(84a) Spray Drying Scale-up Based on a Development By Design Approach

The traditional scale-up approach of pharmaceutical manufacturing processes involves substantial testing at scale which leads to the expenditure of tens and sometimes hundreds of kilograms of product in a very expensive and time consuming endeavour. The main reason for this experimental based approach is the underlying complexity of pharmaceutical manufacturing processes, the lack of process understanding and scale independent correlations.

At present, the scale-up paradigm as shifted from this experimental based “Trial & Error” approach to a process understanding QbD (Quality by Design) approach through the advances in PAT (Process Analytical Technology) measurement tools and modelling tools ranging from simple heuristics, to mechanistic and statistical models and to more advanced tools such as CFD (Computational Fluid Dynamics), DEM (Discrete Element Methods) and PBM (Population Balance Models).

Spray drying is one such example of a pharmaceutical manufacturing process where the QbD initiative was instrumental in process understanding and in building mathematical models. Due to its remarkable capability in manipulating powder/particle characteristics such as size, morphology, density and level of residual solvents, it has become one of the most sought after unit operations for the manufacturing of ASDs (Amorphous Solid Dispersions) in order to overcome poor water solubility/bioavailability of oral drugs [1]. Spray dryers in the pharmaceutical industry are available in a wide range of scales: from lab units where milligrams of material can be produced to very large commercial units capable of handling several tons per day. One particular concern during development of pharmaceutical spray dried materials is the effect of scale-up on critical quality attributes, where a less careful scale-up strategy may lead to considerable losses of very expensive materials and jeopardize the timelines of a clinical program. As such, the need for robust process development methodologies is critical to minimize the consumption of materials and reduce development time and time to market. The quantities of API required in the early stages of development are typically small, but may increase by many orders of magnitude as a drug candidate advances through the clinical phases and reaches the market. This requires multiple scale-up steps along the process [2].

With 73% of the novel drugs approved by FDA in 2016 falling into one or more expedited approval categories (Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review) CMC development is increasingly on the critical path of drug development. Under these programs, work that traditionally takes ten years often must be compressed into two or three, where specialized experience and expertise is required to successfully develop robust and cost-effective processes that assure the same levels of quality [3].

The work presented here describes a development methodology case study for a spray-dried product from the lab to commercialization. This methodology, termed DbD (Development by Design), aims at a process development in a timely and cost-effectively manner with minimal expenditure of time and drug substance during development and encompasses three stages: i) Familiarization Stage at the Lab-Scale: In this stage the goal is to develop scale-independent dimensionless correlations to support the multiple scale-up steps; ii) Scale-up for clinical supply: In this stage the scale-up is performed, through simulation tools, under GMP without experimentation at industrial scale and iii) Process Intensification and Design Space definition: This stage is performed close to validation when the risk for the clinical program is minimal. Experiments are conducted to improve process efficiency and support the definition of the design space. Rather than tens to hundreds of kg, as little as 30 g may be required for testing. These results clearly demonstrate that we have been able to combine thermodynamic, drying kinetics, atomization and CFD (Computational Fluid Dynamics) modelling, extensive process knowledge, and a database of over 1000 successful spray-drying batches to accelerate the development and commercialization of drugs.

[1] Newman, Ann, Gregory Knipp, and George Zografi. “Assessing the Performance of Amorphous Solid Dispersions”, Journal of Pharmaceutical Sciences 101.4 (2012): 1355-1377.

[2] Marco Gil, João Vicente, Filipe Gaspar. “Scale-up methodology for pharmaceutical spray drying”, Chemistry Today, 28, (2010):18-22.

[3] Food and Drug Administration (FDA), (2016) Novel Drugs Summary.