3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation of these innovative drug products. Extensive research has been conducted on the compliance of 3D-printed drug products to a pediatric quality target product profile. The 3D-printed tablets were of particular interest in providing superior dosing and release profile similarity compared to conventional drug manipulation and compounding methods, such as oral liquids. In the future, acceptance of 3D-printed tablets in the pediatric patient population might be better than current treatments due to improved palatability. Further research should focus on expanding clinical knowledge, providing regulatory guidance and expansion of the product range, including dosage form possibilities. Moreover, it should enable the use of diverse good manufacturing practice (GMP)-ready 3D printing techniques for the production of various drug products for the pediatric patient population.

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three‐Dimensional (3D) printing of medicines, which enables small‐scale manufacturing at the point‐of‐care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D‐printed tablet formulation at the point‐of‐care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D‐printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D‐printed tablets a randomized, an open‐label, 2‐period, crossover, single‐dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC_0‐t) and maximum plasma concentration (C_max) ratios were within the limits of 80.00–125.00%. The manufacturing process provided reproducible 3D‐printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC_0‐t and C_max ratios were within bioequivalence limits (AUC_0‐t 90% CI: 87.28–104.14; C_max 90% CI: 80.23–109.58). For the first time, we demonstrate the development of a 3D‐printed tablet formulation at the point‐of‐care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine.

Purpose: Pharmaceutical three-dimensional (3D) printing is an innovative production technique which enables the manufacturing of personalized medicine at the point-of-care. A reliable 3D printer is paramount for the successful implementation in clinical practice. In this paper, the design strategy of a pharmaceutical semi-solid extrusion 3D printer is described, where the concept of quality-by-design is applied. Methods: The technical design stages are divided in the conceptual design and detailed design stage. The minimal viable product, critical process parameters and implemented control strategies were defined. Results: The critical process parameter with the highest impact is the temperature of the cartridge during preheating, i.e. prior to the production process. The temperature is controlled with an accurate thermistor, closed feedback loop and thermal isolation. The temperature can be monitored at all times using the graphical user interface and there is an audit trail using the logging system. Software was developed conforming to GAMP5. Conclusions: Build-in control strategies in the design of the pharmaceutical 3D printer can mitigate risks during the production process of personalized medicine. The regulatory landscape surrounding 3D-printed drug products remains challenging. By using this design approach, relevant guidelines were taken into account during the design of a pharmaceutical 3D printer. Future development of the 3D printer should include the incorporation of process analytical technology tools and upscaling of feedstock production to further support the implementation of personalized medicine 3D-printed at the point-of-care.

Three-dimensional (3D) printing can produce tablets for individual patients at the point-of-care, e.g. in a hospital pharmacy. The quality of these tablets needs to be verified before they are dispensed. However, conventional quality control is not feasible for point-of-care manufacturing. In this study, the suitability of near-infrared (NIR) and Raman spectroscopies was explored for the assessment of furosemide drug content in 3D-printed tablets. Tablets of three different diameters (2.7, 4.5 and 6.2 mm) containing furosemide 10 – 25% w/w, with a dose range of 3.5 – 35 mg furosemide per tablet, in a polymer matrix of Gelucire 48/16 and glycerol, were produced using a semi-solid extrusion 3D printer. Weight distribution was determined and content uniformity was assessed using HPLC-UV. Content data were linked to NIR and Raman spectra. Subsequent partial least squares regression (PLS) models encompassed good predictive values (root mean square error of prediction (RMSEP) = 0.8242%; RMSEP = 1.307%, respectively). NIR and Raman spectroscopies are suitable for non-destructive analysis of personalized 3D-printed furosemide tablets. NIR provides robust bulk quantification, while Raman spectroscopy gives detailed chemical insight, especially including the low-frequency region. Subsequent PLS regression provides an easy approach for clinical practice, due to its transparency, robustness and ease of validation.