Secondary Drying Scale-up Methodology: Eliminating a Bottleneck with a Lean Development Approach

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

T. Porfirio^1,2*, 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 framework

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 accumulation.

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:

·         Reduce secondary drying process time through process optimization;

·         Support secondary drying development and scale-up;

·         Tech 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.

[1] Gianfrancesco, 2012. New method to assess water diffusion in amorphous matrices during storage and drying. Food Chemistry, 132, 1664-1670

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

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

[4] 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