Abstract3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Fused deposition modeling (FDM) 3D printing was used to produce 3D printed tablets with the thermo-sensitive model peptidomimetic drug enalapril maleate (EM). Two different formulations were prepared to investigate the degradation of enalapril maleate during the FDM 3D printing process. Soluplus® and Eudragit® E PO were chosen as polymers. After hot-melt extrusion (HME) and FDM 3D printing, both formulations were characterised regarding their solid-state properties using DSC and XRD. The degradation of the drug was analysed by determination of the content in the extrudates and 3D printed tablets, and dissolution was assessed. Various approaches have been attempted to prevent degradation of enalapril maleate, including utilization of a larger nozzle diameter and higher printing speeds to reduce heat exposition. None of these approaches were successful in preventing drug degradation. However, significant differences in the amount of degradation between the two formulations with different polymers could be observed. Thus, the FDM 3D printing process was not feasible without any degradation for the thermo-sensitive drug enalapril maleate. A maximum of 85.55 ± 1.48% enalapril was recovered in Eudragit® E PO tablets printed with a 0.4 mm nozzle at a temperature of 180 °C and with a speed of 30 mm/s.

The aim of this research was the production of extrudates for the treatment of hypertension and heart failure and the investigation of the degradation of the peptidomimetic drug enalapril maleate (EM) during hot-melt extrusion (HME). A fast HPLC method was developed to quantify enalapril maleate and possible degradation products. Screening experiments revealed that the diketopiperazine derivative (Impurity D) was the main degradation product. Hot-melt extrusion of enalapril maleate with the polymer Soluplus® enabled extrusion at 100 °C, whereas a formulation with the polymer Eudragit® E PO could be extruded at only 70 °C. Extrusion at 70 °C prevented thermal degradation. A stabilizing molecular interaction between enalapril maleate and Eudragit® E PO was identified via FT-IR spectroscopy. Dissolution studies were carried out to study the influence of the formulation on the dissolution behavior of enalapril maleate. These promising results can be transferred to other thermo-sensitive and peptidomimetic drugs to produce extrudates which can be used, for instance, as feedstock material for the production of patient-specific dosage forms via Fused Deposition Modeling (FDM) 3D printing.

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