Expert Review of Medical Devices

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3D printed drug delivery devices: perspectives and

technical challenges

Mirja Palo, Jenny Holländer, Jaakko Suominen, Jouko Yliruusi & Niklas
Sandler

To cite this article: Mirja Palo, Jenny Holländer, Jaakko Suominen, Jouko Yliruusi & Niklas
Sandler (2017) 3D printed drug delivery devices: perspectives and technical challenges, Expert
Review of Medical Devices, 14:9, 685-696, DOI: 10.1080/17434440.2017.1363647

To link to this article: https://doi.org/10.1080/17434440.2017.1363647

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EXPERT REVIEW OF MEDICAL DEVICES, 2017
VOL. 14, NO. 9, 685–696
https://doi.org/10.1080/17434440.2017.1363647

REVIEW

3D printed drug delivery devices: perspectives and technical challenges

Mirja Paloa, Jenny Holländera,b, Jaakko Suominena, Jouko Yliruusib and Niklas Sandlera
a
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland; bDivision of Pharmaceutical
Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

ABSTRACT ARTICLE HISTORY

Introduction: The technological advancements in the pharmaceutical field are constantly improving Received 9 June 2017
and provide various possibilities for meeting the needs of personalized drug therapy. The three- Accepted 1 August 2017
dimensional (3D) printing technology has endless potential in the fabrication of patient-specific drug KEYWORDS
delivery devices (DDD) and dosage forms as the technological development is progressing. Moreover, Fused deposition modelling;
the rapidly evolving research on 3D printed DDD has enabled us to determine several challenges oral drug delivery;
related to the manufacturing and marketing of personalized drug delivery systems. personalized medicine; solid
Areas covered: In this review, an overview is provided on the relevant accomplishments in the freeform fabrication; tailored
development of 3D printed drug delivery systems, as well as the technical challenges surrounding dosage forms;
the 3D printing of personalized drug-loaded medical devices and dosage forms. Furthermore, observa- three-dimensional printing
tions are presented on the future perspectives of pharmaceutical 3D printing.
Expert commentary: The 3D printing has enabled the fabrication of prototypes of DDD with varying
complexity and shows that customization of drug products is possible. There is potential to improve
patient-specific drug therapies of the future using printing technologies. The technological advancements,
new scientific concepts, interdisciplinary work and defined regulatory guidelines will continue to support
and strengthen the prospects of 3D printing as an option in the manufacture of medical products.

1. Introduction
Since its initial use, three-dimensional (3D) printing technol-
ogy has been used as a rapid and cost-effective prototyping
technique in a wide range of different applications including
aerospace, automotive, construction, jewelry, and fashion [1].
3D printing techniques have been applied in small production
volumes, such as prototyping, customization, and the manu-
facturing of products with complex designs, which are difficult
to manufacture with traditional methods.
In the medical field, 3D printing has been used in dentistry,
tissue engineering, and computer modeling of organs [2].
However, it is still in its infancy in the pharmaceutical field.
Several research groups have been investigating the potential
for 3D printed drug delivery devices (DDD) since the early
1990s, but it was not until 2016 when the first 3D printed
pharmaceutical product was approved by the US FDA [3,4].
The term 3D printing, also called solid freeform fabrication,
additive manufacturing, rapid prototyping, and digital fabrication,
has been intensively researched in the medical and the pharma-
ceutical field for the past decades. The 3D printing is an umbrella
term for about two dozen 3D printing processes, which use
various printer technologies, hundreds of materials, different reso-
lutions and speeds [5]. The first 3D printing technique, stereolitho-
graphy (SLA), was invented by Charles Hull in 1986 [6]. Since then,
several other printing technologies have been developed, for
example fused filament deposition (FDM) by Scott Crump in
1992 [7] and three-dimensional printing (3DP) by Emanuel Sachs
in 1993 [8]. The techniques utilized in the pharmaceutical field are
SLA, selective laser sintering (SLS), inkjet-based 3DP, extrusion-
based FDM, and pressure-assisted microsyringe (PAM) printing.
The following features are common to all the 3D printing
technologies [2]:
● The object is created from a 3D model, obtained from
computer-aided design (CAD), computerized tomogra-
phy, or magnetic resonance imaging scan data.
● The 3D model is sent to the printer’s software as a file. In
the software, the 3D model is sliced into a layered struc-
ture, which determines how the layers are constructed.
● The 3D object is printed by a layer-by-layer approach.
The presented overview on the 3D printed dosage forms and
DDD presented is largely based on the Master’s thesis by
Holländer [9]. The review aims to summarize the recent advance-
ments in the pharmaceutical development of 3D drug delivery
systems (DDS) and drug-loaded medical devices, as well as the
concurrent technological and regulatory challenges. Finally, key
remarks are provided on the current state and the future per-
spectives of 3D printing in pharmaceutical manufacturing.
2. 3D printing technologies in pharmaceutics
The SLA technique was one of the first 3D printing techniques
introduced as a commercial system [2,6]. In the SLA process,

CONTACT Niklas Sandler niklas.sandler@abo.fi Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Biocity,
Tykistökatu 6A, FI-20520 Turku, Finland
© 2017 Informa UK Limited, trading as Taylor & Francis Group
686 M. PALO ET AL.
the layered 3D structures are built by solidifying a thin layer of
the liquid resin on the movable platform and curing the
polymer with an ultraviolet (UV) laser beam across the liquid
surface in a defined depth according to the CAD design.
Photoinitiators are added to the system for the conversion of
light energy into chemical energy by free radical formation.
Thus, post-processing with UV-curing is often necessary to
improve the mechanical properties of the printed structures,
since the conversion of the reactive groups of the resins is
usually incomplete [10]. The original SLA systems use epoxy-
or acrylate-based monomers that are not suitable for the
development of DDS [11]. However, biodegradable macromers
used in tissue engineering, including polycaprolactone (PCL),
poly(propylene fumarate), trimethylene carbonate, and poly(D,
L-lactide) (PDLLA), could be suitable also for pharmaceutical
applications [12].
In SLS, materials in a powder form are sintered by a laser
beam. The 3D structures are built by the fusion of thin powder
layers with a high-power pulsed laser beam and by controlling
the movement and heating of the SLS fabrication platform [2].
The suitable materials for SLS should be thermally stable below
their melting temperature to enable the powder fusion by
heating. The SLS printing of 3D structures leaves powder resi-
dues on the final structures and processing leftovers; thus,
requiring posttreatment of the formulations and protocols for
the waste collection or powder reusage [13]. SLS is traditionally
used with metal powders; however, polymers like polyamide,
polystyrene, polypropylene, and thermoplastic elastomers are
commercially available for SLS [14].
In the 3DP, also called binder jetting, the 3D structure is
built up with powder as the build material and liquid as the
binding material [2]. Briefly, the 3DP printing process consists
of two main steps that are repeated to produce a layered
3D structure. First, a layer of powder is spread onto the build
plate with a roller. Second, the binding material is jetted onto
a predefined location on the powder layer by movable inkjet
printhead(s) and the powder is bound together only in the
printed areas. Several commercially available 3DP printers
have been utilized in the development of printed DDD and
scaffolds [15–19].
After the first patented FDM technique in 1992, several
single or multi-extruder systems utilizing the fused filament
fabrication technique have entered the market [20,21]. The
FDM experimental desktop printers are relatively cheap and
versatile. The FDM process uses solid polymer filaments that
Figure 1. The design concept of three-dimensionally (3D) printed drug delivery devices (DDD) for personalized therapy.
are fed into the printer through a polymer-liquefying heating
block. The molten polymer is deposited on the build plate
through the printhead [22]. Upon repeating that process,
layered structures are formed after polymer solidification.
The FDM process uses material for two different purposes: (i)
to build the object and (ii) to support the overhangs of the
model. So far, the APIs have been incorporated in the fila-
ments mainly by impregnation or hot melt extrusion (HME).
The FDM printing of the drug-loaded polymer filaments results
usually in a 3D structure, where the drug is (molecularly)
dispersed throughout the polymer matrix [23]. Since FDM is
a solvent-free method, it usually does not require drying steps
or posttreatment [24].
The PAM method, also called semi-solid extrusion (EXT), is
another extrusion-based 3D printing technique. It involves a
layer-by-layer deposition of semisolid or paste materials
through mechanical, pneumatical or solenoid-based extrusion
[25,26]. A single polymer layer is deposited on the build plate
through the nozzle which is moving in the X-Y orientation.
When the layer is completed, the build plate is lowered and
the process is repeated. The PAM systems are often called
bioprinters with the extrusion-based bioprinting technique,
because this method was first utilized to print living cells
and other biologics for the fabrication of living tissue and
organs [26]. To avoid confusion, bioprinting should be used
only when printing living cells and biologics, whereas the
technique should be referred to as PAM or EXT 3D printing
when inert materials are printed [22,25,26].
3. 3D printing of personalized drug delivery devices
Printing technologies are evolving fast and offer various
potential applications in the pharmaceutical field. One of the
benefits of pharmaceutical 3D printing is providing opportu-
nities for individualization of drug therapies and customization
of DDD. The overall development concept of 3D printed DDD
in personalized medicine is presented on Figure 1.
The need for personalized medicine has received growing
attention for many years already. Several patient groups, such
as pediatric and geriatric patients could benefit from the
personalization of the DDD [27,28]. There is a need for custo-
mized DDD due to the genetic variations in the treatment
responses [29]. The development of diagnostic tests based
on genetics makes it possible to optimize treatments for
every patient.

The 3D printing allows manufacturing DDD with varying
geometries and/or with modified drug-release profiles that are
challenging to achieve by conventional drug manufacturing
techniques. Drug-release kinetics can be controlled by the
DDS design and by the selection of polymers and their com-
binations. In the printed DDS, the dosing can be adjusted
according to the individual needs of the patient by changing
the dimensions of the printed formulation and/or by modify-
ing the content of the solid material(s). The facility and versa-
tility to independently tailor the drug delivery of multiple
drugs from the 3D printed DDS makes it suitable for patient
groups that need several drugs simultaneously, for example
patients with metabolic diseases [30]. These DDS could be
obtained by designing formulations with complex inner struc-
tures and compartmentalized matrix systems.
Aprecia® Pharmaceuticals, founded in 2003, was the first
pharmaceutical company to launch a 3D printed drug product
[3,4]. In 2008, the ZipDose® Technology was invented as a
proprietary 3D printing technique mainly for manufacturing
high-dose and easy-to-swallow products for central nervous
system therapeutics. Other pharmaceutical companies, such as
GlaxoSmithKline (GSK), have expressed interest in this field as
well [31]. Printing techniques have been studied to generate
high-throughput screening arrays for drug screening and drug
testing [32]. The collaborations between pharmaceutical and
printing companies are aiming to provide cheaper and more
personalized healthcare solutions in the future [2]. In addition,
3D printed human skin and organs offer an alternative for
animal testing in cosmetic and biomedical research [2,33].
Besides 3D printing technologies, the two-dimensional (2D)
printing technologies, i.e. inkjet and flexographic printing,
have also been applied in the pharmaceutical field. The inkjet
printers are non-contact systems that are based on either
continuous or drop-on-demand jetting technologies, whereas
flexography is a rotary-type contact printing method [34,35].
Reviews on the applications of 2D printing technologies in
pharmaceutics have been provided by Kolakovic et al. [36],
Alomari et al. [37], and Preis et al. [38].
3.1. Stereolithography
The SLA technology has been successfully applied in tissue
engineering [12,39–42] and in prototyping of customized surgi-
cal implants [43–47]. However, the use of SLA in pharmaceutical
applications is limited by the availability of photopolymerizable
Figure 2. Drug delivery devices by stereolithography (SLA). Images of drug-loaded tablets (a) [52] and topical patches (b) [53], and scanning electron micrographs of
drug-doped microneedles (c) [54]. Reprinted from [52,53] with permission from Elsevier. Reprinted from [54] by permission of John Wiley and Sons, Inc.
EXPERT REVIEW OF MEDICAL DEVICES 687
oligomers that would be biocompatible and approved for
human use [22]. As an additional drawback, the SLA printers
operate primarily with single materials. Thus, the fabrication of
formulations with multiple materials, such as polymer mixtures
and drug-loaded structures, is limited [48].
The manufacturing speed and the physical size of the desk-
top printers contribute to the suitability of the SLA fabrication
of personalized DDS at the point of care [48–50]. The high
accuracy and resolution of the SLA printed structures makes it
an attractive approach for the preparation of DDS with com-
plex 3D inner structures [10,48]. Furthermore, the UV photo-
polymerization has shown no significant drug degradation
(<5%) after processing [51–53].
For pharmaceutical applications, SLA has been studied for the
manufacturing of drug-eluding scaffolds [51], topical patches
[53], torus-shaped tablets [52], and microneedles [54–56] with
poly(ethylene glycol) diacrylate (PEGDA) as the base material
(Figure 2). Goyanes et al. [53] prepared the drug-eluding topical
patches with salicylic acid according to a scanned image of an
individual’s nose (Figure 2(b)). The flexibility of the nose-shaped
patches was adjusted by controlling the degree of crosslinking
between PEGDA chains with the addition of poly(ethylene
glycol) (PEG) as a filling agent. In transdermal drug delivery, the
micro-SLA method has shown to be suitable for preparing micro-
needles with various shapes [56] and antimicrobial coatings
[54,55]. The SLA-fabricated DDS are suitable for personalized
medicine with patient-customized size and drug loading at
high accuracy and inter-formulation uniformity [52–54].
Nevertheless, SLA has several technology-driven limitations
that restrict its applicability for printing pharmaceuticals (Table 1).
To be able to manufacture DDD with higher drug loadings, the
API must be adequately soluble in the polymer, which restricts
the use of SLA for high-dose DDD. So far, the drugs have been
dissolved in the photopolymer for the preparation of DDD with
low drug loadings of 1–5.9% [51–53]. However, the manufactur-
ing of printable objects with homogenously suspended particles
(with loadings up to 53%) has been reported [10]. This indicates
that the SLA printing of DDS from resins containing undissolved
drug particles at higher drug content could be possible.
3.2. Selective laser sintering
The SLS technique has been investigated in the pharmaceutical
field only by a few research groups [13,57–60]. The designed
DDD with customized porosity and microstructures have been
688 M. PALO ET AL.
Table 1. Challenges of stereolithography (SLA) printing in the preparation of
drug delivery devices (DDD).
Topic Challenges
Materials Limited availability of photopolymerizable materials for SLA-
printed DDD that would be biocompatible and nontoxic
for human use.
API The photopolymerization process and the post-processing
with UV-curing could be unsuitable for the APIs and
restrict the SLA applicability in the production of DDD.
Dosage form The fabrication of multi-component formulations is limited,
design especially at higher drug loadings.
Process The printing speed of a conventional SLA process is
relatively low compared to other 3D printing methods.
Cost The SLA printing instruments are comparatively expensive.
3D: three-dimensional; API: active pharmaceutical ingredient; DDD: drug deliv-
ery device; SLA: stereolithography; UV: ultraviolet.
prepared with nylon [13], polyamide [57], poly(L-lactic acid)
(PLLA) [58], and PCL [58–60] as the polymeric base material.
The impact of several process parameters on the porosity of
the scaffolds was investigated by Low et al. [13]. In the designed
DDD, the inner and outer parts were manufactured with differ-
ent porosities. The results showed that the porosity of the DDD
could be controlled by varying the powder bed temperature, the
length between the dense walls and the SLS laser power. Leong
et al. [58] demonstrated the versatility of SLS in the manufactur-
ing of microporous DDD. The SLS printed discs with controlled
porosity were obtained by varying the laser power intensity and
the laser scan speed. In another study, the same research group
manufactured four different cylinder-shaped formulations to
investigate how varying the number of dense rings in the struc-
ture impacts the initial burst release of drugs [59]. The initial
burst release followed by a slow and constant release was
reported for all designs with the lowest release obtained for
the formulation containing the highest number of dense rings.
Salmoria et al. [60] manufactured a reservoir-type DDS with the
model compound progesterone by SLS. The drug-loaded DDS
with the API either within the core or within the core and the
shell of the device showed controlled zero-order drug release.
For the fabrication of tailored DDD, the SLS method pro-
vides possibilities for controlling the porosity and the drug-
release kinetics of the 3D printed structures. Nevertheless, the
contribution of this method to the pharmaceutical manufac-
turing has remained modest so far. The limited use of SLS in
pharmaceutical field is driven by the disadvantages related
mainly to the printable materials and the process parameters
(Table 2). Besides these restrictions, the low interest in SLS has
also been caused by the lack of affordable printers [2].
Table 2. Challenges of selective laser sintering (SLS) printing in the preparation
of drug delivery devices (DDD).
Topic Challenges
Materials Limited availability of pharmaceutical excipients and APIs, which
are suitable for SLS without degradation at high energy levels.
Process The production of SLS-fabricated DDD is time consuming. SLS
printing speed is limited to approximately 1–5 cm/h.
Posttreatment of the printed DDD is required due to non-sintered
powder residue on the final structures.
Waste SLS produces significant powder waste after printing process.
Cost The SLS instruments are comparatively expensive due to the low
amount of commercially available printers.
API: active pharmaceutical ingredient; DDD: drug delivery device; SLS: selective
laser sintering.
3.3. 3D printing
The 3DP is a simple, versatile, low cost, and high-speed process
that provides various possibilities for the preparation of perso-
nalized DDS as well as for customizing the composition and
properties of drug-eluding implants. The physicochemical prop-
erties of the dosage forms, and the drug-release profiles could
be adjusted by using different polymers and/or ratios between
the bulk material, API(s), binding agents, and other excipients.
Furthermore, the appearance and the therapeutic performance
could be tailored by adjusting the size and shape of the DDD
and by incorporating functional excipients (e.g. drug release-
modifying agents, colorants, taste masking agents, etc.), into the
binder solution or the bulk powder mixture.
Since the printing process is performed at ambient tempera-
ture, the 3DP is suitable for thermolabile drugs and excipients.
However, printing parameters such as the time interval between
two printing layers, and the distance between the nozzles and
the powder bed must be optimized for successful 3DP printing.
The drawbacks of the 3DP technique are presented in Table 3.
The first 3DP pharmaceutical formulations were built up
from PCL, polyethylene oxide, and dye-loaded binder solu-
tions, demonstrating that 3DP can reproducibly fabricate
DDD with controlled release profiles [61]. Since 1996, several
DDD and implants have been designed and developed to
tailor and control the release of pharmaceuticals for better
therapeutic effect. For example, Lin et al. [62] manufactured
three different designs for subdermal implantation of ethiny-
lestradiol: (i) the single-channel device, where the drug was
incorporated in the channel; (ii) the device with the drug
homogenously distributed in the polymer matrix; and (iii) the
device, where the drug was placed under a concentration
gradient into a polymer matrix. The in vitro and in vivo studies
showed that the drug release from the single-channel device
(i) stayed at a steady level for the first five weeks before
Table 3. Challenges of three-dimensional printing (3DP) in the preparation of
drug delivery devices (DDD).
Topic Challenges
Materials The availability of suitable nontoxic solvents for increasing
the binder solution capacity for dissolved/solubilized
materials is limited.
Dosage form Compared to other methods, the 3DP has lower printing
design resolution and poorer surface quality that can result in
imprecise printing results and affect the DDS/DDD
performance. This could be improved by the additional
post-processing.
Process The preprocessing of the starting powder materials might
be necessary to ensure the suitable particle size
distribution and powder flowability for uniform filling of
the power bed.
Clogging of the printhead might occur during printing of
nonhomogeneous binder solutions.
Migration of the binder solution contributes to the
deflections from the original design and the
inhomogeneity between the printed DDS/DDD.
The 3DP dosage forms have typically lower inter-product
homogeneity and higher risk for internal agglomeration.
The porosity of 3DP products is poorly controllable.
DDD quality Lower mechanical strength of 3DP products limits their
packaging, administration, and overall handling
processes.
3DP: three-dimensional printing or binder jetting; DDD: drug delivery device;
DDS: drug delivery system.

declining gradually, whereas other designs (ii, iii) showed a
higher drug-release rate from the DDD within the first weeks.
The structural integrity of the single-channel DDD (i) was
maintained during the implantation of 5 months.
For certain indications, the local delivery of antibiotics is
more advantageous compared to the systemic drug delivery,
providing a relatively higher therapeutic efficacy and a lower
systemic toxicity. Local delivery of antibiotics by 3DP implants
to treat diseases such as chronic osteomyelitis and bone
tuberculosis has been studied by several research groups
[18,63–69]. For example, drug-eluting 3DP ceramics based on
tricalcium phosphate (TCP) have been investigated by
Gbureck et al. [63,65] with vancomycin, ofloxacin, tetracycline,
levofloxacin and by Inzana et al. [67] with rifampicin and
vancomycin. The use of TCP-based 3DP systems has several
advantages compared to the established polymethylmetha-
crylate drug-eluting scaffolds manufactured by conventional
methods: (i) higher release rate due to the porous structure, (ii)
no need for a second surgery to remove the implant, and (iii)
the possibility of incorporating several antibiotics [63].
Recently, Wu et al. [18] studied columnar-shaped, doughnut-
shaped, and multilayer doughnut-shaped implants with PLLA
matrix and isoniazid as the model antibiotic (Figure 3(a)). The
implants showed an initial burst release, but the release from
multilayer doughnut-shaped implants stabilized after few days
due to the constant effective surface area. In another study, Wu
et al. [68] manufactured multilayered concentric multidrug
implants containing antimicrobial tobramycin and levofloxacin
in a PDLLA matrix for sustained and programmed drug release.
In these multidrug implants, an orderly release of the drugs
from the periphery to the center was obtained. The antimicro-
bial drug with effectivity in low concentrations could be utilized
in these types of implants [18,68]. However, higher drug
loadings could be achieved by dispersing the drug in the
powder bed, compared to the incorporation of the API into
the binder solution.
In the personalized DDS design, the 3DP of pharmaceuti-
cals has been mainly aimed at manufacturing dosage forms
with layered 3D structures and highly variable drug loadings
to control and modify the drug-release profile. Oral dosage
forms, including tablets [15–17,19,71] and fast-disintegrating
tablets (FDTs) [70,72–75], have been successfully prepared by
Figure 3. Drug delivery devices by three-dimensional printing (3DP). Images of
a drug-loaded doughnut-shaped tablet (a) [18] and the cross-section of a fast-
disintegrating drug delivery device with a predefined inner structure (b) [70].
Reprinted from [70] by permission of John Wiley and Sons, Inc.
EXPERT REVIEW OF MEDICAL DEVICES 689
3DP with pharmaceutical grade excipients as matrix forming
agents and binding additives.
Katstra et al. [15] fabricated cellulose-based delayed-release
tablets with chlorpheniramine maleate within the binder solu-
tion. The printed tablets had the API-loaded layers in between
the placebo bottom and top layers. Furthermore, Katstra et al.
[15] used a fluorescein-activated binder solution to evaluate
the binder jetting uniformity of the 3DP process. A good
correlation between the fluorescence intensity and the
expected fluorescein content showed that it could be possible
to precisely define the drug amount by controlling the API
concentration in the binder solution. Rowe et al. [16] fabri-
cated four different types of complex oral DDS, including
immediate-extended, breakaway, enteric dual pulsatory, or
dual pulsatory devices, with chlorpheniramine maleate and
diclofenac as model APIs. The drug-release rate from the 3DP
printed DDS could be controlled by the polymer(s) and their
concentration(s) either in the powder matrix or in the binder
solution [15,71].
The 3DP technique has shown to be beneficial for produ-
cing DDS with variable doses, especially at high drug loadings.
In the study by Yu et al. [19], the controlled-release tablets
were manufactured by adding the API in the powder bed
instead of the binder solution; thus, achieving higher drug
loadings compared to the earlier studies, where the drug
was dissolved in the binder solution. The drug loadings up
to 68% of the weight of the 3DP-printed tablets were
obtained. The drug-release profiles were influenced by the
polymers that were incorporated into the DDS core and the
drug concentration gradient in the tablets. Yu et al. [17]
further increased the drug loading in the 3DP tablets by
incorporating the drug both in the powder bed and in the
binder solution. These acetaminophen tablets were fabricated
with a doughnut-shaped multilayered 3D structure. In addi-
tion, they showed that the printing of top and bottom layers
with an inert and impermeable polymer hindered the diffusion
of water and drug, and the incorporation of a release-retar-
dant material into the binder solution in the peripheral region
of the tablets prevented initial burst release and provided a
linear drug release.
The high porosity of the 3DP-printed tablets contributes to
the rapid disintegration of the DDS within the oral cavity. Lee
at al. [72] prepared mannitol-based oral FDTs with captopril,
where the dispersion time for each FDT decreased when the
binder saturation level (binder liquid content per tablet) and
the level of the additive powder decreased. Yu et al. [70,73]
manufactured oral FDTs with a loose powder core to obtain a
fast disintegration and dissolution of acetaminophen that was
dispersed in the powder bed at 40% loading (Figure 3(b)).
Moreover, the first prescription drug product on the US mar-
ket that is manufactured using a 3DP technology has been
formulated to disintegrate within a few seconds in the mouth
when taken with a sip of liquid [3,4,75]. The antiepileptic
Spritam® (levetiracetam) tablets for oral suspension from
Aprecia® Pharmaceuticals are available in four different
strengths with the API content of 60–90% in the bulk powder
mixture. Levetiracetam, cellulose, mannitol, and colloidal sili-
con dioxide are incorporated in the powder matrix of these
690 M. PALO ET AL.
tablets, and the binder solution contains mainly water, PVP,
Tween 20, and glycerol [4].
3.4. Fused deposition modeling
FDM is perhaps the most extensively investigated 3D printing
technique in the pharmaceutical field. The flexibility of FDM
allows manufacturing of drug-eluting devices and DDS with
various geometries (Figure 4(a)) and/or modified drug-release
profiles for patient-specific treatments at high reproducibility
[24,76]. The drug dosing could easily be adjusted through the
adjustment of the physical parameters of the designed DDS
(Figure 4(b)) [76] or by changing the infill percentage of the
formulated dosage forms [80,81]. Despite its various applica-
tions, several challenges in the printing of DDD have also been
identified over the years (Table 4).
In the FDM-printed products, the drug is incorporated
into the printable filaments prior to printing. The impreg-
nation of APIs into polyvinyl alcohol (PVA) filaments has
been investigated for printing tablets with different shapes
at various drug loadings [24,80,81]. The impregnation pro-
cess is based on passive diffusion and requires saturated or
highly concentrated drug solutions; therefore, it is an
expensive and time-consuming process [22]. Another draw-
back is that the drugs are mainly incorporated on the sur-
face of the filaments, resulting in a low loading percentage
[24,80,81]. The higher solubility the drug has in the impreg-
nation liquid, the smaller percentage of the drug is loaded
into the polymer filament [81].
Compared to the impregnation method, HME can be used
to prepare filaments with higher drug loading in the range of
5–40% [76,77,82–87]. In the HME process, the melted polymer
is mixed with the drug and other excipients. Depending on
the properties of the drug, i.e. its melting point and solubility
in the polymer, the drug either (i) dissolves, (ii) melts, or (iii)
disperses in the molten polymer [23]. Tablets with different
shapes (e.g. caplets, cubes, pyramids, torus, etc.) and drug-
release profiles have been manufactured from extruded PVA
filaments with drug loadings of 5–10% [77,82,83]. The higher
drug loading reduced the quality of the filaments and/or the
DDS [77,82,83]. However, the addition of plasticizers could
help to increase the drug loading of the HME filaments com-
pared to the original PVA filaments [84,85]. The release profile
Figure 4. Drug delivery devices by fused deposition modelling (FDM). Images of printed drug delivery systems (DDS) with adjustable dosing by scaling (a) [76] and
different geometries (b) [77], and printed prototypes of intrauterine systems and filaments with 15% of drug loading (c) [78,79]. Reprinted from [76–79] with
permission from Elsevier.
Table 4. Challenges of fused deposition modeling (FDM) in the preparation of
drug delivery devices (DDD).
Topic Challenges
Materials Due to the heating step in the FDM printing, the materials
are limited to thermoplastic polymers.
API Traditional drug-loaded filaments from thermoplastic
polymers that require high processing temperatures are
generally not suitable for the preparation of DDS with
thermolabile APIs.
Dosage form The design of complex structures might require printing of
design support structures that need to be removed during post-
processing.
Process FDM printing process requires pre-preparation of printable
filaments.
Compared to HME, the drug incorporation into the polymer
filaments by impregnation is time consuming and results
in a lower drug loading yield.
API: active pharmaceutical ingredient; DDD: drug delivery device; DDS: drug
delivery system; FDM: fused deposition modeling.
of the drugs has been reported to be dependent on the shape
of the tablets, particularly on the surface area/volume
ratio [77].
In addition to the original feedstock material PVA, other
pharmaceutical grade polymers have also been investigated for
FDM, including PVP [86], methacrylic polymers [76,84,85,87],
cellulose derivatives [85], polyvinyl caprolactam-polyvinyl acet-
ate-polyethylene glycol graft copolymer (Soluplus®) [84,85], and
PVA-polyethylene glycol graft copolymer (Kollicoat®) [85].
In addition to single drug systems, FDM method is feasible
for producing DDS with multiple APIs. For example, PVA-based
caplets with two APIs (acetaminophen and caffeine) printed as
layered caplets or caplet-in-caplet systems have been success-
fully manufactured with a multi-extruder FDM printers [82].
Furthermore, fabricating DDD from drug-free filaments and
filling them with APIs after printing, allows changing the API
or the formulation without affecting the printing process [88–
90]. These alternative FDM-printed DDS could be suitable also
for thermolabile APIs [88–90]. For example, Markl et al. [88]
fabricated one compartment cylindrical devices from PVA or
poly(lactic acid) (PLA) with carbamazepine powder filling, and
two-compartment cylindrical devices from PVA with saquina-
vir and halofantrine within the inner and outer compartments,
respectively [88]. Besides the design aspects of the formula-
tions, Markl et al. [88] showed that X-ray computed microto-
mography and terahertz pulsed imaging were suitable for

qualitative and quantitative characterization of the microstruc-
tures of the 3D printed oral devices.
Despite the successful manufacturing process, the thermal
analysis of the FDM formulations has indicated that high
processing temperatures can lead to significant degradation
of thermolabile APIs [81,87]. However, a suitable polymer
system could help to stabilize the crystalline API within its
matrix at temperatures above the melting point of the API
[77]. Nevertheless, for thermolabile drugs, polymer filaments
with melting point below the degradation temperature of the
API are needed despite the short heating time in the
printhead.
A lot of research has also been published on FDM printed
scaffolds and implants, whereas the amount of scientific
publications on drug-loaded implants or medical devices
prepared by FDM printing is limited [78,79,91–94]. Printed
devices from drug-loaded PLA filaments with antimicrobial
nitrofurantoin have been studied to investigate the potential
of producing custom-made devices (catheters) and implants
(discs, beads) for controlled drug release and personalized
drug therapy [91–93]. Intrauterine systems with anti-inflam-
matory indomethacin as the model drug have been prepared
by FDM from filaments based on slowly biodegradable PCL
[78] and a nondegradable polymer ethylene-vinyl acetate
(EVA) [79] (Figure 4(c)). Furthermore, Goyanes et al. [53]
manufactured personalized-shaped patches containing sal-
icylic acid with aid of 3D scanning technology and FDM
printing. The nose-shaped structures were printable from
PLA filaments, whereas PCL filaments were suitable for pro-
ducing circular patches [53].
In general, FDM method allows preparing DDD with good
mechanical properties at relatively high resolution. Therefore,
sufficient control of the mass of the printed units and the high
dosing accuracy of the APIs can be achieved [24]. Nevertheless,
the FDM printing process is a complex interplay between many
variables that need optimizing for each new feedstock material
and the printed DDD design.
3.5. Pressure-assisted microsyringe
The PAM extrusion method has found use in the pharmaceu-
tical field quite recently. It is advantageous in producing per-
sonalized DDS with multiple drugs and in fabricating DDD and
drug-eluding scaffolds from pastes, hydrogels and other vis-
cous polymer systems.
Rattanakit et al. [95] were the first to utilize a PAM-based
laboratory-constructed printer for the preparation of DDD. The
biodegradable DDD were printed with a PVA-based paste
containing dexamethasone that was deposited either on
poly(lactide-co-glycolide) (PLGA) films or sandwich printed
with PLGA to fabricate DDD with a scroll configuration. The
drug-release kinetics depended on the geometry of the DDD,
e.g. the thickness of the printed film, and showed a controlled
long-term release up to 4 months.
The PAM printer with a multi-head extruder system can be
highly beneficial for fabricating layered DDS with multiple
drug-release profiles. For example, Khaled et al. [96] prepared
bilayer tablets with guaifenesin to mimic the drug-release
profiles of commercially available guaifenesin bilayer tablets.
EXPERT REVIEW OF MEDICAL DEVICES 691
The mechanical properties of the printed dosage forms com-
plied with the USP specifications for weight variation, thick-
ness, hardness, and friability. Expectedly, the hardness and the
friability of the printed tablets differed significantly from the
commercial compressed tablets due to the lack of compres-
sion force in the 3D printing process.
In other studies, Khaled et al. [30,97] demonstrated the
feasibility of PAM printing in the manufacturing of compart-
mentalize tablets with multiple drugs. The three-compartment
tablets [97] and five-in-one polypills (Figure 5) [30] were
designed to physically separate the drugs to avoid incompat-
ibility issues and to achieve a desired independent control of
the drug release. The mechanical properties of the designed
polypills were acceptable for handling without any loss of
structural integrity [30,97].
PAM has also been applied to develop carrier systems for
targeted cell therapy. For example, Song et al. [98] manufactured
3D printed drug carriers for the transplantation of xenogeneic
cells. The PAM printing was performed with cyclosporin A loaded
PLGA microspheres, which were mixed with an alginate hydrogel.
The 3D structure was strengthened by blending the drug-loaded
hydrogel with a PCL/PLGA structure during the printing.
Drug-eluting scaffolds manufactured by PAM have been
investigated by Zhu et al. [99] and Martínez-Vázquez et al.
[100]. Zhu et al. [99] manufactured dual drug-eluting implan-
table scaffolds for the treatment of osteoarticular tuberculosis
with isoniazid and rifampicin. The prepared scaffolds exhibited
higher mechanical strength, drug loading capacity, and pro-
longed drug-release profile compared to the commercial cal-
cium phosphate scaffolds, where the drugs were absorbed on
the surface of the scaffolds by a dropping method.
Most chemotherapeutic drugs have poor aqueous solubility
and can cause severe adverse effects if administered systemati-
cally; therefore, they are usually delivered locally as injections or
implants. Yi et al. [101] printed a local delivery patch for the
delivery of the chemotherapeutic 5-fluorouracil. A high drug-
loaded paste, containing a polymer blend of PLGA and PCL, was
extruded as a biodegradable patch and implanted in pancreatic
cancer model mice. The drug release from the patches was
adjusted by altering the surface area, porosity and thickness of
the patch.
PAM is a suitable printing technique for many biocompatible
materials [102]. Nevertheless, the PAM printing process has also
some significant manufacturing limitations [102,103] (Table 5).
Materials with viscosity ranging from 30 to > 6 × 107 mPa·s have
been exploited in the PAM printers. Despite of that, the drug
loading capacity of semi-solids is limited by the rheological prop-
erties of the materials and might require significant adjustment of
the printing parameters. The utilized printing temperatures are
moderate and the printing is often performed at room tempera-
ture; therefore, PAM is highly suitable printing method for thermo-
labile APIs. Furthermore, changing between the different materials
could be easily achieved with multi-head extruder systems.
4. Regulatory perspective on 3D printing of drug
delivery devices
Although it was not until recently FDA approved the first 3D
printed oral dosage form submitted under the 505b(2) pathway,
692 M. PALO ET AL.
Figure 5. Drug delivery devices by pressure-assisted microsyringe (PAM) printing. Image of drug delivery systems (DDS) with multiple drugs (left) and the schematic
structural diagram of the DDS design (right) [30]. Reprinted from [30] with permission from Elsevier.
Table 5. Challenges of pressure-assisted microsyringe (PAM) printing in the
preparation of drug delivery devices (DDD).
Topic Challenges
Materials The polymers with crosslinking mechanism or shear-
thinning properties are highly preferred.
The printability of the materials is affected by their
rheological properties. The applied extrusion forces are
dependent on the viscosity of the semisolids.
API The APIs are required to be dissolved or uniformly dispersed
in the semisolid printing material.
Dosage form The printing resolution of PAM printing is limited by the
design nozzle size of the microsyringes.
Process Drying of the printed formulations might be required before
final solid formulations are obtained. This could be
avoided by crosslinking during printing.
The PAM printing process is relatively slow extrusion
technique.
DDD quality The mechanical strength and durability of the printed
formulations is low. Posttreatment, e.g. by crosslinking,
might be applicable to improve these properties.
API: active pharmaceutical ingredient; DDD: drug delivery device; PAM:pressure-
assisted microsyringe.
the FDA has already for 10 years reviewed and cleared many 3D
printed non-implantable and implantable medical devices
through the 510(k) process. The medical devices that have been
approved by FDA have all been reviewed and accepted according
to the existing regulations by recognizing similarities and differ-
ences with existing technologies [104]. Naturally, the printed DDD
must be made in accordance with the current chemistry, manu-
facturing and control (CMC) standards as set forth in FDAs 21 CFR
200 & 300 series and other relevant guidance, and thus follow the
same pathway and manufacturing requirements as conventional
medical devices/products.
On 10 May 2016, FDA issued a draft guidance document for
the additive manufactured devices, where the design, manu-
facturing, and testing issues are taken into account [105]. The
scope of the guidance is to describe the flow of the manufac-
turing process and to outline the critical design, manufactur-
ing and post-processing parameters. Additionally, the draft
guidance outlines the process validation and device testing
considerations. The current pharmaceutical regulations are
being reassessed to resolve issues related to the process
units, pharmaceutical ink formulations, printers, printing
designs, and the final printed DDS.
In personalized drug therapy, the marketable 3D printed
medicinal products will also face several regulatory hurdles
derived from the aspects of personalized medicine [106,107].
Due to the complexity of 3D printed DDD and dosage forms,
many issues on the liability, intellectual rights and data pro-
tection need to be addressed to protect manufacturers and
the end-users. The exploitation instructions, appropriate sto-
rage conditions and safety of the computationally designed
dosage forms and medical devices, as well as the patient-
related data, must be ensured to avoid possible liability
problems related to the misuse of the information and to
minimize the risk for manufacturing errors. As with any new
production line/system, the validity procedures should be
strictly determined and the responsible bodies should be
appointed to avoid any fraud or negligence. It must be men-
tioned that with the advent of improved online analytical
systems, such as different kind of spectrometers, there are
good prospects for integrating quality control tools to printers
in an inexpensive way to monitor the quality of every
printed DDD.
In the European Union legal framework, the marketed
medicinal products are subjected to the Directive 2001/83/EC
related to the medicinal products for human use, when the 3D
printed devices are either ‘prepared industrially or manufac-
tured by a method involving an industrial process’ [108].
Medicinal products that do not fall under that category should
be evaluated on case-by-case basis. The 3D printed DDS may
also be defined as magistral formula, officinal formula, or
investigational medicinal products, if the appropriate regula-
tory requirements are fulfilled. In addition, it should be noted
that the recently published European Union regulations on
medical devices that will come into force in spring 2020 will
define the rules and acceptance criteria for the medical
devices and in vitro diagnostic medical devices. To date,
there are no valid legislations, neither national nor interna-
tional, that would cover the 3D printed DDS and DDD as a
separate category of medicinal products.
5. Expert commentary
3D printing is in an intriguing state from the pharmaceutical
development viewpoint. The rapidly increasing research in the
field has led to the fabrication of complex prototypes of DDS
and DDD with the aim to provide customized drug products
and to improve the patient-specific drug therapy. However,

the introduction of 3D printing into the pharmaceutical indus-
try has barely started with the first commercial product reach-
ing the US market in 2016. A considerable increase in the
activity and the interest in the field by the pharmaceutical
industry can be seen after the approval of Spritam® by FDA.
With the technological advancements as well as the new
concepts generated in the scientific community, solid dosage
form design and the manufacturing concepts have the possi-
bility to develop and evolve. The researchers have been coura-
geous in synthesizing and testing the feasibility of novel
materials, and developing dosage forms and complex designs
for advanced and more accurate drug therapy. Since the
applications of 3D printing expand over a vast range of dis-
ciplines from electronics to medicine, the scientific collabora-
tions and interdisciplinary work could help to establish smart
pathways for achieving novel therapeutic solutions.
After approximately two decades, the possibilities and lim-
itations in the 3D printing of pharmaceuticals have started to
form, which has also been the driving force for reviewing
regulatory documents to provide up-to-date guidelines for
the pharmaceutical manufacturers. Nevertheless, it is expected
to take several years, before the legal aspects of pharmaceu-
tical printing are clearly understood, and 3D printing can be
considered a natural part of the pharmaceutical manufactur-
ing system. It remains to be seen whether the compounding
route will play role in bringing the technology and drug
manufacture closer to the patient.
6. Five-year view
The development of 3D printed medical devices is expected to
progress by the knowledge-driven design within the next
5 years and beyond. The experimental manufacturing of DDS
and other medical products by advanced and emerging tech-
nologies, e.g. 3D printing, will continue to increase at a steady
pace. As the utilization of 3D printing evolves, viable business
models that allow improved therapies by printing will be
founded. This approach will be especially suitable for certain
therapies, where there is a need for tailoring of drug delivery,
dosing and/or the geometry of the devices.
From the research and technical development point of
view, the production units with integrated quality control
systems will start to emerge on the market to permit printers
to be used closer to the patient at hospitals and pharmacies.
This allows quality-by-design pharmaceutical manufacturing
and real-time monitoring at the production unit and the
development of high quality dosage forms and devices.
Furthermore, different 3D printing methods are expected to
support the development of complex delivery systems with
easily controllable parameters for personalized drug therapy.
We will most likely see printers and printheads developed for
specific products rather than having one-printer-fits-all solu-
tions. From a technological aspect, tailored printable materials
might be needed; 3D printers and software have to be
designed in a manner that they meet the specific needs of
pharmaceutical manufacturing to ease the progress of imple-
menting 3D printing for better treatments.
EXPERT REVIEW OF MEDICAL DEVICES 693
Key issues
● Concepts of 3D printing of pharmaceuticals have evolved
rapidly over the last few decades. The fabrication of 3D
printed drug delivery devices (DDD) has enabled the devel-
opment and production of formulations with complex
structures that are difficult or impossible to achieve with
traditional manufacturing techniques.
● The 3D printing provides various opportunities for the indi-
vidualization of drug therapy and for the patient-specific
tailoring of DDD and drug delivery systems (DDS).
● The 3D printing is an umbrella term for several 3D printing
methods, which are based on different technological pro-
cesses and use various types of materials. The main techni-
ques applied in pharmaceutics are fused deposition
modelling (FDM), jetting-based three-dimensional printing
(3DP), pressure-assisted microsyringe (PAM) extrusion print-
ing, stereolithography (SLA) and selective laser sinter-
ing (SLS).
● In general, the 3D printed products are produced according
to a computer-aided design (CAD) that is sliced into prin-
table layers. A layer-by-layer fabrication approach is used to
obtain the final solid 3D structures.
● The 3D printing is suitable for the fabrication of DDS with
tailored doses, multiple drugs and/or controlled drug
release kinetics. The personalization of the 3D printed
DDS can be achieved through the customized design of
the DDS, including the use of dosage forms with various
geometries, the scaling of the dosage form dimensions and
the formulation of compartmentalized dosage forms.
● The technological challenges of pharmaceutical 3D printing
are mainly related to the limited availability of suitable
materials, the incompatibility of the drugs with the printing
conditions and the need for post-processing.
● The fabrication of 3D printed DDD and DDS must be in
accordance with the current pharmaceutical manufacturing
standards for conventional medical devices/products.
Currently, the 3D printed DDD and DDS are not a separate
category of medicinal products.
● In the future, the scientific collaborations within the 3D
printing community in academia and industry will be cru-
cial for establishing smart solutions and pathways for novel
therapeutic concepts to improve treatments in specific
areas. The technological solutions with the hardware, soft-
ware and integrated quality control units aimed specifically
for pharmaceutical applications would immensely support
the progress of 3D printing within the field.
Acknowledgments
The authors would like to thank Risto Hakala, Joonas Mikkonen and
Christine Talling from Bayer Oy for review of the text.
Funding
This paper was funded by the Abo Akademi University.
694 M. PALO ET AL.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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