Advancing 3D printing for personalized pediatric medicines: quality, safety, and Good Manufacturing Practice compliance

Abstract

Three-dimensional (3D) printing is a transformative technology that enables dose individualization in pediatric medicine and advances precision medicine. This facilitates the production of personalized drug formulations with variable dosages, sizes, and release profiles, thereby overcoming the limitations of conventional manufacturing. However, ensuring safety and efficacy requires optimization of critical quality attributes, robust analytical methods, and compliance with good manufacturing practices (GMPs). The PolyPrint consortium is developing innovative polymers and a GMP-compliant fused deposition modeling (FDM) 3D printer. This review covers the formulation strategies, quality considerations, and process validation of 3D-printed pediatric medicines, emphasizing regulatory compliance, printability, and engineering approaches for quality assurance in pharmaceutical applications.

Highlights

This review explores the potential of 3D printing for pediatric dose individualization and precision medicine, focusing on quality attributes, process parameters, safety measures, innovative polymer development, and GMP-compliant printer design to enable safe and effective individualized therapies.

Introduction

Pharmaceutical 3D printing, also referred to as additive manufacturing, has emerged as a ground-breaking technology with the potential to revolutionize the production of pediatric medicines. The inherent flexibility of this approach makes it particularly suitable for the automated manufacturing of solid oral dosage forms tailored to individual patient needs. Solid medicines offer numerous advantages over liquid formulations in pediatric therapy, including superior microbial, chemical, and physical stability, precise dosing accuracy, and the ability to incorporate controlled-release properties. However, traditional manufacturing methods often limit dose variation to incremental ranges, which can impede the customization necessary for effective pediatric treatments. 3D printing addresses these limitations by enabling the precise fabrication of medicines with fully customizable dosages. Using computer-aided design (CAD) software, dosage forms can be created layer-by-layer in virtually any shape or size, providing a versatile platform for individualized therapy. This capability not only simplifies dose modifications but also addresses challenges related to patient acceptability by allowing the design of dosage forms that are more suitable in size and appearance for children. Furthermore, 3D printing facilitates the production of small batches, down to a single personalized dosage form, making it a promising solution for decentralized manufacturing settings such as hospitals, compounding centres, and community pharmacies.

Among the various 3D printing technologies under investigation for pharmaceutical applications, fused deposition modeling (FDM) stands out as a particularly promising candidate for pediatric medicine production. In FDM, drug-loaded polymer filaments are fed into the printer’s heated print head, where they are melted and extruded onto a temperature-controlled print bed. A kinematic system moves the print head along the x, y, and z axes, enabling the layer-wise deposition of the drug-polymer matrix to create the desired dosage form. The filaments used in this process are typically manufactured through hot-melt extrusion (HME), an industrial process that ensures high-quality intermediate products. This approach provides two significant advantages: first, a well-developed formulation and HME process yield filaments that undergo rigorous quality testing; second, the incorporation of the active pharmaceutical ingredient (API) into the polymer matrix minimizes the risk of drug exposure for operators. In comparison to other 3D printing technologies, such as binder jetting and selective laser sintering, FDM offers distinct advantages for pharmaceutical use. Techniques requiring the handling of powders or aqueous intermediates pose challenges related to contamination risks, operator safety, and quality control. For example, semi-solid formulations prepared in decentralized settings demand extensive analytical testing to ensure uniform API distribution, which may not be feasible for small-scale batches. Conversely, the FDM approach streamlines the production process while maintaining high safety and quality standards, making it highly suitable for producing pediatric medicines.

Despite the increasing interest in 3D printing for pharmaceutical applications, the formalization of quality considerations for excipients, formulations, processes, filaments, and final dosage forms remains insufficiently addressed. To bridge this gap, organizations such as the United States Pharmacopeia (USP) and the International Association for Pharmaceutical Technology (APV) have taken significant steps toward establishing standards and guidelines for 3D-printed medicines. A notable initiative includes a four-day workshop co-organized by these organizations, which focused on addressing critical quality and regulatory challenges while showcasing the potential of 3D printing to revolutionize personalized medicines and dietary supplements. Future applications may involve prescribing 3D-printed polypills incorporating multiple APIs or customized dosage forms tailored to individual therapeutic needs. As the adoption of this transformative technology continues to grow, addressing the technical, regulatory, and quality assurance aspects will be essential for its successful integration into pharmaceutical manufacturing, particularly in advancing individualized therapies for pediatric and precision medicine.

Regulatory agencies such as the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and United States Pharmacopeia (USP) are actively working to establish guidelines for 3D-printed pharmaceuticals. The FDA’s approval of Spritam^® (levetiracetam), the first 3D-printed drug, has set a precedent for regulatory pathways, emphasizing the need for clear compliance frameworks. While universal guidelines for 3D printing in pharmaceuticals are still under development, agencies currently rely on existing Good Manufacturing Practice (GMP) and quality control frameworks to ensure safety, efficacy, and consistency. Additionally, organizations such as the EMA and USP are evaluating quality requirements for excipients, printability, and dissolution profiles to align 3D-printed medicines with established pharmacopoeial standards. However, integrating 3D printing into existing regulatory pathways poses several challenges, particularly in adapting traditional quality control and validation approaches for decentralized or small-batch manufacturing. Unlike large-scale pharmaceutical production, 3D printing enables dose customization at the point of care (e.g., hospitals, pharmacies), raising concerns about batch consistency, process validation, and real-time release testing. Since current pharmaceutical regulations are designed for batch-based manufacturing, regulatory agencies must consider new risk assessment approaches to ensure drug-excipient compatibility, stability, and print accuracy while maintaining compliance with safety and efficacy standards. Furthermore, GMP compliance for 3D printing in hospitals and pharmacies presents unique challenges, as decentralized pharmaceutical manufacturing does not fit neatly within traditional GMP environments. Critical factors such as cleanroom conditions, operator training, raw material quality, and end-product sterility must be addressed to ensure regulatory approval. Given the absence of specific GMP guidelines for decentralized 3D printing, regulatory bodies are evaluating whether hospital-based production should follow pharmaceutical GMP standards (ICH Q7) or more flexible compounding regulations. To facilitate regulatory approval, risk assessment and validation strategies for 3D-printed medicines must focus on process validation, in-process monitoring, and end-product testing. Key considerations include establishing reproducibility in print resolution, drug uniformity, and mechanical integrity, implementing real-time quality assessment techniques such as Near-Infrared (NIR) and Raman spectroscopy, and ensuring uniform API distribution, release kinetics, and stability. Additionally, regulatory approval strategies should demonstrate compliance with pharmacopoeial specifications for dissolution profiles, bioavailability, and impurity testing, ensuring that 3D-printed pharmaceuticals meet the same stringent quality and safety standards as traditionally manufactured medicines [1,2,3,4,5].

Pediatric 3D-Printed Medicines: Key Traits & Regulations

The development of pediatric formulations must adhere to strict regulatory guidelines established by global health authorities such as the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and World Health Organization (WHO). These agencies ensure that pharmaceutical products intended for children meet safety, efficacy, and quality standards. Given the unique physiological and developmental differences in pediatric patients, regulatory frameworks have been designed to address age-appropriate dosage forms, excipient safety, bioavailability considerations, and risk assessment protocols. With the emergence of 3D printing in pharmaceutical manufacturing, new challenges arise in quality control, batch validation, and Good Manufacturing Practices (GMP) compliance, particularly in decentralized settings such as hospitals and pharmacies.

FDA Regulations for Pediatric Medicines

Ensuring the safety and efficacy of pediatric medicines is a critical regulatory priority, given the unique physiological and developmental differences in children. The U.S. Food and Drug Administration (FDA) has implemented specific legislative frameworks to address the challenges associated with pediatric drug development and to encourage pharmaceutical companies to conduct appropriate studies in children. Two key legislative acts, the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA), play a crucial role in shaping regulatory requirements for pediatric medicines. These laws aim to promote age-appropriate formulation development, ensure adequate clinical data for pediatric populations, and provide incentives for pharmaceutical companies to engage in pediatric research. With the rapid emergence of 3D printing (3DP) technologies in pharmaceuticals, these regulatory considerations must be extended to ensure that personalized, on-demand pediatric medications produced via 3D printing adhere to existing safety and quality standards [6, 7].

The Pediatric Research Equity Act (PREA), enacted in 2003, mandates that pharmaceutical companies conduct pediatric studies for new drugs, biologics, and labeling changes of already approved drugs when the medication is expected to be used in children. This requirement ensures that pediatric patients receive properly studied and dosed medications rather than relying on off-label adult formulations, which may lead to under- or overdosing risks. The PREA applies to all new drug applications (NDAs), biologics license applications (BLAs), and efficacy supplements submitted to the FDA unless the drug has been granted a waiver or deferral. Importantly, the PREA does not require pediatric studies for drugs that are not intended for pediatric use or those that qualify for a full waiver due to safety concerns or lack of meaningful therapeutic benefit for children. However, for emerging technologies like 3D-printed medicines, the application of PREA remains an open discussion. As 3D printing enables tailored dosage forms, modified release profiles, and combination therapies, regulatory agencies may need to assess whether drugs developed using on-demand 3D printing require additional pediatric-specific studies to ensure efficacy and safety [8, 9].

The Best Pharmaceuticals for Children Act (BPCA), signed into law in 2002, complements the PREA by offering incentives for voluntary pediatric research. Unlike the PREA, which mandates pediatric studies for certain drugs, the BPCA encourages companies to conduct pediatric trials by providing six months of additional market exclusivity for products that successfully complete FDA-requested pediatric studies. This exclusivity applies even if the results of the pediatric trials do not lead to labeling changes, making it an effective tool to drive pediatric research. The BPCA applies to both new and already approved drugs, allowing pharmaceutical companies to explore pediatric-specific modifications, such as age-appropriate dosage forms, taste-masked formulations, and liquid suspensions for children. With the advent of 3D printing, companies may seek BPCA incentives to conduct research on personalized pediatric formulations created through 3D printing. Given that 3D-printed formulations allow for customizable doses tailored to a child’s weight, metabolism, and condition, regulatory agencies must evaluate whether these formulations qualify for BPCA-related incentives and if additional post-market studies are required to assess their long-term safety. Despite the growing adoption of 3D printing in pharmaceuticals, the FDA has not yet established specific regulatory pathways for 3D-printed pediatric formulations. However, manufacturers of 3D-printed pediatric medicines must still comply with existing pharmaceutical regulations, which include Good Manufacturing Practices (GMP), risk-based quality assessment, and post-market surveillance. GMP compliance is essential for ensuring that the raw materials, active pharmaceutical ingredients (APIs), and final printed dosage forms meet safety and quality standards. The use of polymers, excipients, and APIs in 3D-printed formulations must adhere to existing United States Pharmacopeia (USP) and FDA guidance for drug products, with additional oversight required to assess printability, stability, and dose uniformity. Unlike traditional manufacturing, where batch production ensures uniformity through large-scale validation, 3D-printed medications are produced in small, personalized batches, raising concerns about batch consistency, contamination risks, and reproducibility across different printing setups. The FDA may need to introduce specific GMP guidelines for 3D printing, focusing on cleanroom environments, printer calibration, and process validation protocols to ensure regulatory compliance [10, 11].

In addition to GMP adherence, risk-based approaches must be employed to assess the variability in 3D-printed pediatric medications. Traditional pharmaceutical manufacturing relies on well-established process analytical technology (PAT) and validation methods to confirm that each batch meets predefined specifications. However, 3D printing introduces new variables such as printer settings, layer thickness, extrusion temperature, and polymer-drug interactions, which could impact drug bioavailability, dissolution rates, and mechanical properties. The FDA’s risk-based quality assessment framework may need to be updated to account for these novel factors, requiring real-time monitoring and advanced in-line analytical techniques (e.g., Raman spectroscopy, near-infrared spectroscopy) to verify product consistency [12]. Additionally, standardized in vitro and in vivo testing methods must be established to compare 3D-printed dosage forms with their conventionally manufactured counterparts, ensuring that personalized pediatric medications meet the same safety and efficacy standards [13]. Finally, post-market surveillance plays a crucial role in ensuring the long-term safety of pediatric medicines, particularly for novel 3D-printed formulations [14]. Traditional pharmaceuticals undergo extensive clinical trials before approval, but personalized, on-demand 3D-printed medicines may require ongoing real-world monitoring due to their customized nature and small-batch production. The FDA’s Sentinel Initiative, which uses electronic health records and claims data to monitor drug safety, could be leveraged to track the adverse effects, efficacy, and patient adherence of 3D-printed pediatric medications. Additionally, the FDA’s Adverse Event Reporting System (FAERS) may need to incorporate specific reporting mechanisms for 3D-printed drug products, allowing healthcare providers and researchers to identify potential risks associated with personalized pediatric formulations. The implementation of pharmacovigilance programs and patient registries could further enhance safety monitoring, ensuring that 3D-printed pediatric drugs remain a viable and beneficial option for children requiring personalized therapies [15].

EMA and ICH Guidelines & their adaptation to pediatric 3D-printing

The development and approval of pediatric medicines in Europe are governed by strict regulations that ensure the safety, efficacy, and quality of drugs intended for children. The EMA Pediatric Regulation (EC No.

1901/2006) mandates that pharmaceutical companies submit a Pediatric Investigation Plan (PIP) as part of their regulatory approval process. The PIP is a comprehensive development strategy designed to generate the necessary pediatric-specific data before a drug is authorized for use. This requirement applies to new drugs, modified formulations, and new indications for existing medications. The purpose of this regulation is to ensure that children receive medicines that have been rigorously tested and optimized for their unique physiological and developmental needs, rather than relying on off-label use of adult medications. Given that pediatric patients have different metabolic rates, organ maturation levels, and drug absorption profiles compared to adults, the regulatory process ensures that each formulation is specifically tailored to meet these requirements. The regulation also aims to stimulate pharmaceutical research and innovation in pediatric drug development, ensuring that industry stakeholders actively engage in the creation of age-appropriate dosage forms. However, with the rise of 3D printing technologies, regulatory frameworks must evolve to accommodate the customization, scalability, and decentralized nature of 3D-printed pediatric medicines, which differ significantly from traditional batch-manufactured drugs. In addition to EMA regulations, the International Council for Harmonisation (ICH) E11 guidelines serve as a scientific framework for conducting pediatric drug trials, ensuring that medicines intended for children are safe, effective, and appropriately dosed. The ICH E11 guidelines cover various aspects of pediatric drug development, including age-stratified dosing recommendations, the safety of excipients in pediatric formulations, and pharmacokinetic (PK) and pharmacodynamic (PD) considerations. Age-stratified dosing is critical since drug metabolism, clearance, and absorption vary significantly between neonates, infants, children, and adolescents. The guidelines recommend stratified dosing studies to ensure that medicines are optimized for each pediatric age group, preventing both overdosing (toxicity) and underdosing (ineffectiveness). Excipient safety profiles are another crucial component of the guidelines, as some excipients that are safe for adults can pose significant risks to children. For example, propylene glycol and benzyl alcohol have been associated with toxicity in neonates due to their immature metabolic pathways. Regulatory agencies require robust toxicological evaluations of excipients used in pediatric formulations, especially in novel drug delivery systems like 3D printing, where excipient concentrations might differ from traditional formulations. Furthermore, pharmacokinetic (PK) and pharmacodynamic (PD) considerations play a vital role in pediatric drug development. Since children have immature enzymatic activity, altered gastric pH levels, and variable renal clearance, PK/PD studies are necessary to optimize drug absorption, distribution, metabolism, and excretion (ADME) profiles. The ICH E11 guidelines emphasize the importance of clinical trials tailored to pediatric populations rather than simply extrapolating adult data. In the case of 3D-printed medicines, PK/PD profiles could be altered due to differences in drug release mechanisms, surface area, and polymer-based excipient interactions, necessitating additional bioequivalence studies to ensure consistent therapeutic effects [16].

With the introduction of 3D printing technologies in pediatric drug manufacturing, both EMA and ICH guidelines need to be adapted to address novel challenges that arise from the unique characteristics of on-demand, personalized medicine production. One of the key challenges is the decentralized nature of 3D printing and batch control in non-industrial settings. Traditional pharmaceutical manufacturing operates in centralized GMP-compliant facilities, where quality control, batch validation, and regulatory oversight are standardized. However, 3D printing allows for the production of medicines at hospitals, pharmacies, or even point-of-care settings, making batch consistency, quality control, and regulatory compliance more complex. To ensure patient safety, regulatory agencies may need to develop new GMP guidelines tailored for decentralized pharmaceutical 3D printing, focusing on real-time monitoring, error detection, and risk assessment for non-industrial settings [17].

Another critical regulatory adaptation involves real-time release testing (RTRT) for ensuring consistent drug release profiles in 3D-printed dosage forms. In traditional pharmaceutical manufacturing, rigorous quality control measures are applied before a batch is released into the market [18]. However, 3D-printed medicines, especially patient-specific formulations, may require on-the-spot verification of drug uniformity, dissolution rates, and mechanical stability. RTRT methods such as spectroscopic analysis (e.g., near-infrared and Raman spectroscopy) and non-destructive imaging techniques could be integrated into the regulatory framework to validate drug content, stability, and performance in real time [19]. Regulatory bodies will need to define acceptable RTRT standards for 3D-printed medicines, ensuring that each printed dose meets pharmacopoeial requirements before being administered to a patient. A final key area requiring regulatory adaptation is the pediatric acceptability of printed dosage forms, including taste, swallowability, and patient compliance. Unlike adults, children have specific preferences and physiological limitations that must be considered when developing dosage forms. 3D printing offers unparalleled flexibility in designing child-friendly drug formulations, allowing for the creation of mini-tablets, orodispersible films, chewable formulations, and multi-drug polypills. However, regulatory guidelines must be established to evaluate patient acceptability criteria, including flavour masking strategies, texture modifications, and ease of swallowing. The development of standardized taste-masking evaluation techniques, along with age-appropriate swallowability studies, will be crucial for regulatory approval. Since 3D printing enables unprecedented levels of formulation customization, regulatory agencies must also ensure that dose variability, structural integrity, and drug stability remain within safe limits across different formulations [20].

Age-Appropriate Dosage Forms and Excipient Safety

One of the most critical regulatory challenges in pediatric drug development is ensuring that formulations are age-appropriate, safe, and effective. Unlike adults, children experience significant physiological differences, including variations in drug metabolism, absorption, distribution, and elimination. These differences are primarily influenced by immature organ functions, enzyme activity, gastric pH, intestinal permeability, and renal clearance, which evolve as the child grows. Consequently, regulatory agencies such as the FDA, EMA, and WHO emphasize the need for pediatric-specific dosage forms that align with developmental pharmacokinetics and pharmacodynamics (PK/PD). The absence of appropriately designed pediatric formulations often leads to off-label drug use, where adult medications are split, crushed, or reformulated, increasing the risk of inaccurate dosing, poor efficacy, or toxicity. To address this, regulators mandate that pediatric drugs be tailored according to distinct age-based dosing categories, ensuring that neonates (0–28 days), infants (1–12 months), children (1–12 years), and adolescents (12–18 years) receive therapeutically optimized, safe, and well-tolerated treatments [21, 22].

Pediatric formulations must address age-specific acceptability and administration challenges, as younger children have distinct physiological and developmental needs. Neonates and infants often require liquid formulations due to their inability to swallow solid dosage forms; however, these present stability concerns, excipient-related safety risks, and taste-masking challenges. In contrast, older children and adolescents can tolerate mini-tablets, chewable formulations, or orodispersible films (ODFs), which offer greater stability, dose precision, and improved adherence compared to liquid medications. 3D printing technology presents a transformative opportunity in pediatric medicine by enabling customized dosage forms with tailored release profiles, precise dosing, and patient-specific designs. This personalization is particularly valuable in chronic diseases requiring long-term medication use, where improving adherence and therapeutic outcomes is critical. Regulatory agencies, including the FDA and EMA, recognize the potential of 3D-printed pediatric formulations in bridging gaps in pediatric drug development, but concerns remain regarding quality control, stability, and compliance with Good Manufacturing Practices (GMP) [23, 24].

Ensuring excipient safety is a major regulatory priority in pediatric formulations, as immature metabolic pathways in neonates and infants make them more vulnerable to toxic excipient effects. Some commonly used excipients in pharmaceuticals pose significant risks, including benzyl alcohol (linked to gasping syndrome in neonates, causing metabolic acidosis and CNS toxicity), propylene glycol (which may accumulate and lead to hyperosmolarity, lactic acidosis, and neurological disturbances), and polysorbates/polyethylene glycols (PEGs) (associated with hypersensitivity reactions and systemic accumulation in young children). Regulatory bodies strictly evaluate excipients used in pediatric drugs, ensuring that only excipients with established safety profiles and proven tolerability in children are permitted. The use of thermoplastic polymers in Fused Deposition Modeling (FDM) 3D printing has gained interest in pediatric and personalized medicine due to its customization, flexibility, and ability to create precise dosage forms. However, 3D-printable polymers must meet strict thermal, mechanical, and chemical requirements to ensure stability during heating and processing, processability for smooth extrusion, and compatibility with active pharmaceutical ingredients (APIs) to maintain drug efficacy. During FDM printing, polymers undergo mechanical stress, particularly due to the pinching effect within the print head, which impacts filament integrity. Key properties such as Young’s modulus (>300 N/mm²), tensile strength, and brittleness determine printability and structural stability. The three-point bending test is commonly used to assess these properties, ensuring optimal breaking stress (2,941–3,126 g/mm²) and breaking distance (>1–1.5 mm). Additionally, polymers must support API incorporation, dissolution, and controlled drug release without compromising stability, mechanical integrity, or printability (Table 1).

Table 1. Excipients suitable for use in pediatric 3D-printed dosage forms [25,26,27]

Excipient class	Example excipients	Function	Suitability for pediatric 3D printing
Polymers (Film formers & binders)	Hydroxypropyl Methylcellulose (HPMC), Ethyl Cellulose (EC), Hypromellose Acetate Succinate (HPMCAS), Polyvinyl Alcohol (PVA)	• Provides mechanical strength and flexibility.	• Generally safe in pediatric formulations
		• Controls drug release.	• Well-tolerated in modified-release dosage forms
		• Enhances printability.	• Stable under FDM printing conditions
Plasticizers	Polyethylene Glycol (PEG 4000, 6000), Triethyl Citrate (TEC), Glycerol, Sorbitol	• Improves filament flexibility and processability	• PEG is widely used but requires intake monitoring
		• Prevents brittleness during extrusion and printing	• Triethyl citrate and sorbitol are safer alternatives for Pediatrics
Taste-masking agents	Sucralose, Mannitol, Xylitol, Cyclodextrins (β-cyclodextrin)	• Masks bitter drug taste	• Sweeteners like sucralose and mannitol improve compliance
		• Enhances palatability for pediatric patients	• Cyclodextrins can reduce drug bitterness and increase solubility
Surfactants & solubilizers	Poloxamers (Pluronic F68, F127), Sodium Lauryl Sulfate (SLS) (low conc.), Lecithin	• Enhances drug solubility	• Poloxamers are widely used in pediatric formulations
		• Improves dispersion in polymer matrices	• Lecithin is natural and well-tolerated
			• SLS should be used in minimal amounts to avoid GI irritation
Disintegrants	Croscarmellose Sodium, Sodium Starch Glycolate (SSG), Crospovidone	• Facilitates rapid disintegration in oral dosage forms	• Helps in formulating orodispersible and fast-dissolving films
			• Suitable for pediatric 3D-printed tablets
Stabilizers & anti-oxidants	Ascorbic Acid (Vitamin C), Sodium Ascorbate, Tocopherols (Vitamin E)	• Prevents oxidation and degradation of APIs	• Generally regarded as safe (GRAS) in pediatric applications
		• Enhances shelf stability of formulations	- Suitable for 3D-printed formulations requiring long-term stability
pH Modifiers & buffering agents	Sodium Bicarbonate, Citric Acid, Sodium Citrate	• Adjusts pH for drug stability	• Safe for pediatric use in controlled amounts
		• Controls dissolution rate	• Supports effervescent or dispersible formulations in 3D printing
Wetting agents	Polysorbates (Tween 20, Tween 80), Propylene Glycol (low conc.), Glycerol Monostearate	• Enhances drug dissolution	• Polysorbates and glycerol esters are safe alternatives
		• Reduces surface tension for uniform dispersion	• Propylene glycol should be limited in neonates due to toxicity risks

For 3D-printed pediatric formulations, excipient evaluation becomes even more complex due to the unique thermal and mechanical stresses involved in the printing process. Fused Deposition Modeling (FDM) 3D printing, one of the most widely explored techniques in pharmaceuticals, exposes drug-polymer mixtures to elevated temperatures (~100–250°C), raising concerns about excipient degradation, impurity formation, and loss of pharmacological activity [25]. Regulatory agencies require that excipients used in 3D printing undergo rigorous stability testing to assess their thermal degradation profiles, polymer-drug interactions, and potential formation of harmful byproducts [26]. Additionally, the high polymer content in 3D-printed formulations ( >50% w/w in some cases) raises concerns about long-term safety, particularly in pediatric populations. Prolonged exposure to high molecular weight polymers such as methacrylates, ethyl cellulose, or hydroxypropyl methylcellulose (HPMC) must be evaluated carefully, considering their potential effects on the developing gastrointestinal system and metabolic clearance. Another key regulatory challenge is establishing bioequivalence between 3D-printed and conventionally manufactured dosage forms. In traditional pharmaceuticals, bioequivalence studies ensure that different formulations of the same drug produce similar plasma concentration-time profiles, demonstrating comparable efficacy and safety. However, 3D-printed drugs may exhibit variations in dissolution rates, porosity, surface area, and drug release mechanisms, requiring new bioequivalence assessment protocols. Regulatory agencies must establish standardized testing criteria for 3D-printed pediatric medicines, including in vitro dissolution studies, in vivo pharmacokinetic evaluations, and accelerated stability testing. Ensuring batch-to-batch consistency and reproducibility in hospital or pharmacy-based 3D printing settings further complicates regulatory oversight, necessitating the development of real-time release testing (RTRT) methodologies for quality assurance [27].

Quality control and batch validation

Unlike traditional pharmaceutical manufacturing, where large-scale batch production ensures consistent quality control (QC) measures, 3D printing introduces new challenges in maintaining uniformity, reproducibility, and regulatory compliance. The batch-to-batch variability in 3D-printed medicines is significantly higher due to differences in printer calibration, filament composition, and environmental factors, which can impact the final product’s dosage accuracy, mechanical integrity, and dissolution profile. Since 3D-printed drugs are often produced in small batches or even as single-unit personalized doses, the conventional approach of testing a small sample from a batch may not be feasible. Instead, regulatory agencies emphasize the need for in-process monitoring and real-time release testing (RTRT) to ensure that every printed dosage form meets the required specifications [28].

One of the key challenges in 3D-printed pediatric formulations is maintaining dose uniformity within and between printed batches. Unlike tablet compression, where uniformity is ensured through thorough powder mixing and compaction, 3D printing depends on the controlled deposition of drug-polymer filaments or ink layers, which may vary based on extrusion consistency, temperature fluctuations, and print head stability. Small variations in nozzle temperature, extrusion speed, or layer adhesion can result in differences in API distribution, leading to dose variability. To address this, real-time spectroscopic analysis techniques, such as near-infrared (NIR) spectroscopy and Raman spectroscopy, have been proposed to monitor API dispersion, polymer melting behavior, and filament integrity during the printing process. Implementing inline spectroscopic sensors can help detect inconsistencies before the final dosage form is completed, reducing waste and ensuring high-quality products in every batch. Another critical issue is the lack of clear regulatory guidelines on acceptable batch sizes for decentralized 3D printing in hospitals, pharmacies, and compounding centres. Unlike large pharmaceutical manufacturers, where batches are validated through extensive QC procedures and stability studies, hospital-based 3D printing operates in a much smaller, demand-driven model. The question arises whether each printed drug should be treated as a separate batch or if a series of identical doses printed over a short period can be collectively validated. Regulatory agencies must establish clear criteria for batch definition, batch testing requirements, and stability assessment in decentralized settings. This is particularly important when pediatric medicines are printed on-demand in hospitals, as regulatory oversight must ensure that each individualized dose meets safety and efficacy standards before administration [29].

Good Manufacturing Practices (GMP) compliance

Good Manufacturing Practices (GMP) are essential for ensuring drug safety, efficacy, and consistency in pharmaceutical production. However, applying GMP regulations to 3D-printed medicines presents unique challenges, particularly due to the decentralized nature of on-demand printing in hospitals, pharmacies, and research institutions. Unlike traditional pharmaceutical manufacturing, where rigorous batch validation and controlled environments are standard, 3D printing introduces process variability due to differences in printer models, printing techniques, material sources, and operator expertise. To ensure regulatory compliance and patient safety, new GMP frameworks specific to 3D-printed pharmaceuticals must be developed, focusing on material traceability, equipment calibration, cleaning validation, and process standardization.

One of the most pressing GMP challenges in 3D printing is cleaning validation and cross-contamination risk. Unlike tablet presses, which are dedicated to specific drug formulations, 3D printers are often used for multiple APIs and formulations, raising the risk of residual drug carryover and cross-contamination [30]. Certain 3D printing techniques, such as fused deposition modeling (FDM), require polymeric filaments containing APIs to pass through the printer’s heated extruder, which may retain microscopic drug residues even after cleaning. Similarly, inkjet-based 3D printing methods that use liquid APIs must ensure complete removal of previous drug residues before switching formulations. GMP guidelines must address validated cleaning protocols, ensuring that all components in contact with the drug substance are thoroughly cleaned and tested before subsequent use. This includes nozzles, print heads, heating chambers, and drug reservoirs, all of which must meet predefined residual drug limits [31].

Another significant GMP concern is material traceability and printer calibration. Traditional pharmaceutical manufacturing relies on strict documentation of raw materials, active ingredients, and excipients, ensuring that each component meets pharmacopeial standards. However, 3D printing introduces new variables, such as filament production methods, polymer degradation during heating, and the impact of printing parameters on drug stability. For example, hot-melt extrusion (HME)-processed filaments used in FDM 3D printing must maintain consistent drug loading, uniform filament diameter, and mechanical properties to ensure reproducibility [32]. Any variations in extruder temperature, filament feed rate, or moisture content can alter the drug’s bioavailability, stability, and dissolution rate. To comply with GMP, pharmaceutical-grade filaments and inks must undergo rigorous quality control testing before use, with batch records, Certificates of Analysis (CoA), and stability data maintained for regulatory audits. Additionally, in-process and post-print testing must be standardized to ensure consistent quality and reproducibility in 3D-printed pediatric medicines. While conventional pharmaceutical manufacturing relies on batch testing for uniformity and stability, 3D printing requires innovative approaches, such as non-destructive testing methods like Raman spectroscopy, NIR spectroscopy, and computed tomography (CT) scanning. These techniques allow real-time monitoring of drug distribution, porosity, and mechanical strength without destroying the printed dosage form. Regulatory agencies must define clear acceptance criteria for printed drug uniformity, API content accuracy, and mechanical integrity, ensuring that every printed dose meets pharmacopoeial standards before administration. Ensuring sterility and stability of printed medications is another crucial GMP requirement. Many 3D-printed pediatric formulations, such as orodispersible films (ODFs) and rapidly dissolving mini-tablets, have higher moisture content and require specialized packaging to prevent degradation. Unlike conventional solid oral dosage forms, which undergo terminal sterilization or aseptic processing, 3D-printed medicines often lack defined sterilization guidelines. Regulatory agencies must establish clear protocols for microbial contamination prevention, sterility testing, and packaging requirements, particularly for hospital-based 3D printing, where production occurs outside traditional cleanroom environments [33, 34].

Taste masking approaches & efficacy evaluation

Taste plays a significant role in the acceptability and adherence to pharmaceutical formulations, particularly in oral dosage forms, as poorly tasting medications can negatively impact patient compliance, especially in pediatric and geriatric populations. Taste masking is therefore essential in formulation development, with the sensory perception of taste involving both the olfactory and gustatory systems. The gustatory system, located on the tongue, detects various taste sensations such as salty, sour, sweet, bitter, and umami, while the olfactory system is responsible for detecting volatile compounds that trigger the sense of smell. To effectively mask unpleasant tastes, it is crucial to understand the nature of poorly tasting compounds and apply appropriate strategies. These techniques vary based on the physicochemical properties of the active pharmaceutical ingredients (APIs) and excipients, and several methods can be integrated into pharmaceutical printing technologies to create taste-masked dosage forms, though research and patents in this area remain limited.

Use of Sweeteners and Flavors: One of the simplest and most widely applied techniques for taste masking is the addition of sweet-tasting excipients. These include natural sugars such as sucrose, glucose, and fructose, sugar alcohols like sorbitol, mannitol, and xylitol, or artificial sweeteners such as saccharin, aspartame, cyclamate, and acesulfame. In addition to masking the taste of bitter compounds, these sweeteners can also enhance patient compliance, especially when combined with Flavors that produce pleasant olfactory signals. For instance, volatile compounds like menthol or synthetic and natural Flavors (e.g., peppermint, citrus) can be incorporated into the formulation to further suppress undesirable tastes. However, it is important to note that the effectiveness of this technique may diminish over time due to the evaporation of volatile compounds during manufacturing or storage. Therefore, stability studies are crucial to ensuring long-term consistency of the taste masking effect.

Inclusion Complexes: Inclusion complexes, such as those formed with cyclodextrins, are widely used to entrap and mask the taste of bitter or unpleasant-tasting substances. Cyclodextrins can form inclusion complexes by encapsulating the drug molecule within their cyclic structure, preventing its direct contact with taste receptors on the tongue. Similarly, polyelectrolytes (both cationic and anionic polymers) can also be employed to encapsulate the bitter drug molecules, either in solution or within a solid dosage form. This method is particularly effective in masking strong-tasting compounds without altering the chemical properties of the drug. The inclusion complexes can be incorporated into the printed dosage form, providing an additional level of taste masking, as the bitter compounds are physically confined within the complex and are not easily released during oral administration.

Viscosity Modifiers: High-viscosity hydrophilic polymers, such as hydroxypropyl methylcellulose (HPMC), guar gum, and sodium alginate, can also be employed to mask taste. These polymers form a gel-like structure upon contact with saliva, slowing down the dissolution and hydration of the dosage form. By reducing the rate of disintegration and dissolution, the active ingredient has less opportunity to interact with the taste receptors on the tongue, thus diminishing the perceived bitterness. This method is especially useful in oral dosage forms like tablets or capsules, where slower release is desired to both enhance patient experience and control drug delivery over time [35].

Physical Barriers: Another effective method of taste masking is the use of barriers to slow or prevent the contact of the drug with saliva and taste receptors. These barriers can be formed both inside and outside the printed dosage form [36]. For example, coating the drug with an impermeable layer or incorporating it within a polymer matrix can delay the release of the active ingredient until it has passed beyond the oral cavity, thereby avoiding taste detection. Such barriers are commonly used in extended-release formulations, where the drug is gradually released over a longer period, reducing the likelihood of taste perception during administration [37].

The effectiveness of taste-masking strategies is typically assessed through various in vitro and in vivo testing methodologies. Advanced dissolution setups are often used to simulate the release profile of the drug and its interaction with saliva. These systems can measure the rate of drug release, which is critical for determining whether the masking agents are functioning as intended. Additionally, electronic tongues, which simulate human taste perception, can be used to evaluate the sensory properties of the formulation, providing objective data on the masking effect [38]. In vivo studies, such as the Brief-Access Taste Aversion (BATA) model, are used to assess the real-time response of the organism to the drug’s taste. This model exposes test subjects to a brief, controlled exposure to the bitter substance and then measures their aversive reactions. These results can provide valuable insight into the human taste response, which can be correlated with clinical acceptability [39].

Hot-Melt Extrusion for Filament Production

In the realm of 3D printing, particularly for pediatric applications, filament extrusion via hot-melt extrusion (HME) serves as a foundational step for producing suitable filaments. These filaments are required for Fused Deposition Modeling (FDM) 3D printing, a technology that holds significant potential for the personalized production of pharmaceutical dosage forms. Filament extrusion, a multi-step process, begins with the preparation of polymer blends containing active pharmaceutical ingredients (APIs). This step demands meticulous attention to various factors, such as polymer selection, API homogeneity, and process parameters, to ensure the desired quality attributes of the final product. A key recommendation from the U.S. Food and Drug Administration (FDA) is the adoption of Quality by Design (QbD) approaches for formulation and process development, which has been particularly impactful in the pharmaceutical melt extrusion sector [40, 41].

Challenges in filament quality control

In pediatric 3D printing applications, ensuring the uniformity of both filament diameter and API distribution is of utmost importance. The slightest inhomogeneities in either of these attributes can significantly impact the consistency and effectiveness of the printed dosage form, especially in lower-dose pediatric formulations. In typical hot-melt extrusion processes, extrudates are often milled or pelletized before further processing, but in FDM, the extruded filament is used directly for printing. As a result, any variability in diameter or API distribution directly translates into dosage inconsistencies, potentially violating pharmacopeial requirements for uniformity. This is particularly critical when dealing with pediatric medicines, where the doses are smaller, and even small variations can compromise the intended therapeutic effect. Therefore, precise control over filament diameter and API content distribution is essential to ensure compliance with uniformity of dosage unit monographs.

Powder feeding and material homogenization

A crucial aspect of the filament extrusion process is the feeding of polymers, excipients, and APIs into the twin-screw extruder [42]. Twin-screw extruders, unlike single-screw machines, operate with a partially filled barrel, and as such, the material flow is influenced by the feeding rate of the feeder system. Factors such as Specific Feed Load (SFL) and Residence Time Distribution (RTD) are significantly impacted by the efficiency and precision of the feeding process. To minimize fluctuations and ensure uniform mixing, various dosing devices, such as vibrating trays or loss-in-weight gravimetric feeders, are employed [43]. These devices allow for precise control over the material flow, helping to maintain a consistent feed rate. The correct choice of feeder is crucial for managing the flow properties of the materials being extruded, especially when dealing with low dosing rates or poor flow characteristics [44].

Melting process efficiency in filament extrusion

The success of the hot-melt extrusion process is closely linked to the melting efficiency of the polymer materials. Polymers with low melt viscosities and high thermal conductivities generally exhibit more efficient melting, leading to a more homogeneous melt that is easier to extrude. The extruder’s design, including screw configuration and the presence of kneading elements, also plays a pivotal role in ensuring that the polymer melts uniformly and flows smoothly through the extruder barrel. Inadequate melting or poor mass flow can lead to blockages or increased torque within the extruder, potentially affecting the overall process efficiency and product quality.

To further improve the homogeneity of the filament, particularly in terms of diameter, a melt pump is often used. This device stabilizes melt fluctuations by metering the flow of molten material at a constant rate, ensuring consistent pressure and temperature throughout the extrusion process. The use of such devices becomes crucial in pediatric formulations, where min variations in diameter can result in significant differences in API content, thus impacting the dosage uniformity.

Post-extrusion cooling and filament diameter control

After extrusion, the cooling process plays a critical role in maintaining filament integrity. Pharmaceutical-grade polymers, often water-soluble and API-laden, require a cooling method that prevents contamination or dissolution of the filament. Unlike conventional FDM filaments like acrylonitrile butadiene styrene (ABS) or polyether ether ketone (PEEK), which can be easily cooled using water baths, pharmaceutical filaments require either passive cooling via conveyor belts or active cooling systems like air rings or tunnels. These methods prevent the excessive swelling of the polymer material and ensure that the final filament diameter remains consistent. A common phenomenon during extrusion known as “die swell” can complicate the extrusion process. Die swell refers to the expansion of the molten polymer beyond the die’s design diameter due to the relaxation of polymer chains after exiting the extrusion die. This expansion can result in a filament with a larger diameter than intended, which can be detrimental to the precision required in pharmaceutical applications. To mitigate die swell, several strategies can be employed, such as increasing the temperature at the die or using a pulling unit to draw the filament to the desired diameter. The speed of the pulling unit is adjustable and plays a key role in achieving the target diameter, which is crucial for the consistency of the final printed dosage forms. For pediatric formulations produced via FDM 3D printing, the successful extrusion of filaments requires an intricate balance of factors, including material selection, feeding precision, melting efficiency, and post-extrusion cooling. To meet the rigorous standards for dosage uniformity and API content, process optimization through a QbD approach is essential. Through careful management of process variables and continuous monitoring of key quality attributes, the production of high-quality and consistent pharmaceutical filaments for pediatric applications is achievable. Given the potential of 3D printing to revolutionize pediatric drug delivery, particularly for personalized treatments, ongoing advancements in the hot-melt extrusion process and QbD methodologies will be critical to ensuring safe and effective outcomes (Fig. 1).

Fig. 1.

The four key components in the filament extrusion process: a) Gravimetric feeders for precise material dosing, b) Cooling via ring air-knives to stabilize the filament temperature, c) Tripton triple-axis laser micrometer for accurate diameter measurement, and d) Twin-screw extruders for efficient melting and extrusion of polymer blends.

Characterization of API-Loaded Filaments

The successful development and optimization of filaments for pharmaceutical applications require thorough evaluation using both offline and inline analytical techniques. These methods allow for a comprehensive understanding of the material properties, drug release behaviour, and process control, ensuring that the final product meets the desired quality attributes for clinical use.

Offline characterization

Offline characterization of filaments primarily involves visual and instrumental assessments, which are vital for evaluating physical attributes and performance under varying conditions.

Visual Inspection: A simple yet effective method for preliminary evaluation of filament quality is visual inspection. This process can help identify any potential degradation, such as changes in color or the formation of crystalline structures in the active pharmaceutical ingredients (APIs), especially when high drug loadings or thermally sensitive APIs are involved. Any visible signs of degradation can indicate instability, which requires further investigation [45].

Mechanical Property Evaluation: The mechanical properties of filaments, which include tensile strength and flexibility, are essential for determining their feedability during the extrusion process. Over time, these properties can change due to enthalpy relaxation or the hygroscopic nature of the excipients, which can absorb moisture. The absorbed water acts as a plasticizer, reducing the glass transition temperature (Tg) of the polymeric matrix. As a result, this can not only alter the mechanical properties but also impact the stability of the API, leading to potential degradation. Thus, it is important to quantify water absorption and its effects on the filament’s mechanical and chemical stability.

In Vitro Dissolution Testing: To assess the release profile of the drug from the filament or final tablet, in vitro dissolution studies are carried out. These studies follow compendial monographs to determine the amount of API dissolved over a specific time, thus providing insights into the release behaviour and performance of the formulation. Such tests are crucial for understanding the bioavailability and controlled-release capabilities of the drug delivery system [46].

HPLC Analysis for Content Uniformity: High-Performance Liquid Chromatography (HPLC) is widely employed to determine the content uniformity and to analyze the distribution of the drug within the filaments and tablets. This method allows for precise quantification of the active ingredient and ensures consistent drug content across the formulation. HPLC is also critical for the detection of related substances or degradation products, providing insights into the stability and quality of the filament [47].

Inline characterization

Inline characterization tools provide real-time, non-destructive analysis of filament properties during the Hot Melt Extrusion (HME) process. These technologies are instrumental in ensuring consistent quality control, process optimization, and real-time monitoring, which is crucial for pharmaceutical manufacturing.

In-Line Spectroscopy: Various spectroscopic techniques are commonly employed to characterize the filaments during the extrusion process. UV-Vis spectroscopy has proven effective in monitoring the concentration of active ingredients in the polymer matrix. Studies have demonstrated its ability to quantify API content, such as in the case of estradiol, estriol, and ibuprofen formulations [48]. In particular, the tool can monitor cleaning-in-place strategies, ensuring the effective removal of residual APIs from equipment. Furthermore, UV-Vis spectroscopy has been applied to determine API load in solid dispersions, with linearity ranges varying based on formulation specifics. For example, carbamazepine showed linearity from 5–30%, while theophylline was linear within 2.5–10%. The simplicity of univariate data analysis, combined with a 1 Hz measurement frequency, makes UV-Vis spectroscopy a reliable tool for real-time data acquisition. NIR spectroscopy is widely used for studying drug–polymer interactions and validating continuous API quantification methods during HME processing. NIR enables real-time monitoring of the drug concentration in the filament and can help in adjusting the formulation in the extrusion die. Raman spectroscopy, coupled with NIR, has been used for real-time analysis of solid-state characteristics, such as distinguishing between solid solutions and solid dispersions based on Raman peak profiles [49, 50].

In-Line Rheometry: Rheological properties, such as viscosity and flow behaviour, play a crucial role in the extrusion process, influencing both the quality and the efficiency of filament production. In-line rheometry provides real-time measurements of the torque and pressure within the extruder, giving valuable insights into the effects of drug load and formulation ingredients on the extrusion process. Continuous rheological monitoring aids in optimizing extrusion parameters, ensuring the proper formation and consistency of the filaments. Furthermore, it allows for immediate corrective actions to maintain the desired filament properties.

Optical Coherence Tomography (OCT): OCT is a non-invasive imaging technique that is particularly useful for examining the surface properties and thickness of filaments, especially when produced via processes like hot-melt co-extrusion. OCT allows for precise measurements of coating layers and ensures uniformity in the filament’s structure. For example, OCT has been applied to evaluate the integrity of core/membrane interfaces and membrane thickness in formulations containing progesterone and ethylene vinyl acetate. This technology helps ensure the final product’s consistency and quality by providing high-resolution, real-time imaging of the filament’s surface and internal structure. Both offline and inline characterization techniques are crucial for optimizing the production of API-loaded filaments used in pharmaceutical applications. Offline methods such as visual inspection, mechanical property analysis, dissolution testing, and HPLC play an important role in ensuring the quality and stability of the filaments. Meanwhile, inline techniques like UV-Vis and NIR spectroscopy, in-line rheometry, and Optical Coherence Tomography enable real-time monitoring and control of the extrusion process, enhancing process understanding and enabling corrective actions to ensure consistent quality. The combination of these analytical tools allows for a holistic approach to filament characterization, which is essential for developing high-quality, reliable drug delivery systems.

Characterization of the Solid State in Drug-Polymer Systems

The characterization of solid-state properties is a critical aspect of pharmaceutical development, particularly for active pharmaceutical ingredients (APIs) incorporated into polymer matrices. While some analytical tools can determine specific aspects of solid-state properties, other techniques offer deeper insights into the material’s behaviour and characteristics. The solid-state form of an API significantly influences the performance of the final dosage form, especially in terms of dissolution rate, bioavailability, and stability.

Impact of Solid-State Properties on API Performance: Poorly soluble APIs, which constitute a significant proportion of drug candidates, often present challenges in achieving adequate bioavailability. One strategy to address this issue involves formulating the API as an amorphous solid dispersion (ASD), where the crystalline structure of the drug is disrupted, resulting in molecular dispersions stabilized within a polymer matrix. This amorphization enhances solubility and dissolution rates, improving bioavailability. Conversely, APIs can also be incorporated into filaments while retaining their crystalline structure. This structural integrity impacts the mechanical and rheological properties of the filaments, which in turn influence the printability of final dosage forms, especially in technologies such as fused deposition modeling (FDM). The presence or absence of crystalline structures, therefore, plays a pivotal role in process development, quality control, and stability assessments.

Crystallinity Assessment in FDM-Printed Dosage Forms: Assessing the degree of crystallinity in FDM filaments and final dosage forms is essential for ensuring the robustness of the manufacturing process. While advanced in-line measurement systems are emerging, traditional techniques such as differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) remain the most commonly employed methods. These techniques are effective in determining the degree of crystallinity and phase transitions in the material. However, their sensitivity to detect small crystalline fractions in predominantly amorphous systems may be limited. Polarized light microscopy is another valuable technique that can detect small crystalline fractions in ASD formulations. Although highly sensitive, this method lacks the ability to provide quantitative data or differentiate between crystalline and amorphous components. For FDM-printed dosage forms, it is imperative to consider the entire manufacturing process when evaluating crystallinity, from initial formulation to intermediate and final products.

Factors Influencing Solid-State Stability and Transformation: The stability of ASDs is influenced by the solubility and miscibility of the API within the polymer matrix. During manufacturing, the thermal and mechanical energy applied facilitates molecular dispersion and reduces the size and number of crystal nuclei. However, excessive energy input can lead to unintended recrystallization or phase separation, negatively impacting the stability and performance of the dosage form. Maintaining the solid-state properties of ASDs during storage and shipment is also critical. For FDM-printed dosage forms, an additional layer of complexity arises due to the second heating cycle during the printing process. The thermal impact during printing can potentially impair the chemical stability of the formulation and induce recrystallization of the API. These transformations can compromise the product’s efficacy, shelf life, and patient outcomes [51].

Analytical Techniques for Solid-State Characterization: Differential scanning calorimetry (DSC) is extensively utilized to evaluate the thermal behaviour of APIs and polymer matrices, providing insights into glass transition temperatures, melting points, crystallization events, thermal stability, and the physical state of materials. X-ray powder diffraction (XRPD) is another key technique, effectively distinguishing between crystalline and amorphous phases, though its sensitivity to detect min crystalline fractions in predominantly amorphous systems is limited. Polarized light microscopy complements these methods by identifying small crystalline traces within amorphous matrices, albeit without quantitative capabilities or selectivity [52, 53]. Fourier-transform infrared spectroscopy (FTIR) is valuable for studying molecular interactions between APIs and polymers, as well as phase transitions, while thermo gravimetric analysis (TGA) monitors thermal stability and mass changes that could indicate degradation or volatilization, often used alongside DSC. Dynamic mechanical analysis (DMA) assesses the mechanical properties of materials, such as storage and loss modulus, which are critical for understanding filament performance during FDM printing. Together, these analytical techniques address the multidimensional challenges of solid-state characterization in drug-polymer systems. For FDM-printed dosage forms, controlling crystallinity is crucial to ensure product quality and performance. By integrating thermal, mechanical, and structural analyses, robust formulations can be developed to maintain stability during manufacturing, storage, and patient use, emphasizing the need for an end-to-end approach to optimize the solid-state properties of drug-polymer systems for desired therapeutic outcomes [54].

Towards Pharmaceutical-Grade 3D Printing

The adaptation of FDM printing for pharmaceutical manufacturing requires a multidisciplinary approach involving mechanical engineering, material science, and regulatory expertise. By addressing current limitations in printer design, feeding mechanisms, and safety protocols, it is possible to develop GMP-compliant 3D printers capable of producing high-quality, personalized pharmaceutical products. These advancements would not only improve the efficiency of drug production but also expand the potential of personalized medicine through on-demand manufacturing at the site of care. Fused Deposition Modeling (FDM) has long been an established technology, primarily used in consumer and industrial sectors. Despite its state-of-the-art status, significant challenges arise when attempting to adapt this technology for pharmaceutical manufacturing. While the industrial sector primarily focuses on geometric precision, pharmaceutical applications demand higher standards for dosing precision, quality control, and compliance with Good Manufacturing Practices (GMP). Existing off-the-shelf 3D printers fall short in addressing these stringent requirements, as they lack mechanisms to verify the amount of active pharmaceutical ingredients (APIs) processed. This gap in quality assurance limits their application in pharmaceutical settings, where the production process must be both efficient and verifiable.

Challenges with current FDM printers in pharmaceuticals

Unlike traditional pharmaceutical manufacturing, which allows for destructive testing, the slow pace and small batch sizes of 3D-printed dosage forms demand non-destructive, in-line quality control to ensure uniform distribution of active pharmaceutical ingredients (APIs). Most consumer-grade 3D printers are ill-suited for pharmaceutical applications due to contamination risks, lack of verification mechanisms for API uniformity, and non-compliance with Good Manufacturing Practice (GMP) guidelines. These printers often feature exposed mechanical components, lubricated moving parts, and complex geometries that are difficult to clean, increasing the risk of cross-contamination. Additionally, APIs, particularly toxic or volatile compounds, pose significant risks to operators, yet many existing designs lack critical safeguards such as enclosed systems, air filtration, and surfaces made from cleanable, contaminant-free materials [55, 56].

Redesigning FDM printers

To comply with Good Manufacturing Practice (GMP) standards and address the specific needs of pharmaceutical applications, significant adjustments are required in the design and operation of Fused Deposition Modeling (FDM) 3D printers. Below are the critical areas for redesign to ensure that FDM printers are suitable for pharmaceutical manufacturing, illustrated in the flow chart (Fig. 2).

Fig. 2.

Flowchart illustrating “Redesigning FDM printers for GMP-compliant pharmaceutical manufacturing”.

Motion system and printer architecture

Conventional Cartesian printers, which use linear movement along the x-, y-, and z-axes, are commonly used in general applications but present contamination risks when adapted to pharmaceutical environments. For instance, exposed mechanical components, lubricated moving parts, and unsealed axes can lead to contamination of the printed products, making these printers unsuitable for cleanroom conditions. To mitigate these risks, the design must undergo a fundamental overhaul.

Recommended design improvements:

Segregation of Subsystems: In GMP-compliant printers, the subsystems (material handling, processing, and motion systems) should be isolated into separate, controlled environments. This approach ensures the avoidance of cross-contamination and maintains a particle-free and sanitized atmosphere throughout the printing process.

Isolated Print Chamber: The print chamber should be isolated from moving components to prevent contamination. Additionally, all surfaces in the chamber should feature simple, smooth geometries without sharp angles or joints, which can be difficult to clean and may harbor contaminants.

Enhanced User Safety: Given the potential toxicity of certain Active Pharmaceutical Ingredients (APIs), printers should incorporate safety features like air filtration systems and hermetically sealed enclosures. These elements help protect operators from exposure to hazardous substances during the printing process.

Feeding mechanism, filament design, and storage

Traditional FDM printers rely on counter-rotating rollers with gear wheels to transport filament, an approach that is ineffective for pharmaceutical-grade filaments, which tend to be more brittle and prone to deformation. Such systems are prone to filament slippage, breakage, and contamination, which can lead to inconsistent material deposition and product failure.

Proposed Solutions:

Smaller Filament Units: Replacing large spools with smaller, encapsulated filament units reduces the chances of storage instability and helps minimize the risk of cross-contamination during material handling. These units can be designed with controlled storage conditions, such as those seen in pharmaceutical blister packaging.

Revamped Feeding Mechanism: Instead of using roller- or gear-based systems, the feeding mechanism should be redesigned to incorporate piston-driven mechanisms, which reduce slippage and filament breakage. This ensures a more consistent and controlled material feed, essential for precise dosage formulation.

Hermetically Sealed Storage: To prevent contamination and degradation, filament storage should be hermetically sealed and stored under strictly controlled conditions. This would preserve the integrity of the pharmaceutical-grade filaments, ensuring their quality and safety during use.

Hotend and coldend modifications

Traditional hotend designs prioritize high throughput and speed, often subjecting materials to extreme temperatures. However, this is problematic for pharmaceutical-grade materials, as many APIs are thermolabile and degrade under high heat. Additionally, traditional air-cooled coldends, with their complex geometries and cooling fins, pose cleaning challenges and increase the risk of contamination.

Optimized Design Features:

Uniform Heat Input: To prevent thermal degradation of sensitive APIs, the hotend should be engineered to provide a uniform heat distribution. This minimizes thermal stress on the materials, ensuring their stability and preserving the efficacy of the APIs during the printing process.

Water-Cooled Coldends: Transitioning from air-cooled to water-cooled coldends will enhance temperature control, allowing for more precise management of the filament’s temperature during extrusion. This modification will also improve cleanability, reducing the risk of cross-contamination between batches.

Modular Print Head Design: The print head should be modular and easily demountable, similar to the designs used in hot-melt extruders. This will facilitate thorough cleaning between uses, reducing the risk of cross-contamination between different drug formulations and ensuring GMP compliance.

By addressing these critical design areas, FDM 3D printers can be adapted to meet the stringent requirements of pharmaceutical manufacturing, ultimately ensuring the production of safe, effective, and high-quality pharmaceutical products (Fig. 2).

Ensuring GMP compliance and operator safety

To meet Good Manufacturing Practice (GMP) standards, all components of a 3D printer that come into contact with Active Pharmaceutical Ingredients (APIs) must be constructed from approved materials that are both resistant to cleaning agents and durable enough to endure repeated cleaning cycles without degradation. These materials should be free of joints, undercuts, and other complex geometries that can harbor contaminants, ensuring ease of cleaning and minimizing the risk of cross-contamination. Additionally, the design of the printer must be such that any moving parts, materials, or residues that come into contact with the APIs are properly contained and sanitized after each use. In terms of operator safety, pharmaceutical-grade 3D printers must incorporate advanced protective features to prevent harmful exposure to APIs and their vapors. Air filtration systems are essential to capture and neutralize hazardous particles or volatile compounds that may be released during the printing process, protecting workers from potential inhalation hazards. Furthermore, printers should be equipped with enclosed print chambers that prevent direct exposure of APIs to operators, thus reducing the risk of accidental contact with toxic or potentially harmful substances. Automated monitoring systems can enhance safety by detecting contamination risks in real time and triggering alerts or corrective actions to mitigate such risks, ensuring a safe working environment and maintaining the integrity of the pharmaceutical products being produced. These measures collectively contribute to not only compliance with GMP guidelines but also to a safer and more efficient pharmaceutical manufacturing process.

Quality control and process monitoring

3D printing has gained significant attention in the pharmaceutical industry for the production of personalized medications, with the potential to revolutionize dosage forms and delivery methods. However, despite its promise, 3D printing, particularly using Fused Deposition Modeling (FDM) technology, has faced several challenges, primarily related to process reliability, quality control, and accurate dosing of Active Pharmaceutical Ingredients (APIs). These limitations have hindered the widespread adoption of 3D printing in pharmaceutical manufacturing, as the technology has been associated with frequent print failures, poor resolution, anisotropic mechanical properties, slow production speeds, and unsatisfactory surface finishes. The root cause of these issues lies in the lack of robust process and quality control mechanisms, a concern that remains prevalent in the field today, especially for applications requiring precise dosing, such as pediatric formulations.

Although some progress has been made in implementing inline quality control in 3D printing processes—especially in technologies like Selective Laser Sintering (SLS) or Selective Laser Melting (SLM)—these approaches are still in experimental stages in FDM-based systems. These methods mainly focus on thermal monitoring (e.g., melt pool analysis in SLS) and layer-by-layer monitoring, but they do not adequately address the unique quality attributes needed for pharmaceutical manufacturing. Specifically, the measurement of chemical content, solid-state characteristics, and API distribution is critical in ensuring the safety and efficacy of 3D printed pharmaceutical products. For FDM to be considered for clinical-scale pharmaceutical manufacturing, there is a pressing need for improved quality control systems that focus not only on process parameters but also on product integrity and API content accuracy.

Key Parameters for In-Process Control

To establish a reliable and reproducible 3D printing process, it is crucial to monitor various in-process parameters. These can be broadly categorized into three main groups: machine parameters, extruded material parameters, and chemical analysis of the printed product [57].

Machine Parameters: Machine parameters, such as the motor and heater current, temperature of the nozzle and cooling zones, and vibrations during the printing process, can be controlled via industrial control systems without the need for additional sensors. These parameters are critical for ensuring consistent print quality but are not sufficient for monitoring the chemical attributes of the printed product. For example, the motor current can be used to detect issues like a blocked nozzle, which can lead to under-extrusion and chemical degradation of the printed material. However, the reliance on these indirect parameters necessitates comparative data from well-understood processes to ensure that they can provide accurate quality assurance [58, 59].

Extruded Volume and Mass Monitoring: Dedicated sensors integrated into the 3D printing system can offer a more direct and reliable method of quality control. Monitoring the extruded volume or mass of the filament as it is being printed is crucial for ensuring that the final dosage form contains the intended amount of API. This can be achieved by using optical systems to measure the distance between the nozzle and the printed object, which can detect issues like under-extrusion. Cameras can also be employed to monitor the movement and quality of the filament, ensuring that the printing process remains consistent throughout. Additionally, the use of integrated balances to measure the actual mass of the printed filament provides further accuracy, ensuring that each printed dosage meets the required specifications. Such in-process controls are especially important for producing accurate dosages in personalized medicines, where small deviations in API content could lead to significant variations in therapeutic outcomes [60].

Non-Destructive Chemical Analysis: The ability to perform non-destructive chemical analysis on the printed product is one of the most promising advancements for 3D printed pharmaceuticals. Real-time chemical analysis can ensure that the active ingredient is incorporated into the final dosage form in the correct amount and that the solid-state properties of the API are preserved during the printing process. Various spectroscopic techniques, such as Near-Infrared (NIR) chemical imaging and Raman spectroscopy, have been explored in the literature as potential tools for monitoring the API content and solid-state characteristics of 3D printed pharmaceuticals. For instance, NIR imaging can be used to quantify the amount of API in the printed dosage form, while Raman spectroscopy has been applied to investigate the amorphous and crystalline forms of drugs like fenofibrate in solid oral dosage forms. These techniques enable the monitoring of the drug’s chemical structure and distribution without damaging the product, offering significant advantages over traditional destructive testing methods [61, 62].

The integration of advanced sensors and in-process monitoring systems has the potential to enhance the reliability and quality of 3D printed pharmaceuticals, but several challenges remain [63]. Key obstacles include the high cost of sophisticated analytical equipment, which may be impractical for smaller-scale or point-of-care settings, and the logistical difficulties of incorporating non-destructive chemical imaging systems into existing 3D printing platforms [64]. Despite these challenges, there are significant opportunities for improvement. As sensor technologies become more affordable and compact, real-time quality control can become more accessible, even in decentralized production environments [65]. Additionally, implementing feedback loops based on sensor data to adjust printing parameters in real-time can enhance manufacturing efficiency by ensuring that each dosage form meets the required specifications, minimizing waste, and optimizing yields [66]. This is especially vital for producing personalized medicines at the point of care, where accuracy and speed are critical for patient safety and efficacy [67]. Ultimately, for 3D printing to realize its full potential in pharmaceutical manufacturing, it is crucial to adopt a comprehensive approach that includes monitoring machine parameters, measuring extruded volumes, conducting real-time chemical analysis, and incorporating continuous feedback systems [68]. With ongoing advancements in sensor technology, data analytics, and spectroscopic techniques, pharmaceutical 3D printing can overcome current limitations, offering a reliable, scalable solution for producing high-quality, personalized medications tailored to patient needs [69].

Advancements in 3D-Printed Pediatric Drug Delivery Systems

The potential for 3D printing in pediatric drug delivery is vast, offering opportunities to create tailored, patient-specific formulations that improve medication adherence and therapeutic outcomes. However, the development of 3D-printed pediatric dosage forms such as mini-tablets, orodispersible films, and polypills presents challenges, particularly in achieving the required precision and ensuring the stability and accuracy of drug dosing. Advances in 3D printing technologies, including improvements in print resolution and customization options, will likely continue to enhance the feasibility and appeal of these formulations. The application of 3D printing technologies in pediatric drug delivery systems has gained considerable attention due to the potential for creating personalized, patient-centric formulations. However, the exploration of solid dosage forms suitable for children remains limited, with only a few options having been investigated for their acceptability and practical use. These include mini-tablets, orodispersible films, orodispersible tablets, and capsules. Although 3D printing offers significant flexibility in design, particularly in terms of geometry and patient-specific customization, its current applications in pediatric dosage forms are primarily restricted to these specific formulations. Moving forward, more clinical trials and regulatory studies are needed to validate the safety, efficacy, and patient acceptability of 3D-printed pediatric medicines. The integration of 3D printing into pediatric pharmaceutical care holds promise for a new era of personalized medicine, where dosage forms are not only effective but also tailored to meet the unique needs of each child. This section provides a comprehensive overview of these dosage forms and highlights the unique advantages and challenges associated with their development via 3D printing technologies.

Mini-Tablets: Precision and Flexibility in Pediatric Dosing: Mini-tablets, typically defined as tablets with diameters of less than 4 mm, are a promising solid dosage form for pediatric patients. These small-sized tablets have demonstrated good acceptability among neonates, infants, and children, particularly when designed with diameters as small as 2 mm. However, the manufacturing of such small objects via 3D printing presents significant challenges, especially when using Fused Deposition Modeling (FDM) printing, where resolution limitations make it difficult to achieve the required dimensional accuracy. The typical nozzle diameter for FDM processes is around 0.4 mm, meaning that mini-tablets with diameters as small as 2 mm are only five times larger than the nozzle diameter. This small scale creates issues with surface quality and mechanical stability during printing, as the cooling time for the material between nozzle passes is very brief, potentially leading to poor layer adhesion. To address these challenges, several strategies have been proposed. Reducing print speed has been shown to enhance dimensional accuracy and surface quality, although this may come at the cost of reduced productivity. Another approach involves modifying the order of printing, such as using layer-wise printing instead of sequential printing, which may reduce cooling time errors but introduces other potential printing defects, such as stringing or blobbing. The accuracy of dose delivery is particularly critical for mini-tablets, as the small size of the tablets means that even minor printing defects can result in significant deviations in drug content. Studies by Krause et al. have demonstrated that as tablet size decreases, the variation in tablet mass becomes more pronounced, highlighting the importance of precision in the manufacture of mini-tablets.

Additionally, 3D printing offers significant advantages in geometric flexibility, allowing for the customization of tablet shapes, colors, and sizes according to individual patient preferences. This customization may improve patient compliance, particularly in pediatric populations, by making the medication more appealing and easier to ingest. For example, Scoutaris et al. successfully replicated the shape and design of chewable candies such as hearts, rings, and animals, using 3D printing to manufacture drug-loaded formulations. This approach has shown potential for improving the palatability of pediatric medicines and enhancing patient adherence to treatment regimens.

Layer-Wise Polypills: Addressing Polypharmacy in Pediatric Patients: Another innovative application of 3D printing is the creation of polypills, which combine multiple active pharmaceutical ingredients (APIs) into a single dosage form. Using layer-wise FDM printing, different APIs can be printed into separate compartments of a single dosage form, which allows for customized, patient-specific formulations. This method overcomes one of the major limitations of traditional tablet manufacturing, which requires compatibility between the APIs in a single mixture. In contrast, the layer-based approach in 3D printing enables the separation of incompatible compounds within the same tablet, offering an effective solution for pediatric patients requiring polypharmacy.

The flexibility offered by 3D printing also makes it possible to tailor the dosage form to the exact needs of individual pediatric patients. However, optimizing the print settings and understanding the underlying processes are critical to ensuring the quality and stability of the final product. Despite these challenges, the ability to create complex, multi-layered polypills opens up new possibilities for personalized pediatric treatments [70].

Orodispersible Films: A Convenient and Effective Delivery System: Orodispersible films (ODFs) have emerged as an ideal drug delivery system for pediatric patients due to their ease of administration and rapid dissolution in the mouth. These films are particularly suited for children who have difficulty swallowing traditional tablets or capsules. The European Pharmacopoeia defines orodispersible films as solid oromucosal preparations designed for quick dispersion in the oral cavity, delivering active substances efficiently. One of the key benefits of ODFs is the ability to modify the dosage through various strategies, including altering the API concentration, adjusting film thickness, or cutting the films to the desired size [71]. While cutting films can be an effective method for dose adjustment, it introduces challenges related to material waste and the potential for human error. Alternatively, 3D printing provides a precise, waste-free approach for manufacturing orodispersible films [72]. Several studies have demonstrated the feasibility of 3D printing ODFs using FDM technology. For instance, Jamróz and colleagues successfully printed ODFs containing aripiprazole, while Ethezazi et al. printed multi-layered films with different APIs, such as paracetamol and ibuprofen, and taste-masking agents. In a separate study, Cho et al. utilized FDM to prepare an orodispersible film containing the poorly water-soluble drug olanzapine. These studies underscore the potential of 3D printing to produce pediatric-friendly dosage forms with the necessary mechanical properties for robust handling and accurate dosing. A particularly interesting advancement in 3D-printed ODFs is the development of bi-layer films, where one layer contains a mucoadhesive polymer such as chitosan, while the other layer contains the drug [73]. This design not only enables unidirectional drug release but also improves the film’s ability to adhere to the mucosal surface, enhancing bioavailability. Though the customization of dose via 3D printing for ODFs has not been fully explored in clinical studies, the existing research demonstrates sufficient mechanical integrity and dosing accuracy, suggesting the feasibility of using FDM 3D printing for pediatric applications [74].

Regulatory Adaptations Needed for 3D-Printed Pediatric Medicines

The integration of 3D printing in pediatric drug manufacturing has the potential to revolutionize personalized medicine by enabling on-demand production of age-appropriate, patient-specific dosages. However, current regulatory frameworks are largely designed for traditional pharmaceutical manufacturing, creating a need for updated guidelines that accommodate the unique characteristics of 3D-printed pediatric medicines. To ensure the safe and effective implementation of this technology, regulatory agencies must adapt and expand existing regulations in several key areas, including decentralized 3D printing, GMP compliance, pediatric-specific formulation standards, and global harmonization efforts. These regulatory advancements will be critical in establishing quality, safety, and efficacy standards for 3D-printed pediatric pharmaceuticals while ensuring compliance across diverse healthcare settings [75, 76].

One of the most promising applications of 3D printing in pediatric medicine is its use in hospital and pharmacy settings to create customized drug formulations tailored to individual patient needs. Unlike traditional centralized drug manufacturing, where pharmaceutical products are mass-produced under strict regulatory oversight, decentralized 3D printing allows for on-site production, significantly reducing wait times for personalized medications. However, this shift from industrial-scale to point-of-care manufacturing introduces several regulatory challenges, including quality control, process validation, batch-to-batch consistency, and storage stability. Regulatory agencies such as the FDA and EMA must develop specific guidelines that address the unique risks and benefits associated with decentralized 3D printing in clinical environments. One major challenge is ensuring uniformity and reproducibility in 3D-printed drug formulations. Since each printed dose may be unique, regulatory agencies need to establish standardized protocols for quality assessment, including real-time release testing, spectroscopic analysis, and automated verification systems to confirm drug content, dissolution rates, and stability. Furthermore, hospitals and pharmacies using 3D printing for pediatric formulations must comply with strict sterility requirements to minimize contamination risks. Unlike large-scale pharmaceutical facilities, where GMP compliance is monitored through extensive batch validation, hospital-based 3D printing units may require modified GMP guidelines that account for smaller batch sizes and real-time customization. Additionally, regulatory oversight mechanisms must be developed to monitor and audit hospital and pharmacy-based 3D printing operations, ensuring they meet the same safety and efficacy standards as traditional pharmaceutical manufacturing. Good Manufacturing Practices (GMP) are essential for ensuring consistent product quality, safety, and efficacy in pharmaceutical manufacturing. While GMP regulations have been well-defined for traditional drug production, 3D printing introduces new variables that require modifications to existing regulatory frameworks. One key consideration is printer-specific validation, as different 3D printing technologies (e.g., Fused Deposition Modeling, Selective Laser Sintering, Inkjet Printing) exhibit varying levels of precision, reproducibility, and material compatibility. Regulatory agencies need to develop standardized validation protocols that assess the accuracy, reliability, and repeatability of each 3D printing platform used in pharmaceutical applications [77, 78].

Another critical aspect of GMP adaptation is risk assessment and process control. Unlike traditional batch manufacturing, where entire production runs can be tested and validated before distribution, 3D printing produces medications in a layer-by-layer manner, potentially leading to batch-to-batch variability. To mitigate these risks, regulatory agencies should require in-line monitoring systems, such as Raman spectroscopy, near-infrared (NIR) analysis, and machine learning-based quality assessment tools, to verify drug content, layer uniformity, and mechanical integrity during the printing process. Additionally, guidelines must be established for equipment calibration, raw material traceability, and cleaning validation, ensuring that 3D printers used in drug manufacturing operate within acceptable quality thresholds. Furthermore, GMP compliance for 3D-printed pediatric medicines must address the unique thermal and mechanical stresses involved in printing drug-loaded polymers. Unlike conventional tablets, which undergo compression or wet granulation, 3D-printed formulations may require higher processing temperatures that could impact drug stability and excipient interactions. Regulatory agencies should establish GMP protocols that include pre-formulation risk assessments, evaluating heat sensitivity, polymer degradation, and active ingredient dispersion. By integrating real-time monitoring, equipment validation, and process-specific risk assessments, regulatory bodies can ensure that 3D-printed medicines maintain the same high standards of safety and efficacy as conventionally manufactured pharmaceuticals [79, 80].

Pediatric formulations present unique challenges due to differences in physiology, metabolism, and patient compliance. Children often require modified drug dosages, taste-masked formulations, and age-appropriate delivery methods to ensure effective and safe treatment. Regulatory agencies should introduce specific 3D printing guidelines that address key pediatric considerations, including swallowability, taste-masking strategies, and bioavailability enhancements [81].

Swallowability is a major concern for pediatric patients, as many children struggle with large or poorly textured dosage forms. 3D printing enables the design of smaller, easier-to-swallow mini-tablets, orodispersible films (ODFs), and chewable formulations, but regulatory agencies must ensure that these novel dosage forms meet established safety and efficacy criteria [82]. Guidelines should specify acceptable tablet sizes, disintegration times, and mechanical properties that align with pediatric swallowing abilities. Additionally, regulations should encourage the use of patient-centric designs, such as printed dosage forms in appealing shapes and colors, to enhance compliance in younger children. Taste-masking strategies are also essential for improving medication adherence in pediatric patients. Since many active pharmaceutical ingredients (APIs) have bitter or unpleasant tastes, 3D printing allows for advanced taste-masking approaches, including polymer coatings, inclusion complexes (e.g., cyclodextrins), and modified drug release mechanisms. Regulatory agencies should require standardized palatability testing for 3D-printed pediatric formulations, ensuring that taste-masking techniques do not compromise drug release, stability, or bioavailability. Finally, bioavailability considerations must be addressed, as 3D-printed medicines may exhibit different dissolution and absorption characteristics compared to traditionally manufactured drugs. Regulatory agencies should establish in vitro and in vivo testing requirements to assess drug release kinetics, absorption rates, and pharmacokinetic profiles in pediatric patients. These regulations will ensure that 3D-printed pediatric medicines maintain consistent therapeutic performance, regardless of their customized nature.

Conclusion: In conclusion, 3D printing holds significant potential for transforming pediatric medicine and precision therapies by enabling the production of personalized dosage forms tailored to individual patient needs. While this technology offers numerous advantages, such as flexible dosages, optimized release profiles, and small-batch production, it also presents challenges that must be addressed to ensure safety and efficacy. Critical quality attributes and process parameters must be thoroughly understood, and robust analytical methods for in-process monitoring and final product evaluation must be established. The ongoing efforts of the PolyPrint consortium in developing suitable polymers, optimizing printing processes, and designing GMP-compliant printers are crucial steps in advancing the clinical application of 3D-printed medicines. By refining these aspects, 3D printing can provide a reliable, scalable solution for personalized drug delivery, ultimately improving therapeutic outcomes and patient care.

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

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