Abstract
The integration of 3D printing (3DP) technologies into personalized medicine manufacture at the point-of-care is garnering significant interest due to its potential to create tailored drug products with precise dosages and other unique attributes. Both preclinical and clinical studies have demonstrated promising outcomes, including pharmacokinetic bioequivalence, improved patient acceptability, enhanced adherence, and the ability to produce consistent, reproducible dosage forms with accurate drug distribution. Some compounding pharmacies around the world are already incorporating 3DP into standard practice for simpler therapeutic treatments. However, further clinical evaluation is required for more complex treatments, such as multi-drug polypills. Conducting clinical trials involving 3DP technologies presents several challenges, including navigating evolving regulatory frameworks, addressing ethical and legal concerns, and complying with new point-of-care manufacturing guidelines. Although regulatory agencies are beginning to adapt their policies to accommodate 3DP, the absence of a comprehensive framework still creates uncertainty for pharmacists and healthcare providers. This article explores the planning and execution of clinical trials involving 3D printed medicines, with a focus on regulatory barriers, patient recruitment, compliance, and the integration of specialized equipment and expertise. It also discusses the implementation of 3DP for personalized drug manufacturing within hospital settings and offers guidance for obtaining clinical trial approval from the Spanish Agency for Medicine and Health Products (AEMPS). By providing these insights and recommendations, this article aims to support international harmonization and facilitate the adoption of 3DP technologies in clinical trials globally.
Introduction
The availability of appropriately designed medications for all types of patient populations remains a notable challenge within the pharmaceutical landscape. Historically, the focus of pharmaceutical research, regulation, and formulation development has primarily been on adult male patients, often overlooking specific needs across different demographic groups [1, 2]. Many medicines on the market are not optimally designed for certain populations, such as paediatrics or elderly, leading to a limited range of suitable drug options that do not always meet specific requirements in terms of dosing and acceptability [1,2,3,4]. Doses are typically calculated based on factors such as an individual’s weight, body surface area, or specific pathological characteristics. In general, the physiological attributes of patients can vary significantly, emphasizing the need for tailored therapeutic approaches. It is well-known that different demographic groups may present unique needs or pathologies, which can significantly impact pharmacokinetics. Therefore, precise formulations and dosing are essential to ensure efficient and safe therapy for all patients. Reports such as the World Health Organization’s (WHO) “Make Medicines Child Size” highlight the broader necessity of improving access to medications that effectively address the health problems of underserved populations, like children [5]. Likewise, regulatory advancements, such as the European Union’s Paediatric Regulation (No 1901/2006) introduced in 2007, demonstrate ongoing efforts to enhance health outcomes across diverse groups [6].
While acceptability is essential for ensuring high adherence to prescribed treatments across all patient populations, it is especially important in paediatric patients [7]. Understanding patient adherence often involves an interplay of many factors that influence whether a patient successfully follows recommendations or completes a therapeutic program. Indeed, the “Guideline on Pharmaceutical Development of Medicines for Paediatric Use” released by the European Medicines Agency (EMA) provides formulation criteria and aspects to take into account [8]. Notably, there are significant differences compared to formulation development for adults, and challenges that must be considered are described; mainly, heterogeneity, precise and appropriate dosing, swallowing difficulties, palatability and acceptability, and excipient safety.
To overcome these problems related to the lack of medications, the use of unlicensed and off-label medicines (i.e., those prescribed and/or administered outside the terms of their marketing authorisation) is frequent in children due to their exclusion from trials during the drug development process [9]. Medicines are usually manually compounded within hospital or community pharmacies with unique attributes tailored to each patient, such as specific dosage or administration form. Compounded medicines are intended for an individual patient and they are prepared by a pharmacist through the combination and customization of active pharmaceutical ingredients (APIs) and excipients [10]. Compounding remains a vital practice for pharmacist and a fundamental pillar to guarantee personalized treatment according to patient’s requirements [11, 12].
Notwithstanding, pharmaceutical compounding exhibits some limitations [13, 14]. It is time-consuming, resource-intensive, not exempt to dosing errors, and sometimes an inflexible approach to meet continuous dose changes. In addition, compounded formulations may present adherence challenges when the final dosage form is not well accepted by the patient; e.g. capsules may be unsuitable for individuals with swallowing difficulties. Liquid formulations are commonly regarded as the preferred oral dosage form for compounding in paediatric patients. However, these formulations often carry a bitter or an unpleasant-tasting due to the drug, and their color and even their packaging make them unappealing and may generate resistance to take it, potentially negatively impact treatment adherence [15, 16]. While these liquid formulations offer flexibility in dosing, achieving precise and consistent dosing can be challenging due to issues such as inhomogeneity and poor palatability. Patients may spit out the medication or sometimes masking its taste with food, resulting in an increased risk of inaccurate dosing due to incomplete uptake, bioavailability changes or even aversion to these foods. These challenges in adherence and dosing accuracy have been associated with hospital admissions and higher healthcare cost [16,17,18], underscoring the critical need for addressing these issues in compounding. Considering these problems, it is essential to explore alternative formulations or methods that can overcome the main limitations of conventional pharmaceutical compounding.
Three-dimensional printing (3DP) of medicines is emerging as a new disruptive compounding technology for the fabrication of a wide range of personalized dosage forms [19] such as printlets (3D printed tablets) [20], extended and controlled-release systems [21, 22], chewable formulations [23,24,25], orodispersible films [26, 27], minitablets [28, 29], polypills (combination of multiple drugs in the same 3D printed dosage form) [30,31,32] as well as tailored food products for specific needs [33, 34] (Fig. 1). In comparison with conventional time-consuming compounding methods, 3DP can quickly and accurately produce patient-customized single or multiple-dose pharmaceutical forms with different shapes, sensory characteristics (colors and flavors), sizes and drug release profiles at the point-of-care, such as hospital or community pharmacies [35,36,37]. The application of this technology is particularly beneficial for patients facing challenges in medication adherence or tolerance, when commercially available dosages are not suitable, and even in situations involving frequent dose adjustments.
Preclinical and even clinical studies of 3DP of medicines have shown promising results at an early stage [38]. Indeed, a study involving 12 healthy adults demonstrated pharmacokinetic bioequivalence between commercial tablets and a 3D printed sildenafil formulation [39]. Recently, the disintegration of 3D printed placebo tablets, prepared by selective laser sintering, was evaluated for the first time in six human volunteers using magnetic resonance imaging [40]. Nevertheless, clinical studies involving personalized printed medicines at the point-of-care remain quite sparse.
The first clinical study was conducted in paediatric patients with a rare metabolic disorder (maple syrup urine disease, MSUD) and demonstrated the acceptability and efficacy of 3D printed chewable tablets, indicating that 3DP offers a viable approach to manufacture personalized medicines on-demand [41]. Additionally, 3DP technology was evaluated as an alternative method to avoid the manual subdivision of levothyroxine sodium tablets in 91 infants with transient hypothyroxinemia [42]. More recently, in the same realm of rare metabolic diseases, a clinical study demonstrated the benefits of preparing chewable printlets containing different amino acids for paediatric patients. For the first time, 3DP enabled the combination of two different treatments into a single chewable printlet, reducing the number of administrations and improving the quality of life of children affected with rare diseases. The study demonstrated that manufacturing and utilizing a dual-component printlet is viable in clinical settings [43]. These studies emphasize that point-of-care 3DP of medicines is becoming a reality in the clinical practice. However, to fully demonstrate this capacity, it is imperative to reinforce these findings with additional clinical studies, particularly in the paediatric population, where the current research is notably scarce. Ongoing research is crucial to substantiate the clinical benefits and enhanced patient acceptability associated with 3D printed pharmaceuticals.
The planning and executing clinical trials with (paediatric) patients involving 3D technologies present significant challenges within both the Spanish and global healthcare landscapes. These challenges arise from the need to navigate complex regulatory frameworks for clinical trials involving medicines, while also ensuring that ethical and legal considerations for participants are fully addressed [44,45,46] and adhering to the in-coming regulations focused on point-of-care 3DP of medicines [47]. Indeed, there is a lack of an established regulatory framework focused on 3D printing and it depends on the country; however, medicines regulatory agencies like the U.S. Food Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) are adapting regulations to support point-of-care manufacturing [48, 49]. The FDA is exploring regulatory strategies to safely implement point-of-care 3DP, emphasizing on quality assurance, validation, and oversight. Through collaboration with industry and healthcare stakeholders, FDA aims to establish a flexible yet robust framework that encourages innovation while prioritizing patient safety. In the United Kingdom, the MHRA has introduced The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025, a new regulatory framework set to come into effect in July 2025 [50]. This framework supports point-of-care (PoC) manufacturing by ensuring safety and quality in the production of innovative, patient-specific medicines at or near the site of treatment. Modular manufacturing—using standardized, portable units—adds flexibility and scalability, making it ideal for producing small batches and personalized formulations within decentralized healthcare settings. In the European Union, the EMA has established the Quality Innovation Group (QIG) to support the integration of advanced manufacturing technologies, including 3D printing, into the regulatory framework. The QIG facilitates early dialogue between developers and regulators, offering guidance on quality-related innovations. Its 2025–2027 work plan emphasizes personalized medicine and includes the development of a ‘Questions and Answers’ document on 3D printing and decentralized manufacturing, aiming to clarify regulatory expectations and support compliance with GMP and quality standards [51,52,53].
In particular, there is a crucial need to take into account the vulnerability of children, particularly as a protected group in clinical trials, since children have the same rights as adults to be treated [45].
In response to this growing need, Vall d’Hebron Barcelona Hospital is leading the launch of a clinical trial, recently approved by regulatory authorities, to assess the feasibility of implementing point-of-care 3D printed medicines for paediatric patients (EudraCT number: 2021-001069-20, EUCT Number: 2024-519149-31-00 and ClinicalTrials.gov ID: NCT06435481 [54]). Therefore, this article evaluates the feasibility of implementing 3DP for personalised drug manufacture within hospital setting. Additionally, this work can serve as a guide to obtain the clinical trial approval by the Spanish Agency for Medicine and Health Products (AEMPS) to manufacture personalised 3D printed medicines in Spain at the point-of-care. With the aim of reaching international harmonization, this article may serve also as a basis for the implementation in other countries.
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Parramon-Teixido, C.J., Rodríguez-Pombo, L., Basit, A.W. et al. A framework for conducting clinical trials involving 3D printing of medicines at the point-of-care. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01868-y
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