(162f) Modelling and Simulation Efforts in Scale up and Characterisation of Semi-Solid Dosage Forms

Generic pharmaceutical industry has to
operate in tight timelines of product development and scale up from lab to
plant. Getting it right the first time demands detailed product & process
understanding and implementing appropriate mechanistic modelling and
Quality-by-design (QbD) approaches in the product life cycle, to minimize
downstream risks. This work provides example cases of such efforts in topical
dosage products.

Topical products are typically in the
form of either emulsions, gels, thick suspensions or even simple solutions. The
efficacy of such products is determined by characteristics like rheology and
morphology (how the drug is dispersed).  Defining, and scaling up the right
manufacturing process with a given set of ingredients, to achieve the right
product characteristics presents as a challenge to the process engineer. Figure
1 shows a simplified process flow diagram for the manufacture of topical
product using an inline mixer while figure 2 captures the relevant critical
materials attributes (CMAs) and critical process parameters (CPPs) that impact
the critical quality attributes (CQAs) of semi-solid dosage form. But in
practical sense, these properties are inter-linked (Figure 3).

Figure 1 – Process flow
diagram

For example, the non-Newtonian rheology varies
not only with CPPs and CMAs but also is an implicit function of globule size
(CQA). Hence, this calls for various mechanistic models, to help predict the
product behaviour. This paper focusses on such models (Figure 4)
obtained from computational fluid dynamics (CFD) coupled with population
balance modelling (PBM) and constitutive models (like shear, energy density). Custom
lab scale experimentation provides the required model parameters. Such efforts are
leveraged to facilitate scale-up of the products from the lab to plant. In a
special case of the use of high shear homogenisers (HSHs) for the manufacture
of thick emulsions/ gels, this work presents some findings on (i) scale-up
algorithm for HSH using shear strain, a novel scale-up parameter for estimating
mixing parameters, (ii) non-linear relationship (Figure 5) between
viscosity and shear imparted into the system, (iii) effect of hold time on
rheology of product.

Specific examples of how this approach
enabled scale-up across 1L, 10L, 200L, 500L and 1000L scales will be discussed