QbD in paediatric formulations.

Ricard Canadell1; Anna Nardi1, Isaac Nofrerías1, Marc Suñé1, Pilar Pérez1,2,
Montse Miñarro1,2, Josep R Tico1,2, Josep M Suñé Negre1,2, García Montoya
Encarna1,2
1
University of Barcelona. Department of Pharmacy and Pharmaceutical Technology.. Avd.
Joan XXIII 27-32 08028 Barcelona. [email protected].
2
Grupo de investigación “Farmacoterapia, Farmacogenética y Tecnología Farmacéutica”
IDIBELL (UB). Avinguda Granvia, 199-203, 08908 L'Hospitalet de Llobregat,
Barcelona, Barcelona

INTRODUCTION parameters of powdered substances that provide the

Obtaining formulations for paediatric diseases is one of necessary information about substance’s
the major challenges to face in the coming years. EMA, appropriateness for obtaining tablets by direct-
in the Guideline on pharmaceutical development of compression technology. The considered parameters are
medicines for paediatric use (1) said in the General as follows:
considerations: Any medicine should be designed to • Bulk density (Da)
meet patient needs and to consistently deliver the • Tapped density (Dc)
intended product performance. A systematic approach • Inter-particle porosity (Ie)
to the pharmaceutical development in accordance with • Carr index (IC)
ICH Q8 could be followed in order to meet these • Cohesion index (Icd)
objectives. When applied, the quality target product • Hausner ratio (IH)
profile (QTPP) should be established taking into • Angle of repose (α)
consideration the specific needs of the paediatric • Flowability (t”)
population. Based on the QTPP the critical product • Loss on drying (%HR)
quality attributes (CQAs) should then be identified as • Hygroscopicity (%H)
well as the formulation and process parameters that • Particle size (%Pf)
may affect them. This approach will help defining the • Homogeneity index (IH)
pharmaceutical design of the paediatric medicinal Definition of characterization parameters
products. Whenever possible, the methods indicated in
One of the indicated administration routes for paediatric pharmacopoeias were applied. If not available, a system
patients is the oral (1), proposing the orodispersible based on the usual practice in galenic research was
tablets as an appropriate formulation. There are different proposed, adapted specifically for the SeDeM Diagram.
technologies for their production, however, direct • Bulk density (Da): In accordance with the method
compression has the most relevant economic interest described in Section 2.9.15 of Eur. Ph.
among drug manufacturers. The correct choice of • Tapped density (Dc): According to the method
excipients and their CMA (Critical Material Attribute), described in Section 2.9.15 of Eur. Ph.
according to their function in the formula, is one of the • Inter-particle porosity (Ie): Ie = Dc –Da / DcxDa
aspects to consider as part of the product drug CQA. • Carr index (IC%): This is calculated from Da and Dc
Considering the methodology SeDeM(2), it is proposed as: IC=(Dc _ Da / Dc)x100
as CMA the compressibility and flowability indexes • Cohesion index (Icd): The cohesion index is
calculated for the major excipient chosen during the determined by directly compressing the product under
development to improve the index of compressibility of study. Determine the hardness (N) of the tablets
the API. These CMA designated could be considered as obtained. Calculate the mean hardness obtained.
specification to control the variability in the excipient • Hausner ratio (IH): This is calculated from Da and Dc
during routinary production due to its importance in the as: IH= Dc / Da
uniformity dosage in paediatric products. • Angle of repose: This is the angle of the cone formed
As an example of the proposed methodology, an when the product is passed through a funnel with the
excipient processed to be used in direct compression, following dimensions: funnel height 9.5 cm, upper
Excipress GR150® (Lactose monohydrate), has been diameter of spout 7.2 cm, internal diameter at the
analyzed. bottom, narrow end of spout 1.8 cm. Calculate the angle
tangent value (a) of the cone by using the following
EXCIPIENT CHARACTERIZATION USING THE equation: Tg(α) = h /r.
SeDeM METHOD • Flowability (t”): In accordance with the method
The SeDeM method is based on the experimental study described in Section 2.9.16-2 of Eur. Ph.
and quantitative determination of the characterization
 • Loss on drying (%HR): This is determined by the
losson-drying test carried out in accordance with
General method 2.2.32 in Eur. Ph.
• Hygroscopicity (%H): Determination of the sample
weight increase after being kept in a humidifier at
ambient relative humidity of 76% (±2%) and a
temperature of 22 _C ±2 _C for 24 h.
• Percentage of particles measuring <50µ (%Pf): particle
size is determined by means of the sieve test in Figure 1. SeDeM diagram for EXCIPRESS GR150®
accordance with the General method 2.9.12 of Eur. Ph. Batch P1038GX.
• Homogeneity index (Iϴ): In accordance with the
general method described in General method 2.9.12 of
Eur. Ph.
The next step is to convert the numeric limits for each
SeDeM parameter to radius values r. At the end, Mean
Incidence values and Good Compressibility Index will
be considered as a CMA(2).

EXCIPRESS GR150® characterization

Using SeDeM method, EXCIPRESS GR150® (Lactose Figure 2. SeDeM diagram for EXCIPRESS GR150®
monohydrate) was characterized, obtaining the Batch P1062GX1
following results, in three different batches:
1(*) 2(*) 3(*) Mean
Da 6,36 6,42 6,00 6,26
Dc 7,67 7,52 7,14 7,44
Ie 2,24 1,90 2,22 2,12
IC 3,42 2,93 3,19 3,18
Icd 9,10 10,00 10,00 9,70
IH 8,97 9,15 9,05 9,06
(α) 4,96 5,09 5,14 5,06 Figure 3. SeDeM diagram for EXCIPRESS GR150®
t" 9,00 9,00 9,00 9,00 Batch P1068GX1
%HR 9,30 8,88 9,46 9,21 The diagram shows good properties of compressibility
and powder flow for EXCIPRESS GR150® that can help
%H 10,00 10,00 9,98 9,99
to active ingredients or formulas with problems in these
%Pf 7,19 7,19 7,39 7,26
aspects.
Iϴ 3,65 2,85 4,30 3,60
(*)1: Batch P1068GX1, 2: Batch P1062GX1, 3: Batch P1038GX. CONCLUSIONS
Table 1. SeDeM experimental radius values results 1.- Considering twelve galenic parameters, the SeDeM
for EXCIPRESS GR150® method allows the excipients characterization and
defines its strong points to consider during the product
1(*) 2(*) 3(*) Mean formula design, specially on compressibility and
Dimension 7,02 6,97 6,57 6,85 flowability index.
Compressi- 2.- Compressibility and Flowability index should by
4,92 4,94 5,14 5,00
bility characterizated as CMA (Critical Material Attribute)
Flowability 7,64 7,74 7,73 7,70 during I+D process in paediatric formulations using
Lubricity/ SeDeM method, to control orodispersible tablets
9,55 9,44 9,72 9,57 uniformity of dosage during the manufacturing process.
Stability
Lubricity/ 3.- In order to keep under control the uniformity of
5,42 5,02 5,85 5,43 dosage during the manufacturing process of the formula,
Dosage
(*)1: Batch P1068GX1, 2: Batch P1062GX1, 3: Batch P1038GX. the excipient routinary results for compressibility index
and flowability index should be near to the experimental
Table 2. SeDeM Mean Incidence values for
values observed. The deviation will be specified
EXCIPRESS GR150®
considering the excipient variability observed during the
1(*) 2(*) 3(*) Mean experimental tests.
IGC 6,49 6,42 6,57 6,49 4.- To EXCIPRESS GR150® for Compressibility index
(*)1: Batch P1068GX1, 2: Batch P1062GX1, 3: Batch P1038GX. a value of 5.0 (-5%) and a value of 7.7 (-5%) for
Table 3. SeDeM Good Compressibility Index for Flowability index were proposed as CMA.
EXCIPRESS GR150® REFERENCES
and SeDeM diagrams were obtained as follow: 1. 1. EMA/CHMP/QWP/805880/2012 Rev. 2
2. 2. Suñé-Negre JM, Roig M, Fuster R, Hernandez C, Ruhi R,
Garcia-Montoya E, et al. New classification of directly
compressible (DC) excipients in function of the SeDeM
Diagram Expert System. Int J Pharm. 2014;470(1–2):15–27.