4.1. Main Findings
Overall, the healthcare professionals participating at the focus group discussions had a positive attitude towards 3D-printed drug products. They could expect many opportunities that 3D printing technology could bring to medical treatment of pediatric patients at hospital settings. A precise dose as well as personalized doses and dosage forms were some of the benefits mentioned by the healthcare professionals. The innovative approach of considering a child’s preferences regarding shape and color of the dosage form involved suggestions of funny shapes like a pink smiley face, a tractor, and a frog. However, the appealing looks of drug products might lead to unintentional drug intake by children. This is unlikely to happen at hospital wards, though, as drug products are stored in cabinets out of the reach for children and nurses administer the medicines to patients. The possibility to print a small-sized dosage form was believed to be a benefit, while the large size of the dosage form was a big concern. Thus, the small size of the formulation was considered a significant prerequisite for adopting printed dosage forms for pediatric patients. Previously, two different shapes of polypills, cylinder and ring shape, having relatively small sizes of 10 mm in diameter and 3 or 6 mm in height have been produced by SLA [14
]. A paracetamol and ibuprofen containing chewable soft dosage form in the form of a LegoTM
-like brick has been developed utilizing embedded 3D printing technology [16
]. The size of this dosage form was 40 × 25 × 15 mm, which would however be probably too big for a child. Awad et al. have used selective laser sintering (SLS) to fabricate miniprintlets (sizes 1 mm and 2 mm) containing paracetamol and ibuprofen [17
In our study, both a small size and appealing shape of the printed formulation were assumed to improve drug acceptance. A study on drug acceptability of orodispersible films revealed that also caregivers suggested child-friendly and appealing shapes of formulations for children [33
]. Additionally, the study showed that more than half of 3–5-year-old children liked orodispersible films very much and that almost all caregivers were willing to use the dosage form. Goyanes et al. investigated the effect of flavor and color on drug acceptability of chewable printlets administered to four pediatric patients [4
]. Preferences of flavor and color were individual; however, the most preferred flavors were strawberry, orange, and lemon. Drug acceptability of different shapes of 3D-printed solid oral placebo formulations has only been investigated in adults [34
]. In future studies on 3D printing of pharmaceuticals for pediatric patients, the size of the formulation should be emphasized as well as the development of innovative and child-friendly formulations and shapes.
Previous studies indicate that manufacturing of polypills is possible by means of 3D printing [14
], but further product development with focus on pediatric patients and relevant drug substances for pediatrics is still needed. According to the healthcare professionals participating in the present study, the availability of polypills, personalized regarding both the combination of drug substances as well as the doses, would benefit the treatment of several medical conditions and would improve adherence to medications, especially in case of polypharmacy and when drug administration during school hours is necessary. Personalized drug combinations and doses for the treatment of HIV and tuberculosis as well as for medication administered after organ transplantation were mentioned as useful additions to current treatment options for children. Paracetamol and ibuprofen are often administered as a combination for the treatment of fever and pain, and this combination was also suggested as a potential polypill by the focus group participants. Pharmaceutical evaluation of potential clinical interactions between the incorporated drug substances prior to drug manufacturing of polypills was considered essential from the medication safety perspective. Indeed, the administration of polypills instead of several oral drug products has gained interest among polypharmacy patients as well [34
]. Therefore, one objective for future investigations on polypills should be the manufacture of patient-specific doses for each drug substance included as well as ways to address potential interactions.
Aspects of medication safety was considered both in relation to the benefits and concerns associated with 3D printing as well as in the prerequisites for adopting printing technology as a manufacturing technique for pediatric dosage forms in hospital pharmacies. The idea of printing drug products directly based on an electronic prescription is a clear improvement to medication safety and the current processes of prescribing and compounding. This subject has been discussed also by Araújo et al. [22
], who suggested that the electronically sent prescription would be directed for production to one of many printers in the compounding pharmacy after having been verified by a pharmacist. The focus group participants were concerned about drug content and distribution in printed pediatric medicines. Therefore, dose verification prior to drug administration was considered a prerequisite. Colorimetric and spectroscopic techniques for the analysis of drug content in printed dosage forms are proposed methods for nondestructive quality control permitting real-time batch release [36
]. For on-demand manufacturing purposes, either handheld, user-friendly analytical devices that are quick to operate or devices that are automated and integrated to the printers have to be incorporated to the production process in order to enable quick response times in hospital pharmacies.
Identification of a drug product by scanning a Quick Response (QR) code imprinted on it gained much interest among the focus group participants, and this feature was considered to improve patient safety. Edinger et al. introduced the idea of using inkjet printing technology to print a QR code onto edible substrates using colorants [9
]. Since then, other investigators have used the same printing method as well to mark an orodispersible film with a QR code aiming to include information on both the patient and the drug product [6
]. The information in the QR code can be modified according to the needs or specifications of the hospital. The participants in this study believed that, in case the printing method used does not enable printing of a QR code, other measures should be taken to ensure identification of the drug product and, thus, to prevent medication errors. In drug development of pediatric medicines, one must consider that the colorant as well as other excipients are safe for use in children, since investigations have shown that neonates and infants are extensively exposed to harmful excipients during oral administration of medicines [38
]. Furthermore, this study shows that healthcare professionals prefer dosage forms containing excipients that enable the administration of the dosage form through enteral feeding tubes as well as after dissolving or dispersing the dosage form in liquid, e.g., water.
The costs of adopting 3D printing as new manufacturing techniques at hospital pharmacies were discussed from two different perspectives. On one hand, waste costs for, e.g., unused drug products were thought to diminish if patient-specific dosage forms would be produced on-demand. On the other hand, there were concerns that personalized dosage forms would be expensive to manufacture. The costs for manufacture of personalized doses by means of printing would, for instance, include investment and annual maintenance costs for the printer; cost of personnel operating the printer; as well as costs for raw materials, packaging materials, and disposable manufacturing equipment. The actual costs depend on the chosen printing technique and studies of cost-effectiveness would be important subjects for further research in order to evaluate which drug substances would be beneficial to produce as personalized doses. The focus group participants were also concerned about how the logistics and the medical formulary at the hospital wards would be affected by a more personalized approach to the manufacture of pediatric drugs and doses. Currently, the wards are able to borrow medicines from other wards in case of unexpected needs. Manufacturing of personalized doses or dosage forms equals drug production on-demand, which in turn generates the prerequisites of short production and delivery times from time of prescription to time of administration. There are some studies regarding 3D printing of drug products where manufacturing times are mentioned [4
]. However, since the production time is one prerequisite for the adoption of printed drug products at hospitals, it would be essential to incorporate more information about the overall manufacturing times (including all manufacturing steps) in research articles, hence making it possible to compare the suitability of different printing methods for on-demand manufacturing.