Quality by Design Approach for Hot-Melt Extrusion Coupled Fused Deposition Modeling (HME-FDM) 3D Printing: A Systematic Review

Abstract

Background: Fused deposition modeling (FDM) is one of the most well-known and often published methods for 3D-printed drug delivery systems. In early scientific reports, the active pharmaceutical ingredients were added by soaking, but later, a new milestone was established, after researchers started to manufacture their own filaments by hot-melt extrusion (HME). The number of publications covering this method has multiplied in the last decade, a wide range of natural and synthetic polymers have been tested with versatile active pharmaceutical ingredient components, and various printing parameters and their effects have been investigated.

Objectives: In this review, we aim to synthesize how the available quality by design approaches and the scientific results established so far can facilitate the creation of a guideline for appropriate quality production of HME-FDM 3D-printed pharmaceuticals.

Methods: Based on PRISMA 2020 guidelines, a systematic search of relevant publications from 2015 to 2025 was carried out using the PubMed database. Twenty-six articles were included, based on number of monitored parameters and methodological description. Reporting of important quality processes and material parameters was assessed.

Results: HME, the FDM, and analytical testing experiences were compared and collected into three tables from the selected publications. In two different sections, the pharmacopeial dosage-form tests and the involvement of process analytical technologies (PAT) were also analyzed. We found that reporting of influential parameters is heterogenous, and lack of robust reporting schemes limits the development of QbD approaches.

Conclusions: Regarding the data, trends were synthetized, and a guideline was created which is limited by inconsistent parameter reporting.

Introduction

Fused deposition modeling (FDM) is one of the most frequently used 3D printing methods, a technique which is based on the deposition of melted layers of thermoplastic materials followed by solidification at room temperature. Such a process holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation [1,2]. It offers several undeniable advantages such as cost-effectiveness, design-flexibility without the need for changing tools, the potential to fabricate complex geometries, and enabling on-demand production of customized components with reduced material waste and lead time compared to traditional systems [3]. Nevertheless, several possible limitations need to be considered, like the limited resolution and surface quality, anisotropic length, and its slowness compared to other 3D printing methods [4]. In case of the pharmaceutical aspect the greatest challenge is the ventilation and the high printing temperature which can lead to the degradation of the active pharmaceutical ingredient (API) and decomposition [5].

In early research, APIs were incorporated into the excipients by soaking: the printable polymer filaments were immersed in a solution or dispersion containing the API. Usually a maximum of 0.06% w/w to 0.25% w/w drug loading was achieved [6]. This limitation motivated researchers to change the manufacturing method, which eventually led to the development of filaments that were not simply wetted by the API solution but directly contained the given API within the filaments through hot-melt extrusion (HME). Although these early attempts reported higher drug loading percentages, the quality of the produced filament was not suitable for 3D printing. The authors declared that the use of other excipients as plasticizers could help to obtain considerably higher drug loading percentages than 10% w/w [7].

Since then, HME has become a widely used technology not only in the pharmaceutical industry but in other fields of industrial manufacturing. Presently, a variety of commercially available drugs are produced by this method, for example, the Lacrisert® ophthalmic insert, Zoladex® injectable implant, Implanon® implant, NuvaRing® vaginal ring, and Eucreas® film-coated tablet. HME can be used for the manufacturing of granules, pellets, tablets, transdermal systems, transmucosal delivery systems, implants, solid lipid nanoparticles, or nanocrystals. It can be applied for solubility and bioavailability enhancement, taste masking, and co-extrusion. Targeted and shaped drug delivery systems, nanopharmaceutics, and filament manufacturing can be performed [8], and also, co-crystal formation can be achieved [9]. Using HME for pharmaceutical applications offers numerous advantages, as it has the potential to create new and novel drug formulations, and it has the ability to be connected to process analytical technology (PAT) [10]. In the case of solid dispersion manufacturing, the process does not require any use of solvent [11]. Some other advantages of using HME in pharmaceutical applications include shorter production time, higher process efficiency, and increased drug delivery efficiency in patients. Restricting factors include the high energy input, which is required for the shear forces during the manufacturing process [12].

Additionally, as HME also uses high temperature, it poses a risk of thermal degradation of the API [13].
Traditionally, HME-FDM technology utilized thermoplastic synthetic polymers, like polylactic acid (PLA), polyvinyl alcohol (PVA), polycaprolactone (PCL), acrylonitrile butadiene styrene (ABS), and high-impact polystyrene (HIPS) [14]. Pereira et al. listed the most routinely used polymers: PVA; polyvinylpyrrolidone (PVP); cellulose-derived polymers such as ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), and HPMC acetate succinate (HPMCAS); acrylates such as Eudragit® E PO, RL, RS, and L; and other polymers like Soluplus®, Kollicoat® IR, PCL, polyethylene oxide (PEO), or ethylene vinyl acetate (EVA) [15]. In the last few years, natural polymers have become more popular due to sustainable approaches. Porwal et al. converted biopolymers like chitosan, cellulose, or hemicellulose into printable polymers [16]. Even the possible use of nanocellulose was investigated due to its biocompatibility, good printability, and biomanufacturing potential [17].

Quality by Design (QbD) is an approach which emphasizes that the quality should be designed in a product prior to manufacturing, based on the observation that most quality problems originate from the way in which the product was designed. The U.S. Food and Drug Administration (FDA) encourages risk-based approaches and the adoption of QbD principles in drug product development, manufacturing, and regulation. In this article, the final quality attributes of the HME products were determined to be as follows: extrudate density, length/thickness/diameter, polymorphic form and transition, content uniformity, and throughput. Meanwhile, the input material attributes which are important are particle size and distribution, fines/oversize, particle shape, melting point, density, solid form/polymorph, and moisture content. The process parameters are the following: screw design, screw speed, screw opening diameter, solid and liquid feed rates, feeder type/design, feed rate, number of zones, zone temperatures, and chilling rate (Table 1) [18].

Table 1. The input material attributes and the process parameters determining the quality attributes of HME products based on Yu et al. [18].

In the case of 3D-printed pharmaceuticals, the main principles of QbD will be the same: the identification and control of the critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) to ensure consistent product performance and safety and provide batch-to-batch consistency. Even though the process should start by first determining the quality target product profile (QTPP), this might be challenging due to the lack of CQAs, CMAs, and CPPs. Prior to the publication of this article, the authors did not find any review articles which would specifically determine the key issues for the HME-FDM process [19].

Later in this review article we aim not only to summarize the importance of the properties listed in Table 1, based on publications in which HME-FDM was used for manufacturing drug delivery systems, but also to draft a guideline in harmonization with the QbD approach to facilitate easier drug development, manufacturing, and registration.

Download the full article as PDF here Quality by Design Approach for Hot-Melt Extrusion Coupled Fused Deposition Modeling (HME-FDM) 3D Printing

or continue reading here

Excipients mentioned in the study:

polyvinylpyrrolidone (PVP); cellulose-derived polymers such as ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), and HPMC acetate succinate (HPMCAS); acrylates such as Eudragit^® E PO, RL, RS, and L; and other polymers like Soluplus^®, Kollicoat^® IR, PCL, polyethylene oxide (PEO), or ethylene vinyl acetate (EVA) .

Arany, P.; Papp, Á.; Nemes, D.; Fehér, P.; Ujhelyi, Z.; Bácskay, I. Quality by Design Approach for Hot-Melt Extrusion Coupled Fused Deposition Modeling (HME-FDM) 3D Printing: A Systematic Review. Pharmaceutics 2026, 18, 569. https://doi.org/10.3390/pharmaceutics18050569

---

Read also our introduction article on 3D Printing here: