3DP Medicines and Medical Devices: History
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Contributor:
Giulia Auriemma
,
Carmela Tommasino
,
Giovanni Falcone
,
Tiziana Esposito
,
Carla Sardo
,
Rita P. Aquino

Novel additive manufacturing (AM) techniques and particularly 3D printing (3DP) have achieved a decade of success in pharmaceutical and biomedical fields. Highly innovative personalized therapeutical solutions may be designed and manufactured through a layer-by-layer approach starting from a digital model realized according to the needs of a specific patient or a patient group. The combination of patient-tailored drug dose, dosage, or diagnostic form (shape and size) and drug release adjustment has the potential to ensure the optimal patient therapy. This document provides an overview on different 3DP techniques to produce personalized medicines and medical devices, highlighting, for each method, the critical printing process parameters, the main starting materials, as well as advantages and limitations.

  • additive manufacturing
  • 3D-Printing
  • rapid prototyping
  • personalized medicines
  • personalized medical devices

1. Introduction

The interest in three-dimensional printing (3DP) in the scientific world, and particularly in pharmaceutical and medical research, has grown exponentially. In fact, the number of scientific papers recorded in the Web of Science Core Collection containing the term “3D printing” in the title increased from 57 in 2012 to 4623 in 2021. In addition, the number of citations of these papers in the same period grew from 23 to 28,438. Narrowing the searching results to the pharmacy/pharmacology category, no result was found in 2012, whereas 553 records were found up to 2021. In the light of this analysis, it is possible to say with certainty that 3DP represents today one of the fastest developing technologies in the healthcare field.
The term 3D printing is defined by International Standard Organization (ISO) as the “fabrication of objects through the deposition of a material using a print head, nozzle, or another printer technology” [1]. This includes a wide variety of techniques able to precisely produce freeform solid objects of a high degree of complexity starting from digital models created with computer aided design (CAD), ensuring great fidelity, reproducibility, and cost-effectiveness [2]. The application of 3DP in the scientific area has become more and more relevant since 2012 [1]. In the pharmaceutical field, a great impact was made with the approval by the FDA in August 2015 of the first 3D-printed drug product, Spritam®. This antiepileptic oro dispersible tablet (ODT) loaded with levetiracetam [3] was obtained by Aprecia Pharmaceuticals by using Massachusetts Institute of Technology (MIT) patented Zip-Dose Technology [4][5]. This 3DP dosage form has a highly porous structure with dose strengths up to 1000 mg that could not be achieved with traditional manufacturing. Thanks to its porous structure, Spritam® is able to disintegrate and dissolve within few seconds upon contact with saliva, helping both elderly and young patients suffering from trouble swallowing pills, known as dysphagia [6][7].
The impact of FDA approval has caused a really fast increase in the number of studies and scientific researches on the 3DP technologies with noteworthy results mainly for the development of tablets [8][9][10][11][12][13][14][15][16], capsules [17][18], orodispersible films [19][20][21][22][23][24], and medical devices [25][26][27][28][29]. Such achievements have brought to the light the real potential of 3DP as an effective tool to realize personalized therapeutic solutions fitting specific patient needs [30][31]. In Figure 1 and Figure 2, just some examples of the recently developed 3D printed customized products are reported with a great variety of structures, shapes, and layers. The remarkable results achieved have certainly not left unmoved the big pharmaceutical companies. The 3D-printed pharmaceuticals market was valued at $175.19 million in 2020 and anticipated to grow to $285.17 million by 2025, representing a significant opportunity to companies able to capitalize on its benefits and overcome its challenges [32]. Several big pharmaceutical companies have accepted the challenge to explore the emerging 3DP technologies, and possibly to integrate them into their workflows, with investments of millions of dollars. In 2020, the company Merck announced plans to work with EOS Group Company ACMC to produce 3D printed tablets first for clinical trials, then later for commercial manufacturing. In the same year, Aprecia announced their long term collaboration with R&D firm Battelle to expand its capabilities within 3D printed pharmaceuticals and advance its 3D printing equipment from clinical supply to commercial scale. Between 2020 and 2021, Triastek raised millions of dollars in funding to support the ongoing development of T19, its first 3D printed product approved by the FDA as an Investigational New Drug (IND), and expand the 3D printed drug product pipeline. T19 is a chronotherapeutic drug delivery system produced by melt extrusion deposition (MED) technology, accepted in April 2021 within the FDA’s Emerging Technology Program (ETP). The company has announced for T19 a New Drug Application (NDA) submission in 2023, but the scenario is rapidly evolving. In fact, the second product of Triastek, T20, received positive pre-IND feedback from FDA in March 2021, and an IND application submission for T20 is planned for the end of the year [33][34].
Figure 1. Examples of 3D printed products for drug delivery. (a) Channeled tablet. Reprinted with permission from reference [35]; copyright (2017) Elsevier B.V. (b) Duo Tablet. Reprinted with permission from reference [36]; copyright (2017) Elsevier B.V. (c) Cube, pyramid, cylinder and sphere-shaped tablets. Reprinted with permission from reference [37]; copyright (2015) Elsevier B.V. (d) Chewable chocolate-based oral dosage forms. Reprinted with permission from reference [38]; copyright (2020) Elsevier B.V. (e) Tablets with honeycomb architectures. Reprinted from reference [39]; copyright (2017). (f) Donut-shaped tablets. Reprinted with permission from reference [40]; copyright (2016) Elsevier B.V. (g) Microneedle patch. Reprinted with permission from reference [41]. copyright (2018) Elsevier B.V.
Figure 2. Examples of 3D printed products for biomedical applications. (a) Nose-shaped device. Reprinted with permission from reference [42]; copyright (2016) Elsevier B.V. (b) Anti-biofilm hearing aids. Reprinted with permission from reference [43]; copyright (2021) Elsevier B.V. (c) Guide used during a surgery for tibial plateau fracture. Reprinted from reference [44]; copyright (2021). (d) Vaginal rings. Reprinted with permission from reference [45]; copyright (2018) Elsevier B.V. (e) 3D printed heart. Reprinted from reference [46]; copyright (2016).
Although 3DP has been only recently explored for the manufacturing of personalized drug delivery systems (PDDS), such technology is well established in various biomedical areas for the creation, e.g., of customized prosthesis, orthopedic implants and anatomical models, surgical instrumentations, etc. Just think, for example, that, since 2001 Sonova has been able to produce hundreds of thousands of custom-made hearing aids every year [47] by 3DP technology. The Sonova model is a significant example of the customized manufacturing of a medical device and how personalization can change, or rather, has changed the hearing aid industry for better. A lot has been done in this specific field, but a lot remains to be done in other biomedical sectors as well as in the pharmaceutical one [48][49].

2. Driving Force in the Developing of 3DP Medicines and Medical Devices

The need for therapeutic approaches specific to the individual, the increasing demand for complex drug-eluting products, medical devices, and advanced drug-device combination products, as well as the growing request of on-demand manufacturing, are the main reasons strongly promoting the use of 3DP technology in both pharmaceutical and biomedical fields.
Personalized medicine, also indicated as precision medicine, is a medical approach that separates people into different groups based on individual needs. Personalized medicine takes into account the genetic profile, lifestyle, environment, weight, sex, and age as well as other specific patient needs. A personalized medical approach could be represented by a medical decision or practice, an intervention, and/or a product being tailored to the individual patient based on its predicted response or risk of disease [50][51]. From this point of view, 3D printing possesses the great potential [52][53][54] of linking the patient, with all its real needs, to tailor-made medicines and treatments (Figure 3 and Figure 4).
Figure 3. Personalized medical approach. * Images adapted from reference [55]. ** Images adapted from reference [56].
Figure 4. Possible advantages deriving from a personalized therapy.
3DP presents the possibility to easily develop patient-centered dosage forms, answering to the need to deliver “the right drug at the right dose and at the right time” [49], e.g., age-appropriate dosing for pediatrics and geriatrics sub-populations [57][58], multiple drug administration in polypharmacy practice [59], and innovative dosage forms, enhancing patient compliance and adherence to treatment with respect to conventional solid dosage forms [56]. Besides the proVazper drug dosage, with this approach, it is possible to produce controlled drug delivery systems with tailored drug release profile and even, multiple drug content. A “customized polypill” is a solid oral dosage [60] form 3D-printed in a complex construct of layers, capable of satisfying more than one therapeutic need at the same time. A “polypill” can be realized as a multi-drug pill, carrying and delivering a combination of drugs with various controlled release mechanisms to treat multiple diseases at once, or as a multi-dose pill, charged with different doses of the same drug to be delivered at different times. In addition, the possibility to guarantee a precise drug loading within the 3D printed structure increases, in general, the safety of all the selected drugs, above all of those characterized by a narrow therapeutic window requiring an exact dosing.
3DP continues to revolutionize the medical device landscape, continually providing higher performing patient specific anatomic models, such as prostheses [61][62][63][64] and dental [65][66] or orthopedic implants [67][68]. Its application is also growing in tissue engineering (TE) and regenerative medicine (RM) for the manufacturing of three-dimensional scaffolds acting as biological substitutes of damaged tissues or organs [69][70][71].
Another exciting opportunity to become a focus area for research and development lies in the powerful combination of drug eluting products and medical devices. Advanced drug-eluting devices providing significant and unique benefits to patients over conventional treatments have been recently developed by different 3DP technologies in the form of antibiotic and chemotherapeutic catheters [72], antimicrobial stents [73] and implants [74][75][76], and even anti-biofilm hearing aids [43] or anti-glaucoma contact lenses [77].
3DP offers a forward-looking view for producing as well as dispensing medicines, moving the attention from traditional mass manufacturing to on demand manufacturing, and thus from centralized towards decentralized facilities (Figure 5). Therefore, based on a patient specific prescription from their doctor, a customized medicinal product with complex geometry and architecture, charged with multiple doses of a specific drug, or even loaded with multiple drugs, can be designed via CAD and produced, when needed, by a 3D printer. Potentially, a hospital, clinic, community pharmacy, or even the patient’s home, may be engaged in the pharmaceutical compounding/production [1]. Recently, Beer et al. investigated the possible implementation of 3DP technologies in the European pharmaceutical system. Among the various scenarios suggested (namely 3D printers in hospital pharmacies, community pharmacies, compounding facilities, patients’ homes, and industry), those involving 3D printing in patients’ homes was presented as the most futuristic, whereas printing at hospitals and pharmacies where other routine compounding is already taking place were shown as more realistic [48].
Figure 5. On-demand manufacturing (customized products) vs. mass manufacturing (traditional medicines, one-size-fits-all). The new scenario opened by 3DP technology.
3D manufacturing may be a good alternative to the compounding practice in hospital settings when a precise dosage, small batches for clinical studies, orphan drugs, and expensive oncology medical preparations are needed. In this case, 3DP appears cost- and material-saving, produces a smaller footprint, and may increase precision dosing, safety, and benefits to the patients. The overall printing process (materials’ control, feedstock setting-up, printing, cleaning etc.) could be slower than the conventional compounding based on simple operations (such as weighing, grinding, mixing, diluting, cleaning), but it is still worth exploring. This great potential has allowed for the creation of point-of-care (PoC) 3D printing centers, which blur the line between the healthcare provider, medical center, and device manufacturer, creating regulatory ambiguity [78]. Currently, the FDA remains undecided about the best way to regulate PoC printing centers. However, they have recently begun working with stakeholders (including engineers, the medical device industry, various 3DP interesting workgroups, PoC manufacturing centers, physicians, and surgeons) through a webinar series hosted by the American Society of Mechanical Engineers (ASME) to develop a regulatory framework [79], following the way opened by the UK agency MHRA [80].
There is a fundamental difference when discussing printing in the context of small-scale compounding in the hospital and pharmacy setting or large-scale manufacturing in the industry setting. In the industrial setting, the main benefits deriving from decentralizing pharmaceutical manufacture are the following [1][30]:
  • Reduced length and cost of transport and storage [81].
  • Quick and real-time responses to patient and market needs due to the possibility to rapidly produce small batches of complex formulations with unique geometries and, furthermore, the concept of digital dispensing in hard-to-reach areas or developing countries [82].
  • Reduced waste and hence reduced costs of developing and dosing due to a precise spatial control over the deposition of materials, limiting the amounts of API (active pharmaceutical ingredient) and excipients in comparison to conventional technologies [83].
Despite these benefits, there are several technical and regulatory challenges that need to be overcome before 3D printing may be widely used for pharmaceutical applications in clinical practice, as shown by only one FDA approval of a 3D printed drug on the market [3], and one on its way [33]. In the industrial setting, a 3D printed product must comply with the current manufacturing and control standards for medical products and devices, specifically the well-stablished Good Manufacturing Practices (GMP). However, 3DP manufacturing has many more issues involving design and production, raw material storage and transport, quality control, risk of counterfeit production, etc. In this regard, significant progress has been made for medical devices, ranging from surgical planning tool to custom surgical devices [84]. In the last few years, various papers have focused on the analysis of critical process parameters as well as product quality attributes and performance criteria, which must be addressed considering the industrial system of quality assurance to guarantee the fulfilment of regulatory standards [84][85]. Implantable medical devices require, for example, along with the careful characterization of starting materials as well as the optimization of 3D printing parameters, additional considerations about cleaning, finishing, and sterilization procedures [86]. In the attempt to allow the overcoming of such hurdles, the FDA released in December 2017 guidance detailing the technical considerations for additive manufactured medical devices, from software and hardware requirements, quality control, up to process validation procedures [87]. As the FDA document highlighted, due to the variability of additive manufacturing methods, there is no possibility to give one universal set of 3DP guidelines. It seems that every single printing method needs different equipment, starting materials, post-processing treatments, laboratories, and hence separate regulatory requirements [84]. The situation is complicated even more with the inclusion of one or more APIs, as it happens for multi-drug medicinal products which must considered possible incompatibilities and APIs’ stability problems. Generally, requirements for drug-eluting products are more demanding than those for medical devices and this is the key reason why there are still no regulations. However, to fully understand the real motivation causing the actual regulatory difficulties, it is essential to analyze this new production approach from a strictly technical point of view.

3. 3D Printing: technical aspects

Technically, 3DP can be defined as a layer-by-layer production of 3D objects from digital designs. This technology belongs to the so-called additive manufacturing (AM) processes because the object is produced through the layer-by-layer deposition of starting materials using a print head, nozzle, or another printer technology. Even the term rapid prototyping (RP) is often used to define 3DP since it generally refers to all techniques able to construct objects from digital models created with CAD software. Therefore, additive manufacturing is mainly referred to as the productive step, involving rapid prototyping through the whole procedure [88]. Despite of the diversity of 3DP methods, all exploit a CAD-CAM system. The process starts from the design of a digital model using CAD software; the latter is converted in a STL. file, a machine-readable format which describes the external surface of a 3D model. After this step, the STL. file is imported to the printer software (CAM software) that, through a slicing process, generates the layers which will be printed in an additive way by the printer.
Various and very different 3D printing techniques exist, depending on the specific technology used. All of them fall within the common definition of solid freeform fabrication (SFF) aiming to focus on the possibility to produce solid free forms with a complex and well-defined architecture. According to the American Society for Testing and Materials (ASTM F2792-12a), AM processes can be classified in seven categories, namely: (1) material jetting, (2) binder jetting, (3) vat photopolymerization, (4) powder bed fusion, (5) material extrusion, (6) energy deposition, and (7) sheet lamination [89] (Figure 6). Further AM classifications may be done based on the physical state of the starting material used to form the product (solid, liquid, and powder-based processes), or even the medium used for its processing (laser beam, ultraviolet rays, thermal means, etc.) [90]. A commonly accepted classification of the different 3DP systems used for pharmaceutical and medical applications is based on three main groups, namely:
  • Printing based ink-jet systems
  • Laser-based writing systems,
  • Nozzle-based deposition systems [54][91].
 
Figure 6. Schematic view of additive manufacturing processes according to ISO/ASTM 52,900:2021 classification [89][90], with in evidence the main AM methods applied in pharmaceutical and biomedical field [54][91].

Ink-Jet Based 3D-Printing Technologies

The idea of “ink-jet” systems originated from computer-operated ink-jet printing, which recreates digital images by propelling ink droplets onto paper. This was adapted for pharmaceutical application by the replacement of the ink with liquid solutions containing APIs and excipients, and normal paper with edible sheets known as substrates. In this case, the major challenge, often underestimated, is the formulation of an API-containing ink with appropriate properties. Specifically, during a generic inkjet-based 3DP process, the ink must be sprayed at a set speed, and through specific motions, into droplets with precise sizes. Operative conditions must be well established to facilitate reliable jetting and homogeneous droplet formation with minimal satellites [88][92]. In addition, the choice of the solvent for the ink formulation, as well as the ink drying rate, could influence the solid state of the loaded API after deposition, and hence its bioavailability [93].
As illustrated in Figure 6, the ink-jet based 3DP technologies can be divided into two types: continuous (CIJ) and drop-on-demand (DoD) inkjet printing [56]. In the first case, the ink is sprayed, mainly through piezoelectric crystals, in a continuous flow. On the contrary, during a DoD process, the ink flow, either provided by a thermal or a piezoelectric device, is provided only as needed. This latter process can be also defined as drop-on-drop deposition (DOD) if the drops are allowed to deposit on each other to form a bed, and drop-on-powder deposition (drop-on-solid, DOS) if the droplets are allowed to deposit on the powder bed; this approach is also known as the TERIFORM® process.
During a drop-on-drop deposition process, droplets of ink are sprayed from the thermal or piezoelectric print head, deposited on the thin layers, and then cured by cooling air or in the presence of high energy light (Figure 7b). In this case, to create support for overhang geometries, it is necessary to use additional material acting as support. The most common materials used for DOD are waxes and ceramics, and this low selection of materials certainly represents a disadvantage. By contrast, the main advantages of DOD are the instantaneous solidification, the efficacy, and the cost-effectiveness.
Molecules 27 02784 g008 550
Figure 7. Ink-jet based printing technology (a) Continuous (CIJ), (b) drop-on-demand (DoD).
In a drop-on-solid process, droplets of ink sprayed from the print head bind the layer of the free excipient powder bed, while unbound powder particles act as a support material preventing the collapse of overhanging or porous structures. After each step, the formed object is lowered, and a layer of free powder is applied by a roller or powder jetting system and the process proceeds (Figure 8). The product quality attributes are strictly dependent on both ink and powder properties. The ink constituents, such as APIs, solvents, or excipients, can influence viscosity and droplet size, and thus the efficiency of powder binding. Instead, the particle size, flowability, and wettability of the powder bed, as well as the cohesion force between particles and printer components, mainly influence the layer height and, consequently, the final resolution of the printed object [56][94]. Moreover, printing speed, droplet volume, and distance from powder bed may play an important role, particularly in affecting the powder bonding between layers along the Z-axis, where they could negatively influence its mechanical strength [1].
Figure 8. Illustration of a DOS deposition process with (a) powder bed layering system and (b) powder bed jetting system.
The main advantage of such technique relies in the high similarity with wet granulation, presenting the possibility to use as starting materials various common excipients of solid dosage forms [95][96][97]. Similar binders work with a wide range of API powders allowing to greatly reduce the complexity of ink formulation. Besides the possibility of a precise location of an exact drug dose, this approach also allows an easy modification of the excipients within the powdered bed to obtain, in the same product, several compartments with different composition or mode of action. The main disadvantage of the DOS approach is represented by the need to perform different post-printing steps, such as drying to eliminate residual solvents and improve the physical resistance or unbound powder removal, and this latter step requires a specialized powder facility [1].
There are a lot of examples concerning the application of the DOS method for the fabrication of tablets [97][98][99][100][101], and the greatest success of this technology was achieved in 2015 with just a tablet, namely Spritam®, based on ZipDose® technology [4][5]. In contrast with conventional compression, the technology yields a product layer-by-layer without using compression forces, punches, or dies. During the process, a powder blend is first deposited as a single layer. Then, an aqueous binding fluid is applied, and interactions between the powder and liquid bind the materials together. The process is repeated several times to produce solid, yet highly porous, friable formulations, even at high dose loading (up to 1000 mg).
The DOS method could also be exploited in the large-scale production of modified release multicomponent tablets. In this case, small variations in porosity resulting from the different adhesion between the layers could alter the structural density of the produced tablets and, consequently, the drug dissolution profile and bioavailability. The technical solution could be the application of a greater amount of binder, which, however, causes an increase of drying time as well as the risk of limited removal of residual solvent [1]. This aspect strongly limits the application of DOS for the production of multicomponent modified release tablets with high quality.

Laser Based 3D-Printing Technologies

The second set of 3DP technologies is that laser-based 3DP technologies. This group includes selective laser sintering (SLS), or selective laser melting (SLM), whose constructive assumptions are similar to the DOS method, and stereolithography (SLA), for which the object is built by the solidification of photosensitive liquids.

SLS is a laser based 3DP technique based on powder solidification by applying a high-energy beam [94][102][103]. As illustrated in Figure 9a, a layer of free powder is applied by roller and each layer is formed by sintering via laser beam that is able to heat just below melting temperature [1]. This technique can be applied to ceramic powders as well as to thermoplastic or metal powders. In this latter case, laser beam must melt the powdered bed and the specific technique is referred to as selective laser melting (SLM) [103].

Figure 9. Illustration of SLS (a) and SLA (b) processes.
Many are the advantages and the disadvantages of such a technique. Ideally, almost any dosage form can be fabricated by SLS with a high level of precision, accuracy, and resolution. In fact, even objects of several cubic centimeters (and hence rather large) can be built with a resolution down to 0.2 micron [104]. SLS can be successfully applied to produce porous, rapidly disintegrating, as well as modified release dosage forms without binding agent, with high drug loading efficiency and good mechanical properties. The latter aspect is very important, because it cannot be reached with other powder solidification methods such as DOS [1]. However post-printing processing is required as the object is built into a powder, and such a step requires specific powder removal procedures and facilities. Other disadvantages are due to the risk of API decomposition after exposure to laser beam, the high variability of mechanical properties, and the limited speed for sintering [1]. The drug degradation in particular has severely limited the use of SLS in the production drug-loaded devices, and a few examples are available [105][106][107][108][109][110][111]. Nevertheless, SLS has been used to process soft materials both in the bioprinting for tissue engineering and in the food industry [112].
The production of a 3D object by SLA is based on the controlled solidification of subsequent layers of resin by photo-polymerization via ultraviolet laser beam or light from a projector (digital light projector, DLP) [113]. During the SLA process, the printed object is bound to the built platform that is immersed in the photopolymer solution (Figure 9b). A digital mirroring device starts a chemical reaction in the photopolymer, which causes the cross-linking of the exposed area. The layer is traced on the surface of the resin.
As with SLS, SLA also is a highly versatile technique allowing to produce objects with high level of precision, accuracy, and resolution. The major disadvantage is represented by the need for post printing treatments to remove residual solvents, eventual supports, and in general, to improve final product properties, e.g., mechanical integrity. Another disadvantage is the potential health hazard due to the use of photo-sensible resins usually considered as carcinogens as well as responsible for a decrease of final product stability and its mechanical properties over time [56]. In addition, the systems exploiting this 3DP method require costly equipment and a long printing time. All these aspects have limited the application of SLA in the pharmaceutical and biomedical fields [114]. However, some applicative examples of SLA are described in the scientific literature [40][59][115][116], also in combination with other 3DP techniques [41][95][117][118].

Nozzle Based 3D-Printing Technologies

The third group of 3D-printing technologies is represented by nozzle-based deposition systems allowing direct writing through extrusion. Such systems deposit ink direct through a nozzle to create a 3D pattern layer-by-layer with controlled composition and architecture [119]. They can be basically divided into processes based on material melting, such as fused filament fabrication (FFF), also referred to as fused deposition modelling (FDM), and processes without material melting, such as semi solid extrusion (SSE), also known as pressure-assisted microsyringe (PAM). Nozzle based 3DP technologies have been highly investigated due to their great versatility, reproducibility, and high scalability potential. A lot of papers in the literature have focused on the application of such techniques to develop pharmaceutical as well as biomedical products.
FFF is a really very investigated 3DP technique because it is cheap, easy to use, and readily available [119][120][121]. Its increasing popularity is mainly due to the progressive availability of compact sized and relatively inexpensive equipment [1][56]. During a FFF process, a thermoplastic polymeric material (mainly in form of filament) is extruded through a warmed-up nozzle and printed layer-by-layer (Figure 10a). Nozzle diameter varies from 0.2 to 0.4 mm, and it has an impact on the final resolution of 3D printed product. Generally, the width of the printed path corresponds to the nozzle diameter, while its height is equal to the half of the width. However, properties of the selected starting material as well as printer settings may induce modifications. During the process, the paths are arranged in layers until the formation of the final object, the resolution of which depends on layer height. Differently, the mechanical characteristics of the printed product are related to a number of outlines that build the external wall of the object and infill pattern (e.g., linear, or hexagonal).
Figure 10. Illustration of FFF (a) and SSE (b) processes.
The development of dosage forms and medical devices by the FFF approach requires a deep understanding of the printing process parameters as well as a thorough formulation study to properly select raw materials. Several critical material requirements need to be considered for their influence on FFF processability as well as 3D printed product quality. In more detail, filament mechanical properties (e.g., elastic modulus and strain at yield) and viscosity at the melted state mainly influence the extrusion step. Rheological properties, and particularly viscosity, surface tension, and relaxation dynamics, have impact above all on layer and intralayer adhesion, and thus on object precision and resolution. Finally, thermal properties (e.g., conductivity, heat capacity, coefficient of thermal expansion, and crystallinity), besides specifically driving process parameter set-up, are often responsible for fiber shrinkage and warpage [122]. Therefore, the careful evaluation of such aspects may avoid processing issues [1]. In general, the main disadvantages of FFF rely in the poor choice of starting materials which, as introduced, is limited to thermoplastic polymers, and the need of preparing filaments in advance, eventually loaded with the drug. Moreover, due to the elevated temperatures associated with this process, the potential risk of drug degradation is a significant issue hindering its use in pharmaceutical field.
Differently from FFF, the SSE process involves a semisolid starting material (in the form of gel or paste) that is extruded through an orifice by compressed air pressure, a syringe plunger, or screw, depending on the specific equipment used, and deposited layer by layer (Figure 10b). Semisolid materials can be easily obtained by excipients commonly employed in the pharmaceutical industry by mixing them in optimal ratios with appropriate solvent(s) to obtain a viscosity suitable for printing. SSE does not require high temperatures but, using materials in form of pastes or gels, a further drying process is needed, implying shrinking or deformation of the printed product. The fabricated object may also collapse during 3D printing if a constructed layer did not harden sufficiently to withstand confinement of the successive layer. The technique is usually confined to a low resolution since an orifice with a size of 0.4–0.8 mm is typically employed. However, an accurate parameterization of the dispensing of the semisolid mass, as well as the use of nozzles smaller in diameter, allows to obtain dosage forms with a good resolution and mass uniformity [123][124]. The main advantage of SSE resides in the possibility to fabricate dosage forms with high drug loading. By using multi-syringe printing, “polypills” may also be obtained containing 3–5 APIs released with different kinetics [125][126].
Each 3DP approach presents specific advantages and disadvantages. The choice that must be made based on the properties of the starting materials as well as the drug to load and the desired performances for the final 3DP products, without forgetting system cost-effectiveness and realizable scale-up.

4. Conclusions

The technology evolution pathway of 3DP from 2012 to date is very notable. It is a fact that at present there is a contribution of 3D-printing to many aspects of healthcare. However, the full range of application remains to be explored in depth.
In the last few years, the healthcare needs of the population have changed, also thanks to the adoption and enhancement of omics technologies in healthcare. There is an increasing demand of patient-tailored treatments to improve efficacy, safety, patient compliance, therapeutic adherence, as well as cost-efficiency. This has strongly moved the attention towards 3D printing technology, which offers innovative, digitally designed solutions able to overcome the issues of the currently marketed traditional products.
Problems impacting 3DP application are mainly four-fold: the strict requirements for excipients, the development of printing software and equipment, the optimization of mechanical properties of products, and the regulatory framework. As regards excipients for pharmaceutical 3D printing, they are relatively restricted, compared to conventional manufacturing processes, mainly for technologies using heat. Much research has updated this field. However, further studies concerning biocompatible, biodegradable, and stable excipients peculiar for 3DP are required. As the complexity of product structure increases, the modeling and slicing software used to design and drive its manufacture as well as equipment, operative procedures, and control system must be constantly refreshed.
From a regulatory point of view, there are still several open questions surrounding how 3D-printed healthcare products can be monitored and evaluated for quality. Although the FDA authorized in 2015 the first 3D-printed tablets, no regulations or guidelines regarding 3D-printed medicines are currently available. Progress has been made for 3D printed medical devices, for which the FDA released in 2017 guidance detailing some technical considerations. However, there is no possibility to give universal guidelines for all 3D-printed technologies and medical devices. A separate assessment of safety and effectiveness may be required for each technology and product, especially for those personalized. Furthermore, when products are customized to the patient, the question of whether 3D printing is classed as a manufacturing or compounding process also has a great impact on regulatory requirements. 

This entry is adapted from the peer-reviewed paper 10.3390/molecules27092784

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