 the “Normal Probability Plot” shows a Gaussian distribution of the fill weight for the trials. Because fluence of the lactose quality and the fill volume and
the “Versus Fits” diagram shows the dots more or less the significant interaction between lactose quality and fill
randomly distributed, the Gaussian distribution is con- volume. There is no influence of vacuum and no interfirmed. The impression of three clouds of data refers to action between fill volume and vacuum. Based on the
the different fill volumes.
The dots are randomly distributed;
contemporaTab l e 6
neously they display the
fixed dosing wheel along Parameters used to calculate the linear model of fill weight vs. lactose quality,
with the low and high fill fill volume, and vacuum.
volumes of the adjustable
Levels
Values
vacuum dosing wheel. Factor
The “Histogram” again Lactose quality
4
GranuLac 200
InhaLac 120
confirms the Gaussian disLactohale 201
tribution because of the
Respitose ML006
symmetrical distribution
3
12 ml ( fixed vacuum dosing wheel)
of the columns. It proves Fill volume
18 ml (low volume of adjustable vacuum dosing wheel)
that there are no obvious
24 ml (high volume of adjustable vacuum dosing wheel)
outliers to the Gaussian
Vacuum
2
–450 Pa; –600 Pa
distribution. The “Versus
Tab le 4
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
152
p-value, the interaction between lactose quality and vacuum is borderline (0.040) but the effect of lactose quality
is so strong that there is an overlap and therefore this
interaction is interpreted as not significant.
The calculation of the variance analysis detects the
main effects and interactions of the variable parameters
of the filling trial. For an overview and summary refer to
Table 9.
4. D iscu s sion
As expected, the setting of the equipment parameters is
essential for the filling process. Some of these were adTab le 7
justed according to existing experience and the pre-trials,
such as type of stirrer, rotation of stirrer, cleaning pressure, filter, scraper, etc. We recognized that they are important and can be adjusted for any single product. The
variable parameters such as fill volume, lactose quality,
and partly vacuum, were defined to be the most critical.
Surprisingly, the vacuum does not play as prominent a
role as expected. It is only important for fine tuning
activities such as fill weight optimization and its RSD.
The most critical parameter is the quality of lactose
used for filling. Therefore, the analysis of filling parameters early on in the development process of medicinal
products is essential. If one uses a special blend of lactose
Tab l e 8
Results of the analysis of variance for fill weight
( focus on p-values).
Linear Model: Particle size distribution vs. lactose
quality, fill volume, and vacuum.
Main effects and interactions
Main effects and interactions
p-values
p-values
Lactose quality
0.000
Lactose quality
0.000
Fill volume
0.000
Fill volume
0.000
Vacuum
0.008
Vacuum
0.176
Lactose quality * fill volume
0.001
Lactose quality * fill volume
0.001
Lactose quality * vacuum
0.621
Lactose quality * vacuum
0.040
Fill volume * vacuum
0.614
Fill volume * vacuum
0.062
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
153
Fig. 4: Residual plots for fill weight.
Originale
Tab le 9
Summary matrix of main effects and interactions.
Main effects
Interactions
Lactose quality *
vacuum
Fill volume *
vacuum
Lactose quality
Fill volume
Vacuum
Lactose quality *
fill volume
Fill weight
+++
++
+
+
–
–
Particle size
+++
++
–
+
+
–
154
parameters need to be adapted to every single product,
resulting in higher uniformity of weight (target < 3 %) as a
reachable target, as proven for most of the described
trials with RSD of 2-3 %.
REFERENCES
[1] U.S. Department of Helath and HumanServices Food and Drug
Administration. Guidance for Industry – Quality Systems Approach to
Pharmaceutical cGMP Regulations. 2006. p. 4.
[2] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
Pharmaceutical Development Q(R2). 2009.
Quality Risk Management. 2005.
Pharmaceutical Quality System. 2008.
[5] Homepage Meggle, product overviews: InhaLac® 120
[updated 2011 Aug 02].
http://www.meggle-pharma.com/index.php/en/products-and-serv
ices/products/product-overview/inhalac-120-sieved[6] Homepage Meggle, product overviews: GranuLac® 200
http://www.meggle-pharma.com/en/products-and-services/products/
product-overview/granulac-200-milled[7] Lactohale® 201 – Inhalation grade lactose
http://abstracts.aapspharmaceutica.com/ExpoAAPS07/Data/EC/
Event/Exhibitors/432/381cd69b-384d-47d0-a27d-f5fec7b2e704.pdf
[8] Respitose® standard grades
http://www.dmv-fonterra-excipients.com/products/inhalation-lac
tose/respitose-standard-grades.aspx
[9] “Performance of Respitose Inhalation Carriers in Salbutamol and
Budesonide mixtures using the Cyclohaler“. S. van Gessel et al.
http://www.dmv-fonterra-excipients.com/applications/applicationsby-dosage-form/~/media/7261DA8DAA9842EDB4F0933F3C3073EC.
ashx
Pharm. Ind. 74, Nr. 1, 145–154 (2012)
due to e. g. inhalation performance, which is hard to fill,
the product could not be manufactured commercially.
Because of the shortened time to market, which is commercially essential for any pharmaceutical company, an
early connection between formulation development and
process development and contact to the filling equipment
supplier is mandatory.
The flowability of four different lactose qualities shows
a good flowability of InhaLac 120, in contrast to very
cohesive materials of Lactohale 201, Respitose ML006,
and GranuLac 200.
The filling experiments were analyzed for two different
aspects: the change of PSD and the fill weights. The
change of PSD was negligible, but the filling process itself
is influenced by the PSD. There was no agglomeration or
segregation tendency noticed and additionally, no tendency of exhaustion of the fine particle fraction.
According to the experiments, the fill weight, as the
most prominent result, is effected strongly by the lactose
quality, the fill volume, and partly by the vacuum. The
particle size (e. g. d50) is also strongly affected by the
lactose quality, the fill volume, but not at all by the vacuum. There are interactions between the lactose quality
and the fill volume, which influences the fill weight as well
the PSD. The interaction of lactose quality and vacuum
influences only the PSD but not the fill weight. Fill volume
and vacuum as an interaction does not influence either
PSD or the fill weight.
The weighing results prove that very different qualities
of lactose can be filled by the vacuum dosing wheel principle: free-flowing to cohesive powders, broad and narrow
PSD products, fine and coarse particles. The process window is broad, according to these results, with a slightly
more sensitive process for the adjustable vacuum dosing
wheel. It is important to know that the utilized process
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