Powder Technology 198 (2010) 310–313

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Powder Technology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c

Evaluation of powder mixing operation during batch production: Application to

operational qualification procedure in the pharmaceutical industry
Andreas S.L. Mendez a,⁎, Gláucia de Carli b, Cássia V. Garcia c
a
Curso de Farmácia, Universidade Federal do Pampa - UNIPAMPA, BR 472 – Km 592, Prédio Administrativo, CEP 97500-970, Uruguaiana, RS, Brazil
b
Curso de Farmácia, Universidade de Passo Fundo - UPF, Passo Fundo, RS, Brazil
c
Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Powder mixing is an important operation routinely used in many industries, including pharmaceuticals. The
Received 10 August 2009 quality of products depends on certain operating conditions, such as the equipment, technical parameters
Received in revised form 18 November 2009 and formulation. In this work, an operational qualification of powder mixing during large scale production in
Accepted 30 November 2009
a pharmaceutical industry was performed. A simple and practical protocol was followed. Using a V-blender
Available online 3 December 2009
and dry powder mixing, the operation was tested to illustrate the effect of mixing time on the homogeneity
Keywords:
of the drug in the mixture, demonstrating that this parameter can be used as a secure parameter to control
Powder mixing this pharmaceutical operation on a large scale during batch production and using an off-line monitoring
Operational qualification technique.
Pharmaceutical industry © 2009 Elsevier B.V. All rights reserved.
Batch production
Off-line monitoring

1. Introduction components (purity, particle size and density), qualification of the

Blending of powders is very common in the pharmaceutical industry
and represents a critical unit operation of the production process of solid
dosage forms. The quality of products depends on the degree of mixing
of their constituent materials, which guarantees the homogeneity of the
final product [1,2]. Furthermore, the pharmaceutical industry is
particularly interested in powder blend content uniformity, since the
majority of marketed products are solid dosage forms such as tablets
and capsules [3,4]. Since many factors can affect the quality of blending,
it is crucial to study them during the development and production of a
new product. Physical characteristics of powders such as particle
density, shape, size/ratio, surface properties and the intensity of
cohesion are very important, principally to determine the tendency of
the mixture to segregate. Aspects related to the equipment, operation
and formulation, such as mixer design and operation, a combination of
operating conditions, and mixture formulation are also important and
require attention [5–7].
After the choice of the qualitative and quantitative composition of
the formulation is made on a pilot scale, a full scale test must be
performed. In this context, the optimization of the operations in the
production process includes the application of concepts, techniques
and traceability requirements. According to Berthiaux et al. [8], the
mixing problem can be broken down into the qualification of the
⁎ Corresponding author.
E-mail address: andreaslmendez@yahoo.com.br (A.S.L. Mendez).
operations (mixers, feeders, etc.) and process qualification, requiring
step-by-step validation, unit operation by unit operation. These
concepts and procedures are included in the process validation
scheme of the EMEA [9] and the FDA [10], and their application is very
important for the reliability of all operations in the pharmaceutical
industrial process.
The process for making a drug product consists of a series of unit
operations (a flow diagram consisting of logically defined steps, or
modules) that result in the manufacture of the finished pharmaceu-
tical [11]. Unit operations that are considered to be critical are
determined through analysis of the process variables and their
respective measured response for each. For the blending operation,
the variables are load, speed and mixing time since blending
uniformity is the main objective [11]. Many works have discussed
the technologies for determining blend homogeneity and optimal
blending time. The two options are in-line, by real-time monitoring of
mixing, or off-line, by using strategies to take periodic samples from
the mixers [12,13]. The choice depends on the available technologies
in the industrial plant and the type of mixing that will be used for the
routine process (batch or continuous blending).
During the production of a pharmaceutical product on a large
scale, or during the scaling-up procedure, it is very important to
determine the operation parameters for all of the steps and as such, is
an obligatory requirement included in process validation documents,
according to regulatory requirements. Since the knowledge of content
uniformity in a mixing powder is essential in order to ensure quality
in the solid final product, all industries must test the ideal conditions

0032-5910/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.powtec.2009.11.027
 A.S.L. Mendez et al. / Powder Technology 198 (2010) 310–313
in order to obtain safe data of this intermediate product. This re-
quirement, like others, is included in a process analytical technology
(PAT) system for developing new efficient tools for use during
pharmaceutical development, manufacturing and product quality
assurance [14]. In this paper, we present and discuss results of
experiments testing the mixing of typical pharmaceutical powders in
a V-blender, on a large scale, with special attention to the effect of
mixing time and the relation to the main theoretical concepts. Most of
the literature studies have focused on the development of new
technologies and application to the laboratorial scale. This work
shows the procedures performed during the production routine,
illustrating the usual procedure used by some companies to validate
the powder mixing operation.
2. Experimental
2.1. Materials
This work was performed during the routine production of 500 mg
acetaminophen tablets in an industry in Brazil, following the
principles of the prospective validation. The components of the
particulate system were acetaminophen (Cosmoquímica, São Paulo,
Brazil), polyvinylpyrrolidone (PVP) (ISP do Brazil, São Paulo, Brazil),
lactose (Chempro Chemikalien, Hamburg, Germany), microcrystalline
cellulose (Gemini Exports, Mumbai, India) and croscarmellose sodium
(Interchemical Intersales, São Paulo, Brazil). Acetaminophen and all of
the excipients were sieved before mixing.
2.2. Blending and sampling experiments
The powders were mixed in a stainless steel V-blender (capacity of
600 L). The blender rotational speed was set at 25 rpm. The V-blender
was filled by loading 328 kg of powder into the right arm, which
corresponds to approximately a 55% vessel filling level. Three industrial
batches of 600,000 tablets of acetaminophen were produced and
monitored by this study. For all batches, the sampling operation was
carried out at periods of 10, 20, 30, 40, 50 and 60 min. For each period,
the V-blender was stopped and three samples of approximately 3.0 g
were collected by using a thief probe at three positions (right arm, left
arm and bottom of the blender). UV spectrophotometric analysis of the
collected samples was performed after each mixing period, and the
quantity of acetaminophen at each time was obtained. For this study,
limits of ±5.0% to control the content homogeneity were adopted.
2.3. Homogeneity assessment and UV spectrophotometric measurements
Homogeneity assessment was performed in order to test the
efficiency of the mixing process. From each collected sample, a
quantity corresponding to exactly 50 mg of acetaminophen was
weighed and was then added to 50 mL of purified water in a
volumetric flask and shaken by sonication for 15 min. An aliquot of
1.0 mL was subsequently transferred to a 100 mL volumetric flask,
which was then filled with purified water, producing a concentration
of acetaminophen of 10 μg mL− 1. Standard solutions of acetamino-
phen at 10 μg mL− 1 were also prepared to perform the quantitative
determination. The solutions were analyzed by UV spectrophotom-
etry using a method described in the United States Pharmacopeia [15].
Measurements of the acetaminophen concentration were performed
using an Agilent UV–VIS 8453E double-beam spectrophotometer at a
wavelength of 244 nm. The results obtained were evaluated and the
relative standard deviations (RSD) determined.
2.4. Statistical analysis
All experiments were evaluated by statistical analysis using
GraphPad Prism 5.01 software. The results were analyzed using
311
ANOVA with a post-hoc Tukey's test. The differences in the parameter
values between the groups were assigned a level of significance and
were only considered to be significant if p b 0.05.
3. Results and discussion
During solid dosage forms production, several points must be
controlled in all of the process steps. These controls must be regular.
Almost every industry in the world depends on a blending or mixing
operation at some stage of manufacture. In pharmacy, the objective of
mixing is to obtain dosage units that each contain the same quantity
of drug [16]. In other words, the aim of mixing is to obtain a
homogeneous association of several solid products; To ensure the
homogeneity, it is necessary to take into account the characteristics of
the raw material, the finished mixture, the equipment used, and the
operating conditions [17].
Focusing on the operation or process control during a routine,
process validation is an important and obligatory tool that must be
introduced to the pharmaceutical industry, following regulatory
requirements [9–11]. According to the FDA [10], process validation
is defined as the collection and evaluation of data from the process
design stage throughout production, which establishes scientific
evidence that a process is capable of consistently delivering quality
products. Validation involves a series of activities taking place over
the life cycle of the product and process, specified by process design,
process qualification and continued process verification. At the
process qualification stage, the sampling plan includes sampling
points, number of samples and the frequency of sampling for each unit
operation.
Powder mixers (tumbler, convective, fluidized or static) are
classified according to their mixing mechanism: convection, diffusion
and shear, isolated or associated [16,18]. The choice depends on the
material to be processed, including characteristics such as density,
particle size and the amount of each component; if these factors are
not tightly controlled, segregation can occur. Systems containing
particles of different properties tend to show segregation under
certain circumstances, which may be detrimental to the quality of the
final product [19]. In this context, mixing validation is very important
and can prevent the possible lack of homogeneity that could be
harmful for pharmaceuticals. The mixing process is validated by the
verification of the homogeneity of mixed powders, for instance, by
taking samples at three different levels of the mixer (top, middle, and
bottom) and determining the amount of each active substance in
these samples [17]. Considering the limits that can be chosen to
evaluate homogeneity, some criteria must be established after
sampling. For example, in the case of a sampling of 10 samples, the
estimated mean must lie in a range if − 7.5%/+7.5% about the real
mean content, or each individual value must lie in a −15%/+15%
interval about the real mean content [8,20].
In this work, the procedure routinely used by many industries to
validate the blending process is presented and discussed. The
blending (in batch) was carried out using the same conditions
typically used during routine production. The mixing time was used as
the main parameter, and variations of the homogeneity were
analyzed at certain time intervals. Other parameters could also be
considered, such as blender geometry, vessel filling level and speed
[21]. Table 1 shows the mean content of acetaminophen as a function
of the mixing time in all of the batches studied. Acetaminophen
content was closer to the theoretical value (500 mg) after the mixing
time of 30 min. The homogeneity increased from the zero time to
30 min, and after 30 min, segregation of the powder may have
occurred, where the solid state rearranges itself and reverses the ideal
powder mixture. This behavior can be better observed in Fig. 1, in
which the drug content increases, reaching 516 mg of acetaminophen
in batch 1 after 60 min of mixing. Observing the results obtained and
considering the established limits (− 5.0%/+5.0%, 475 mg/525 mg),
312 A.S.L. Mendez et al. / Powder Technology 198 (2010) 310–313

Table 1
Acetaminophen content obtained from each collection time during the study of the powder mixing process on a large scale.

Mixing time (min)a

10 20 30 40 50 60

Acetaminophen content (mg) — batch 1 (RSD) 497.91 (0.35) 497.38 (0.59) 500.11 (0.25) 503.40 (0.41) 509.15 (3.22) 515.98 (1.63)
Acetaminophen content (mg) — batch 2 (RSD) 498.58 (0.27) 499.14 (0.18) 500.07 (0.03) 502.02 (0.34) 505.09 (1.09) 506.80⁎ (0.62)
Acetaminophen content (mg) — batch 3 (RSD) 499.47 (0.21) 499.59 (0.23) 499.89 (0.10) 502.50 (0.20) 505.11 (0.75) 507.04⁎⁎ (0.91)
⁎ Significant difference compared with a mixing time of 10 and 20 min (p b 0.05).
⁎⁎ Significant difference compared with a mixing time of 10, 20 and 30 (p b 0.05).
a
The value observed after each mixing time is the mean content from the three positions of blender (right arm, left arm and bottom).

this operation could be considered efficient for mixing the acetamin- carried out after collection of the samples during off-line processing.
ophen formulation for all of the mixing times, and the amount of the The literature has described that one of the main problems in the
drug in the tablet would most likely be within the pharmacopoeial mixing operation is the difficulty of characterizing the quality of the
limits for acetaminophen tablets (±10%) [15]. However, considering
the other operations that could be applied to this intermediate
product, such as granulation and compression, it is very important to
minimize the variations and to maintain the dosage closer to the mean
content. The next steps ensure more reliability, and the correct dosage
can thus be guaranteed.
The results presented in Table 1 also illustrate the occurrence of a
significant difference between the values obtained after 60 min and 10
or 20 min for batches 2 and 3. A major difference in the values obtained
between these times is also seen in batch 1; however, there is no
significant statistical difference in this case. Observing the data
presented in Fig. 2, it is possible to evaluate this dispersion, mainly in
batch 1 (Fig. 2A), which has higher values of RSD. In this same batch, the
individual drug content after mixing times of 40 and 50 min from the
right and bottom positions, respectively, is in the superior limit
established. Considering that the samples were collected from different
positions of the blenders, and even knowing that the particulate
material can suffer a rearrangement and has a tendency to segregate, it
is possible suggest that homogeneity is a function of time. Thus, we can
associate this behavior with the cohesive properties of the material,
which may or may not be present. Cohesion is considered a constitutive
property of materials, which deeply affects the mixing process. The
effects of cohesion are present in the scale up and scale down of unit
operations such as blending, sampling discharge, fluidization and
granulation. The pronounced approximation of the mass and the
tendency to aggregate the particulate material requires major attention
during the control of mixing [6,22,23].
Considering the presence of five excipients, with different
quantities, the dry powder mixing operation exhibits good perfor-
mance, including the equipment, the parameters of mixing (rotation
speed, mixing time and vessel filling level) and the formulation. It is
also important to observe that the analysis of the drug content was

Fig. 1. Evolution of the mean acetaminophen content in the V-blender as a function of Fig. 2. Evolution of acetaminophen content at three positions in the V-blender
the mixing time for the three industrial batches, where UV spectrophotometry was according the mixing time, where UV spectrophotometry was used to quantify the drug
used to quantify the drug present in the powder mix. present in the powder mix. A: batch 1; B: batch 2; C: batch 3.
 A.S.L. Mendez et al. / Powder Technology 198 (2010) 310–313
mixing, since it is difficult to accurately measure the mixture com-
position using an efficient, precise and non-destructive procedure
[4,13,24,25]. To achieve a better control of mixing, PAT was
developed, which is a system for designing, analyzing, and controlling
manufacturing through timely measurements of critical quality and
performance attributes of raw and in-process materials and processes
[26,27]. The PAT initiative requires implementation of in-process
monitoring systems and controls in the mixing process [28]. Several
technologies are proposed for the monitoring of content uniformity
in-line, such as NIR (Near-Infrared Reflectance spectroscopy)
[7,21,29], magnetic resonance imaging [30], electrical capacitance
[31], effusivity [4] and visual observation [1]. These techniques are
very useful in a continuous blend during large productions.
In this study, however, off-line monitoring was used with a batch
tumbler mixer. Many industries do not have equipment for continuous
mixing or the technology for monitoring the quality of mixing in an on-
line analysis. Yet, this absence does not prevent them from achieving
quality dosage forms or from validating their operation and processes
according to the established guidelines. The results presented illustrate
this possibility and demonstrate how certain industries perform the
validation steps during large production. This paper could be a first step
to initiating the understanding and implementation of this simple
technology where necessary in the world.
4. Conclusions
A simple and practical operational qualification procedure has
been proposed to investigate the pharmaceutical mixing operation on
a large scale. The effects of mixing time have been quantified and the
behavior of dry powder mass was evaluated, considering the
equipment (tumbling blender), the filling level (55% approximately),
the rotation speed (25 rpm) and the mixing time (10 to 60 min). A
relation between theoretical concepts and real conditions that are
applied in routine industrial production allowed the association of the
critical operational aspects with the practical effects. The observed
results illustrate that the homogeneity of powder into the blender
depends on mixing time; it is important to consider this parameter to
avoid segregation, mainly in formulations with more complex
composition and elevated powder mass. In addition, this study
demonstrates that it is possible to reliably meet quality standards
even under the simple technological conditions of non-continuous
mixing equipment and off-line monitoring.
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