(542d) Developing HME-Based Drug Products Using QbD and Emerging Science

Hot melt extrusion (HME) is a continuous manufacturing process primarily carried out using co-rotating intermeshing twin-screw extruders (TSE). The process is mostly used in order to produce amorphous solid dispersions of poorly soluble active pharmaceutical ingredients (APIs) by dispersing them in polymer carriers. In addition, it can also facilitate the development and production of products with crystalline API embedded into a polymer matrix and nanopharmaceuticals. Formulation screening for HME based drug product presents a significant challenge in the product development cycle. On the one hand this can be attributed to the complex formulation, process and final product relationship where it is not entirely clear how the chosen formulation is transformed into the final dosage form under selected HME process conditions. On the other hand, being a continuous manufacturing technology, HME traditionally requires a large amount of API (kilograms of premix vs grams available in the early development stages) for successful formulation screening and early process setup. The process setup itself is modular, allowing the process to be tailor-made for any formulation. This might however be problematic in the context of choosing the appropriate and efficient setup for an unknown formulation and it is an additional reason for relatively high quantities of material usually needed for the screening. Effectively solving the multidisciplinary challenge of formulation development, early process screening, effective scale-up and transfer to GMP production represents one the key challenges of the pharmaceutical industry and is especially challenging for novel and imported production technologies like HME.

Methodology

As a response to these challenges, our group has focused on developing scientific tools that allow for a fast and minimum-risk development of HME-based formulations using several advanced tools. These include advanced material screening, small-scale formulation test beds, the design of small-scale processes and the scale-up to GMP production of clinical batches. During the formulation development and screening phase traditional approaches (e.g., assessment of biopharmaceutical and physicochemical properties of the formulation) or modern in-silico approaches (e.g., molecular dynamics, machine learning). Since to this date most of the process setup and scale-up activities are performed experimentally and empirically, one of the goals of our group was to create in silico tools for a rational, science-based process setup and scale-up, while addressing other important aspects, such as an API degradation and overall product quality[1], [2]. The fundamental idea behind process modelling is the break down and the detailed analysis of the key process aspects, among which the most prominent might be the analysis of flow patterns developed as a result of the rotation and geometry of the individual screw element pairs[3]–[5]. A further step is the development of numerical models aimed at understanding and predicting the connection between the independent process variables like the screw speed, throughput, barrel temperature, and screw configuration to the dependent process variables like the resulting melt temperature distribution, SMEC distribution and local and overall residence time distribution[1], [6]–[8]. Once an accurate prediction of the internal process state is possible, a push towards connecting the internal process state, the formulation characteristics and resulting product quality can be made.

Results

Following this approach formulation and process development will be discussed and analyzed. A detailed analysis of the different extruder elements and equipment scales used, based on the results of detailed smoothed particle hydrodynamics (SPH) simulations will be presented and discussed. Moreover, a detailed process analysis based on mechanistic 1D simulations will be performed, comparing various configurations and equipment scales, in the context of scalability and resulting process quality. The overall goal is to present a systematic and holistic framework for rapid, reliable and waste free product development of HME based formulations. Following the Quality by Design (QbD) framework, the pharmaceutical product development should be based on sound scientific principles and quality risk management, with an emphasis on predefined objectives, scientific product and process understanding and process control. Hence, our approach aims at connecting the different formulation properties, desired product quality attributes and the critical process parameters with the help of mechanistic process simulations and advanced formulation design, laying the foundation for automated process setup and scale-up with a prescribed product quality in mind.

Literature

[1] J. Matić, A. Witschnigg, M. Zagler, S. Eder, and J. G. Khinast, “A novel in silico scale-up approach for hot melt extrusion processes,” Chem. Eng. Sci., vol. 204, pp. 257–269, Aug. 2019.

[2] J. Matić, A. Paudel, H. Bauer, R. A. L. Garcia, K. Biedrzycka, and J. G. Khinast, “Developing HME-Based Drug Products Using Emerging Science: A Fast-Track Roadmap from Concept to Clinical Batch,” AAPS PharmSciTech.

[3] A. Eitzlmayr and J. G. Khinast, “Co-rotating twin-screw extruders: Detailed analysis of conveying elements based on smoothed particle hydrodynamics. Part 1: Hydrodynamics,” Chem. Eng. Sci., vol. 134, pp. 861–879, Sep. 2015.

[4] A. Eitzlmayr and J. G. Khinast, “Co-rotating twin-screw extruders: Detailed analysis of conveying elements based on smoothed particle hydrodynamics. Part 1: Hydrodynamics,” Chem. Eng. Sci., vol. 134, pp. 861–879, Sep. 2015.

[5] A. Eitzlmayr, J. Matić, and J. G. Khinast, “Analysis of flow and mixing in screw elements of corotating twin-screw extruders via SPH,” AIChE J., vol. 63, no. 6, pp. 2451–2463, Jun. 2017.

[6] A. Eitzlmayr et al., “Experimental characterization and modeling of twin-screw extruder elements for pharmaceutical hot melt extrusion,” AIChE J., vol. 59, no. 11, pp. 4440–4450, Nov. 2013.

[7] A. Eitzlmayr et al., “Mechanistic modeling of modular co-rotating twin-screw extruders,” Int. J. Pharm., vol. 474, no. 1–2, pp. 157–176, Oct. 2014.

[8] R. Baumgartner, J. Matić, S. Schrank, S. Laske, J. G. Khinast, and E. Roblegg, “NANEX: Process design and optimization,” Int. J. Pharm., vol. 506, no. 1–2, pp. 35–45, Jun. 2016.