Losan Pharma GmbH

Pharmaceutical 3D printing (3DP) is one of the emerging enabling technologies of personalised medicines as it affords the ability to fabricate highly versatile dosage forms. In the past 2 years, national medicines regulatory authorities have held consultations with external stakeholders to adapt regulatory frameworks to embrace point-of-care manufacturing. The proposed concept of decentralized manufacturing (DM) involves the provision of feedstock intermediates (pharma-inks) prepared by pharmaceutical companies to DM sites for manufacturing into the final medicine. In this study, we examine the feasibility of this model, with respect to both manufacturing and quality control. Efavirenz-loaded granulates (0-35%w/w) were produced by a manufacturing partner and shipped to a 3DP site in a different country. Direct powder extrusion (DPE) 3DP was subsequently used to prepare printlets (3D printed tablets), with mass ranging 266-371 mg. All printlets released more than 80% drug load within the first 60 min of the in vitro drug release test. An in-line near-infrared spectroscopy system was used as a process analytical technology (PAT) to quantify the printlets' drug load. Calibration models were developed using partial least squares regression, which showed excellent linearity (R² = 0.9833) and accuracy (RMSE = 1.0662). Overall, this work is the first to report the use of an in-line NIR system to perform real-time analysis of printlets prepared using pharma-inks produced by a pharmaceutical company. By demonstrating the feasibility of the proposed distribution model through this proof-of-concept study, this work paves the way for investigation of further PAT tools for quality control in 3DP point-of-care manufacturing.

Various wet ball nanomilling-screening tools for poorly soluble APIs are available which differ in their milling principle, batch size and number of samples. Here, the transferability of results from screening (small to medium-scale) to pharmaceutical production (largescale) was investigated. Wet ball milling in a dual centrifuge (DC) (10-100 mg API, 40 samples in parallel) was used to identify stable nanoformulations. In addition different sized agitator bead mills were used for scale-up to industrial scales. DC-and small-scale agitator milling (AM) resulted in small and virtually identical API-particles. Additionally, similar API-particles were obtained using two different sized agitator bead mills (batch size 1.5 and 30 kg) and applying comparable specific grinding energies (SGE). The SGE used in the trials represents the grinding limit for this API-suspension. Using lower SGEs, AM results in larger API-particles. All used milling tools had no influence on the APIs crystal structure and wear of grinding media (Zr/Y) is low. The study confirmed the importance to choose the right formulation and process parameters, which positively affect grinding efficacy, particle size distribution and wear contamination. The excellent comparability of results obtained from DC-milling and AM significantly reduces the duration for successful and predictable formulation development.

The development of nanosuspensions of poorly soluble APIs takes a lot of time and high amount of active material is needed. In this publication the use of dual centrifugation (DC) for an effective and rapid API-nanomilling is described for the first time. DC differs from normal centrifugation by an additional rotation of the samples during centrifugation, resulting in a very fast and powerful movement of the samples inside the vials, which - in combination with milling beads - result in effective milling. DC-nanomilling was compared to conventional wet ball milling and results in same or even smaller particle sizes. Also drug concentrations up to 40% can be processed. The process is fast (typical 90min) and the temperature can be controlled. DC-nanomilling appears to be very gentle, experiments showed no change of the crystal structure during milling. Since batch sizes are very small (100-1000mg) and since 40 sample vials can be processed in parallel, DC is ideal for the screening of suitable polymer/surfactant combinations. Fenofibrate was used to investigate DC-nanomilling for formulation screening by applying a DoE-approach. The presented data also show that the results of DC-nanomilling experiments are highly comparable to the results obtained by common agitator mills.