Manufacturing Engineering Challenges of Pharmaceutical 3D Printing for on-Demand Drug Delivery - Juniper Publishers
Juniper Publishers - Open Access Journal of Engineering Technology
Abstract
There are about two dozen 3D printing technologies
available in the market. These technologies differ in terms of layering
mechanism, type of material that can be handled, binding mechanism and
suitability for solid dosage form manufacturing. Based on literature
information and preliminary data, fused deposition modeling (FDM),
selective laser sintering (SLS) and powder-bed 3D printing methods have
emerged as the most promising candidates for delivering on-demand drugs
according to established Good Manufacturing Practice (GMP) guidelines of
the pharmaceutical industry. However, information on interplay of
critical process parameters (CPPs) and critical materials attributes
(CMAs) on the critical quality attributes (CQAs) of the formulations and
products that will determine their in-vitro and in-vivo performance is
not readily available in the literature. Through this mini-review, we
underline the pressing need for the systematic exploration of these
critical factors and present the Ishikawa diagrams for the three
mainstream 3D printing techniques already penetrating the specialized
niches of the pharmaceutical manufacturing market at an extremely fast
pace.
Keywords: Additive
Manufacturing; Critical quality attributes; Compatibility; Fused
filament fabrication; Micro particles; Nan particles; IngredientsAbbrevations: AM: Additive Manufacturing; FDM: Fused Deposition Modeling; FFF: Fused Filament Fabrication; SLS: Selective Laser Sintering; PVA: Polyvinyl Alcohol; CPPs: Critical Process Parameters; CQAs: Critical Quality Attributes; CMAs: Critical Material Attributes; GMPs: Good Manufacturing Practices
Introduction
Additive Manufacturing (AM) in general and
three-dimensional printing (3DP) in particular is emerging technologies
expected to revolutionize pharmaceuticals manufacturing along with other
fields [1-4]. These technologies offer the ability to create limitless
dosage forms that are likely to challenge conventional drug fabrication
methods not only in product quality and efficacy but also in cost
efficiency as 3D printers have already been successful in producing
novel dosage forms within minutes [3]. Three situations where this
on-demand pharmacy capability may be applicable include printing
directly on the implants or tissue scaffolds, printing “just in-time” in
healthcare facilities or in other resource-constrained settings and
printing low-stability drugs for immediate consumption. In all these
scenarios, 3D printing technologies provide attractive solutions to
explore on-demand pharmacy [5]. FDA approved first commercial drug
product based on 3DP technology in 2015 (NDA #207958,
Spritam® (levetiracetam) triturates Aprecia Pharmaceuticals Co) [6]. It
is a high drug loaded tablet that disintegrates in less than 10 seconds
which is atypical even for orally disintegrating tablet. Even though its
underlying manufacturing technology is two decades old, very little
information is available in the public domain about the process and
formulation variables that could affect critical quality attributes of
drug products manufactured by 3DP. Furthermore, quality defects in the
drug products manufactured by 3DP will be entirely different from
compressed tablets. Thus it is essential to evaluate 3DP techniques for
their compatibility with pharmaceuticals from the perspective of
on-demand pharmacy feasibility and application.
3DP Technologies Amenable to Pharmaceutical Manufacturing and Their Unique Aspects and Materials
The primary 3DP technologies that can be used for
pharmaceuticals manufacturing are inkjet-based or inkjet powder-based
3DP, fused deposition modeling (FDM) also called
fused filament fabrication (FFF) and selective laser sintering
(SLS).
Inkjet-based or inkjet powder-based 3DP
Whether another material or a powder is used as the
substrate is what differentiates 3D inkjet printing from powderbased
3D inkjet printing. In inkjet-based drug fabrication,
inkjet printers are used to spray formulations of medications
and binders in small droplets at precise speeds, motions, and
sizes onto a substrate. The most commonly used substrates
include different types of cellulose, coated or uncoated paper,
microporous bioceramics, glass scaffolds, metal alloys, and
potato starch films, among others [2-5]. Researchers have further
improved this technology by spraying uniform “ink” droplets
onto a liquid film that encapsulates it, forming microparticles
and nanoparticles. Such matrices can be used to deliver small
hydrophobic molecules and growth factors [7]. In powder-based
3D printing drug fabrication, the inkjet printer head sprays the
“ink” onto the powder foundation. When the ink contacts the
powder, it hardens and creates a solid dosage form, layer by
layer. The ink can include active ingredients as well as binders
and other inactive ingredients. After the 3D-printed dosage form
is dry, the solid object is removed from the surrounding loose
powder substrate [3-5,7]. Very limited work has been reported
concerning controllable printing parameters in binder jetting
process and materials attributes (active and inactive), which
could substantially affect critical quality attributes (CQAs)
of pharmaceutical formulations. Therefore, having a good
understanding and experimental insight into the practical effects
of such parameters on CQAs seems to be essential. The fishbone
(Ishikawa) diagram for pharmaceutical powder-bed and inkjet
3D printing processes is given in Figure 1.
Fused deposition modeling (FDM)
In FDM/FFF, the object is formed by layers of melted or
softened thermoplastic filament extruded from the printer’s
head at specific directions as dictated by computer software.
Inside the FDM printer’s head the filament is heated to just above
its softening point which is then extruded through a nozzle,
deposited layer by layer immediately followed by solidification
[4-5,7-9]. The speed of the extruder head may also be controlled
to stop and start deposition and form an interrupted plane
without stringing or dribbling between sections although
nanoparticle emissions were detected during the process
[2-3,9-12]. The potential of FDM 3D printing to incorporate
drugs into commercially available filaments has been explored
previously [13,14]. Nonetheless, all those studies highlighted
several challenges involved in employing printing technique for
pharmaceutical applications. The use of elevated temperatures
(185-220 °C) and limited drug loading (0.063-9.5%w/w)
renders it less suitable for many drugs particularly thermolabile
ones [13-15]. FDM 3D printing has been also restricted to a
number of biodegradable thermoplastic polymers such as
polylactic acid (PLA) [16] and polyvinyl alcohol (PVA) [4,13-
15] in comparison to a wide variety of choices for conventional
tableting. Despite the attractive properties of PVA [17] and PLA
[18], the use of high polymer ratio in combination with the need
for high molecular weight of the polymers generates polymeric
matrices with limited porosity, thus resulting in extended drug
release patterns. To increase the flexibility and potential of FDM
3D printing process, never filament formulations also employing
nanocomposite compounding approaches will be needed to
overcome existing limitations of FDM type pharmaceutical 3D
printing. The fishbone (Ishikawa) diagram for pharmaceutical
FDM processes is provided in Figure 2.
Selective laser sintering (SLS)
Like all methods of 3D printing, an object printed with the
SLS process starts as a CAD file. Objects printed through this
method are made with powder materials, most commonly
plastics, such as nylon, which are dispersed in a thin layer on top
of the build platform inside an SLS machine. The laser heats the
powder either to just below its melting point (sintering) or above
its melting point (melt consolidation), which fuses the particles
in the powder together into a solid form. Once the initial layer is
formed, the platform of the SLS machine drops usually by less
than 0.1 mm, thus exposing a new layer of powder for the laser
to trace and fuse together. This process continues again and
again until the entire object has been printed [2,19]. Very limited
information is available in the literature for pharmaceutical
application of the SLS technique [5,20]. The characteristic
limitations of this process are attributed to incompatibilities
between laser energy settings and properties of thermoplastic
polymer used to print drug product. It is important to understand
the interplay of the SLS critical process parameters (CPPs) and
polymeric powder critical material attributes (CMAs) on critical
CQAs, as shown by the Ishikawa diagram in Figure 3.
Conclusion
The most promising 3DP technologies for pharmaceutical
applications and their manufacturing engineering related
challenges were discussed. In all methods, understanding
critical process parameters (CPPs) is equally important as
understanding critical material attributes (CMAs) to ensure
consistent quality of 3D printed solid dosage form. Rigorous
experimental studies are needed to validate process and materials
engineering correlations between CMAs and CPPs, which can
also identify optimal control strategies and potential risk factors
for process failure or deficiencies in terms of pharmaceutical
good manufacturing practices (GMPs). Including all variants
and hybrid approaches, about two dozen 3DP technologies
currently exist in the market each with varying capabilities and
complexities. Although objective assessments of current process
limitations and capabilities assign a higher chance to powder bed and SLS techniques in the race for on-demand drug delivery,
the Darwinian dynamics of technology evolution coupled with
process engineering and materials technology innovations will
determine which particular ones would be indeed the fittest to
survive in the domain of pharmaceutical manufacturing.
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