Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design

Abstract

3d 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.

Figure 1

Selection of Parameters That are Relevant for Pharmaceutical Application of Polymers, Particularly in HME and FDM.

Figure 2

Exemplary Drawing of: (left) a Typical Residence Time Distribution Function of a Hot-Melt Extrusion Process; (right) Fluctuations of the Feed Rate (Black) and Output Fluctuations After Extruder (Red).

Figure 3

(Left) Interquartile Ranges of Diameter Measurements During Extrusion Correlated with SFL of the Extrusion Process [37], (Right) Amount of Filament Within ± 0.02 and 0.05 mm Specification With or Without Two Kneading Zones (KZ 1: 4 × 90°,4 × 60°, 2 × 30°, KZ 2: 8 × 60°, Unpublished Data).

Figure 4

Two Filament Production Lines. (1) Gravimetric Feeders, (2) Twin-Screw Extruders, (3) Cooling via Conveyor Belt (Top) and Ring Air-Knives (Bottom), (4) Three-Axis Laser Micrometers, (5) Winding Unit.

Figure 5

Schematic of an Off-the-Shelf 3D Printer (Left) and a 3D Printer with Separate Build, Motion, and Material Handling Section (Right).