(708c) Secondary Drying Scale-up Methodology: Eliminating a Bottleneck with a Lean Development Approach

Porfirio, T., Hovione
Valente, P., Hovione FarmaCiência SA
Matos, I., Hovione
Vicente, J., Hovione
Temtem, M., Hovione FarmaCiência SA
Semião, V., Instituto Superior Tecnico, University of Lisbon

Secondary drying scale-up methodology: eliminating a bottleneck
with a lean development approach

Porfirio1,2*, P. Valente1, I. Matos1, J.
Moreira1, J. Vicente1, M. Temtem1, V. Semiao2

1 Hovione Farmaciencia
SA, Sete Casas, 2674-506 Loures, Portugal; *tporfirio@hovione.com

2LAETA, IDMEC, Mechanical
Engineering Department,
Instituto Superior Tecnico, Universidade de Lisboa,
Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal

Owing to the short residence time of the
droplets/particles within the spray drying chamber and process constraints to
maintain product quality, most spray drying processes include a secondary
drying (post-drying stage) to reduce residual solvent content to values below
ICH guidelines (International Conference on Harmonization of technical
requirements for registration of pharmaceuticals for human use). In spite of the
widespread use of secondary drying process the physical mechanisms governing it
are not yet fully understood [1, 2]. When using vacuum dryers, this
complementary step is often the bottleneck of spray drying process and thus
there is an increasing need to optimize process conditions to maximize
throughput and ensure product quality. The process optimization for spray dried
dispersions (SDD) is normally challenging due to the presence of an amorphous
polymeric matrix with a glass transition temperature that limits the operating
conditions in order to avoid the crystallization of the product.

A systematic methodology is proposed to allow an
early recognition of scale-up and drying issues before process implementation
on industrial scale to support the SDD development. The methodology includes a model that describes the drying mechanism of
free-flowing powders under-vacuum considering the penetration theory [3,4]. This theory assumes a continuous mixing process with an
alternate fictitious sequences of static periods and perfect mixing periods [5].
The understanding of the drying mechanism is crucial to optimize the process
where the fundamental drying mechanism and mass transfer principles play an
important role. The proposed methodology was created under the Quality by
Design and Development by Design paradigms where the scale-independent relations
(such as drying rate curve) and product/process understanding are found on lab-scale
trials in order to achieve a lean development (Figure 1).

Figure 1: Proposed methodology

The method was constructed including the prior
knowledge and the data of a known product used as reference. Several testes at
lab- and large-scale units were performed for this reference case in order to
establish the relevant equipment’s parameters.

With that, when a new product is introduced, the
proposed methodology provides an analytical assessment to evaluate a glass
transition temperature, density, particle size and other important quality
attributes that are relevant for the drying performance and understanding, e.g.
the plasticization curve of the SDD to assure the amorphous state during the
process since the risk of crystallization grows when the drying temperature is
too close to the glass transition temperature. Succeeding, the product and
process behavior and understanding are attained on lab-scale experiments to
predict scale-independent relation. The lab-scale experiments are also
important to understand the product behavior in terms of agglomeration and

With the obtained scale-independent relation, it is
possible to fit the model parameters and extrapolate for the large-scale unit
where the model parameters of the equipment were previous stablished.

The intended
benefits of this method are:

secondary drying process time through process optimization;

secondary drying development and scale-up;

transfer between secondary drying units.

A case study comprising the secondary drying process development of a SDD
will be presented by following the proposed methodology. In this case study,
operating conditions (namely the temperature and rotation speed) were optimized
by the model without compromising the amorphous state of the temperature in
order to reduce the drying time.

Gianfrancesco, 2012. New method to assess water
diffusion in amorphous matrices during storage and drying. Food Chemistry, 132,

Kougoulos, 2011. Impact of agitated drying on the
powder properties of an active pharmaceutical ingredient. Powder Technology,
210, pp. 308-314

Schlunder and Mollekopf,
1984. Vacuum contact drying of free flowing mechanically agitated particulate
material. Chemical Engineering and Processing, 18, 93-111

Tsotsas and Schlunder, 1986. Contact drying of mechanically agitated
particulate material in the presence of inert gas. Chemical Engineering and
Processing, 20, 277-285

[5] Shani and Chaudhuri, 2012. Contact drying: a
review of experimental and mechanistic modeling approaches. International
Journal of Pharmaceutics, 434, 33-348