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1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 7
1.2.3 Selective Laser Sintering (SLS)
SLS is a form of AM that fuses powder particles together layer-by-layer using a
laser, a directed energy source. SLS requires powder as the input material, so powder
preparation (blending, granulation, etc.) is a precursor step to pharmaceutical SLS.
During SLS, a roller spreads a first thin layer of powder onto the build platform.
The laser scans across the powder layer and sinters the powder in selected locations
according to a 3D image file. Then the platform descends for the next powder layer,
and sintering process repeats until the full part design is complete.
SLS formulations mainly consist of two functional excipients: (i) thermoplastic
polymer and (ii) laser absorbent/pharmaceutical grade colorant.
Currently, Merck KGaA (Darmstadt, Germany) has partnered with AMCM/EOS
(Starnberg, Germany) to provide an SLS platform for one step tablet production
intended for clinical supply, commercial supply, tailored formulation, and product
development (Merck Merck’s 3D Printing Overview
KGaA, Darmstadt, Germany and B. Braun Join Forces in the Development of
Bioelectronic Devices
n.d.).
n.d.; Schrimpf G Merck
1.2.4 Semi Solid Extrusion (SSE)
SSE printing process uses similar principles of printing as FDM, but using a
semisolid working material instead of a melt. Like other AM, SSE requires CAD file
loaded in the printer to start the printing process. SSE uses gel or paste as feedstock
that is then extruded through a syringe, which can be heated if needed to aid material
deposition. Versus FDM, SSE printing can be performed using lower temperatures
(near ambient) making it suitable for thermolabile or thermo-sensitive compounds.
Primary process considerations include viscosity of the raw material at ambient and
at operating temperature, nozzle size, feed rate, and printing speed.
A formulation advantage of SSE is that it can use either paste or gel. Paste
(Seoane-Viaño et al.
excipients in a water/ethanol mixture, whereas gel (Basit and Gaisford
feedstock minimally contains gelling agent/water. Accordingly, an SSE formulation
typically entails: (i) water insoluble polymer as release modifier and/or disintegrant
and (ii) water-soluble polymer as matrix former and/or disintegrant. Hence, formulation development and excipient selection for SSE mainly depend on the desired
properties of the final dosage form and the rheological properties of the semisolid
feedstock to provide consistent deposition at the working conditions of the process.
Recently, CurifyLabs (Helsinki, Finland) has introduced a small platform for
personalized dosing named MiniLab which provides semisolid extrusion directly
into blister packs, decreasing manual compounding work by 72%. According to the
company, this technology has already been applied to serve patients at compounding
pharmacies such as Finnish Oulu Central Pharmacy (Hanaphy
Our Clients n.d.). The proposed deployment of this technology includes clinical
trials (indicated to have started), compounding pharmacy, and veterinary medicine.
2021a) feedstock can contain customary soluble and insoluble
2018)
2022; Labs C Curify-
8 K. Sen et al.
1.2.5 Binder Jet 3D Printing (BJ3DP)
Inkjet/Binder Jet 3D printing requires two feedstocks—a powder mixture and a
binder liquid (“ink”) which selectively binds the powder particles together during
the printing process. Like other AM, the part design and feedstocks are loaded ahead
of printing. During binder jetting, a roller spreads a thin powder layer on the build
platform followed by selective deposition of the liquid onto the powder according
to the part design. Then the platform descends, and the process repeats layer-bylayer until the entire part design is completed. After printing, the parts are dried and
separated from loose, unprinted powder. Drying conditions are determined based
on the materials, typically selecting the highest post-processing rate that does not
adversely impact composition stability.
BJ3DP formulation requires at least one powder and at least one liquid feedstock.
The liquid may be solution or suspension. The powder may be a dry blend,
granulation, or other coprocessed or engineered powder. The liquid is formulated for
reliable jetting and powder binding and typically contains: (i) binding agent (usually
polymer), (ii) surfactant, (iii) humectant, and (iv) aqueous or organic solvents (e.g.,
water, oil, ethanol). The powder mixture may contain: (i) binding agent soluble
in the liquid, (ii) matrix or bulking agent as appropriate, and (iii) disintegrant, if
necessary. The API may be incorporated either as part of the powder or as part of
the liquid feedstock, or both. This optionality is a key difference versus other forms
of AM.
Using BJ3DP, Aprecia Pharmaceuticals (Blue Ash, Ohio, USA) (West and
Bradbury
regulatory approval of a 3D printed medicine (Spritam
a uniquely high-dose (250–1000 mg) fast-disintegrating tablet exemplifying the
company’s ZipDose
plant using Aprecia’s proprietary scaled version of BJ3DP (Z-Free). Recently,
Aprecia has introduced new technology, including equipment for printing dosage
forms directly in blisters (Z-Form) and new pre-formed orodispersible shells that
can be filled with more diverse payloads and assembled analogous to capsules
(ZipCup
introduces-z-form-flex-manufacturing-activity-6987723679329656832-D2Jw?
trk=public_profile_like_view) (Jonathan and Karim 2016; Pollinger and West
2022).
2019) has been a pioneer in AM of pharmaceuticals, obtaining the first
®
family of formulations and is manufactured in a centralized
™
/Z-Fill) (https://fi.linkedin.com/posts/aprecia-pharmaceuticals_aprecia-
®
) in 2015. Spritam is
1.3 Current State of AM Technologies in Pharmaceutical
Practice
Today the deployment of AM is still nascent and poised to impact key aspects of
modern drug delivery practice as well as classical pharmacy practice over time
(Park et al.
2021). For drug delivery, AM promises a new suite of options to
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 9
control localized structure and composition of dosage forms, impacting many of
the core drug delivery goals that have been recurring themes in the field. For
pharmacy practice, AM offers new capabilities for extemporaneous preparation and
individualization of dosage forms, potentially with dosing or release properties that
are difficult to achieve using other manufacturing techniques.
Accordingly, this section is structured to review several prominent pharmaceuti-
cal goals for AM use that cut across aspects of drug delivery and pharmacy practice.
They center on frequent themes or motivations for introduction of AM into the
pharmaceutical field. These goals for AM are as follows:
1.3.1 Personalization, point of use, and on demand manufacturing
1.3.2 Improving bioavailability of low solubility compounds (e.g., BCS II and IV)
1.3.3 Modulating release kinetics of dosage forms
1.3.4 Combining medications into a single dosage unit (“polypill”)
1.3.5 Orodispersible dosage forms
1.3.6 Others AM uses of note
Each goal will be discussed in turn, recognizing there can be some overlap or
combinations of concepts in the examples cited. The type and extent of deployment
of AM technologies differ across these goals, based in part on the strengths and
weaknesses of each technology. The following subsections review the deployment
of AM for each goal, highlighting the most mature usage thus far as an illustration
of the state of the art.
1.3.1 Personalization, Point of Use, and On Demand
Manufacturing
This section focuses on the potential for AM to change what is made, for whom it is
tailored, where and how it is made, and also when it is made. Table
several ways that AM may be used to change the medication itself or the way in
which it reaches the patient.
Pursuing one or more of these goals in tandem can substantially impact the
approach to AM equipment design and deployment.
Figure 1.2 provides a conceptual representation of these effects on equipment
design, illustrated with respect to the distance of the machine deployment from the
patient.
State of the Art
Taken as a whole, the concepts of Table
these ideas have already reached a degree of practical deployment to benefit patients.
Thus far two small-scale (desktop) AM systems are commercially available
for pharmaceutical use: the M3dimaker FDM/SSE-type system from FabRx, and
the MiniLab SSE-based system from CurifyLabs. Subject to any formulation or
processing limitations, each of these systems is able to make dosage forms in various
1.1 are broad in scope. Even so, a few of
1.1 summarizes
10 K. Sen et al.
Shariff et al. (2020)
Goh et al. (2021) Robles et
al. (2019)
Maroni et al. (2017),
Maniruzzaman (2019)
Januskaite et al. (2020)
Okwuosa et al. (2017)
Rautamo et al. (2020)
Saydam and Takka (2020)
Sertoglu (2020)
Labs C Curify-Our Clients
West and Bradbury (2019)
(n.d.)
Size, shape, color, texture, smell, taste for patient
Unique structure or function of the dosage for
specific patient needs (FDC or Polypill)
Aspects Selected Refs
Tab le 1 .1 Types of personalization, point of use, and on-demand manufacture of medicine that are possible using AM
Levels of the drugs (dose) Unique strength and/or concentration of drug Siyawamwaya et al. (2019),
What Number and choice of drugs Combination of drugs in same dosage form matched to
particular patient groups or individuals. Unique release
Type of dosage form across routes of
administration
acceptance or palatability. Exclusion of certain
kinetics. Orodispersible forms. Implants.
Organoleptics;
Excipients
timing, or regimen.
excipients due to patient allergy.
Markings Identifiers or reminders to the patient about identity,
dose loading). Dispersible form.
Pediatric Personalized dosing (attractive dosage form, different
For whom
Geriatric Polypill. Dispersible form. Karavasili et al. (2021)
(Target
Population)
Cancer patients. Conditions that require complex
release profiles-circadian rhythm. Patients with
Specific classes of patients (based on
disease or disorder)
difficulty in swallowing, CVD, HIV, etc. Rare diseases
(Orphan Drug). Visually impaired.
differently using AM.
Centralized Mfg Traditional manufacturing plant, optionally operating
How and
where
Progressively closer to the patient, up to the point of
Decentralized Mfg
care (hospital, pharmacy, clinic)
(e.g., point of use)
When On demand (Extemporaneous) Progressively closer to the time of use. More likely to
be performed with greater proximity to the patient.
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 11
1
Quality & Regulatory Compliance
2
Speed Matched to Demand
3
4
Centralized Plant
Distance
From Patient
Patient
5
Number of Machines
6
Ease of Use
7
Cost per Unit
Onsite (Point-of-Use)
Hospital or Clinic
Local Compounding
Facility or Pharmacy
Size of Machine
Skill for Use
Regio nal H ub
Fig. 1.2 Influence of proximity on the design and deployment of AM for pharmaceuticals
sizes, shapes, and colors, incorporating one or more drugs at dosages tailored to an
individual patient. The small format of each is suited to decentralized use close to
the point of care. The timing can be essentially on demand, with whatever lead time
is needed to account for manufacturing speed and sequencing of orders for patients.
CurifyLabs has indicated that MiniLab is in use at compounding pharmacies in
Finland.
At larger scale in a centralized manufacturing model, Aprecia’s ZipDose formulations use BJ3DP for a more general tailoring of dosage form and formulation to
groups of patients with swallowing difficulties. The technology is largely positioned
for high-dose medicines constituting some of the largest tablets and capsules. The
first commercial example, SPRITAM, provides an easy-to-administer form of the
drug levetiracetam, a highly prescribed first-line treatment for children and adults
with epilepsy. The product has been marketed in U.S. since 2016.
In clinical development, Triastek has received IND clearance for three product
candidates (T19, T20, T21) using FDM-type AM to tailor release kinetics and/or
bioavailability for specific therapies. T19 aims for chronotherapeutic delivery for
rheumatoid arthritis (e.g., administration at night to provide coverage for morning
symptoms). T20 seeks once-daily dosing for a cardiovascular and clotting disorder
medication that is currently given twice daily. T21 is intended for colonic drug
delivery in the treatment of ulcerative colitis while reducing systemic side effects.
Discussion
The personalization of 3D printed dosage forms can be performed in one or more of
the following ways.
The number and choice of drug. Using 3D printing, a dosage form can be
personalized based on the requirement of an individual’s needs with respect to the
choice of drugs and the number of drugs to be incorporated in one pill (polypill).
3D printing allows the creation of medicine with distinctive geometry which makes
12 K. Sen et al.
it easy for the patient to distinguish. 3D printing also has the potential to modify the
flavor or make a chewable version of the medicine according to patient’s preference,
thus increasing treatment adherence (Goyanes et al.
2019). For patients who need
to administer multiple pills in one day, using a 3D printed polypill would reduce
the common issue of dosing error or forgetting to take one or more pills, albeit with
some risk of more severe impact if the polypill itself is missed.
Levels of drug. 3D printing process (such as binder jet, FDM, etc.) allows the
creation of non-standard doses of drug more easily than conventional techniques,
especially for small batches. For orodispersible dosage forms specifically, relatively
high drug loading (>60% w/w) has been demonstrated, which is difficult to achieve
through legacy techniques such as freeze-drying or soft-compression. Moreover,
using the consistency and droplet placement of inkjet 3D printing, a higher content
uniformity can be achieved in extremely low drug loading (μg scale).
Type of dosage form. For tablets swallowed intact, the architecture of dosage
design can affect drug release in a dosage form. 3D printing process allows a
medicine to be positioned internally with local excipients in such a way as to
provide tailored drug release (progressive release, pulse release, delayed release,
etc.). Alternate dosage forms such as orodispersibles or implants can be created
having different capabilities than those from legacy techniques.
Organoleptic properties. The size, shape, color, texture, smell, or taste of a
printed tablets can be customized to provide a better match with a patient’s needs.
Certain excipients can also be excluded based on the patient allergy history (e.g.,
mannitol instead of lactose), a frequent reason for compounding of medicines.
Markings. Dosage forms can be marked a number of unique ways to provide
reminders of drug identity or regimen. For example, for two similarly shaped
and colored dosage forms, a customized marking could potentially benefit elderly
patients in correctly identifying each medicine. Similarly, braille or other raised
markings could be created for the vision-impaired.
3D printing of pharmaceutical medicine can potentially be deployed in three
categories: i. centralized, ii. decentralized, and iii. on demand. Centralized and
decentralized are intended in the spatial sense of equipment placement, whereas
on demand refers to the temporal sense of equipment utilization.
Centralized deployment is analogous to that of the conventional medicine
supply chain, using a single point for mass-production and later distribution to
wholesalers and local pharmacies or the point of use. For this arrangement, the
manufacturing site is rarely near the patients, and significant inventory must be made
in advance. Centralized deployment of 3D printing has already been demonstrated
(Aprecia Pharmaceuticals) using the traditional regulatory process for new drug
approval. In contrast, decentralized deployment involves the use of 3D printing
at multiple small locations, typically closer to the patient, and is still at its nascent
stage. For decentralized deployment, there is a requirement to be performed under
the supervision of a registered pharmacist at a compounding facility in accordance
with appropriate local regulations, which provides increased opportunity for those
medicines to be produced on demand (such as at a hospital, clinical setting, and
pharmacy). The implementation of decentralized 3D printing of medicine is lagging
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 13
behind due to the lack of existing standardization process in the production process
(Aquino et al.
made centrally (Spritam in 2015) occurred several years before availability of the
first AM equipment designed for decentralized compounding (M3dimaker in 2020).
In addition, the cost effectiveness of AM has been demonstrated for centralized
deployment but for decentralized deployment it remains to be seen, based on an
AM study across industries (Thomas and Gilbert
there are signs of early adoption of AM for decentralized use. SSE was used in a
hospital (decentralized) clinical study with different flavors and colors of chewable
for children with rare metabolic diseases (Goyanes et al.
explored to fabricate ODF in a vet clinical setting where the doses of prednisolone
have been personalized for animals (Sjöholm et al.
State of the Art, two small pharmaceutical printers have recently come to market for
decentralized use.
2018). To illustrate this point, the first approval of an AM drug product
2015). Despite those uncertainties,
2019). SSE has also been
2020). Also, as noted under
1.3.2 Improving Bioavailability for Low Solubility Compounds
(e.g., BCS II and IV)
One of the pivotal steps in formulation development is to attain sufficient bioavailability of an API in a suitable dosage form for the patient group, most often via
oral route. Unfortunately, most new drug substances in development (Peltonen
and Hirvonen
maceutics Classification System (BCS) and are classified as BCS II or IV (low
solubility) (Lindenberg et al.
remains a significant priority for industry. Due to high cohesivity of their crystalline
structure, these APIs exhibit low aqueous solubility. Various approaches have been
investigated to increase the solubility of these poorly soluble APIs (Kanaujia et
al.
2015) such as particle size reduction (Jennotte et al. 2020), nanocrystallization,
amorphous solid dispersion (ASD) formation (Ayyoubi et al.
emulsifying drug delivery system (SMEDDS).
The best BA enhancement technique for these drugs differs case-by-case based
on API properties, therapeutic goals, and commercial goals. Similarly, the compatibility of these techniques with each form of AM will depend on those factors as
well as the respective physicochemical phenomena involved in each form of AM.
2018) (~70%) do not meet high solubility criteria for the Biophar-
2004). Increasing bioavailability for these compounds
2021), and self-micro-
State of the Art
Thus far, AM technology has demonstrated early proof-of-principle for BA
enhancement of BCS II and IV compounds. The existing research includes
approximately 26 published studies, all based on in vitro results, encompassing
19 different APIs and making use of ~20 different functional excipients in concert
with AM as part of an overall strategy for improved BA. To date, there do not
appear to be any confirmed examples in the clinical development or commercial
stage (Zema et al.
2017).
14 K. Sen et al.
Table 1.2 summarizes key examples for BA enhancement, grouped by the type
of AM technology. Each AM technology is then discussed in more detail for this
application.
1.3.2.1 FDM
FDM and HME-FDM platforms have the capability of amorphizing low solubility
drug crystals and mixing with thermoplastic polymer to form solid dispersions
that are stable during storage. Incorporation of disintegrant in the formulation
enables quick expansion and/or pore formation in the matrix once it encounters
gastrointestinal fluids, hence faster disintegration, higher surface area, and more
rapid dissolution of the amorphized API (Saydam and Takka
2020). Based on
the desired drug release kinetics, the composition can be modified as well. For
an IR dosage form, an IR polymer (or polymer plus plasticizer) for HME can
be incorporated, along with a pore former/disintegrant. In contrast, for SR, one
can avoid the disintegrant. The release kinetics of the printed tablets can be
additionally improved by incorporating innovative design in the tablet image file
such as channels (Sadia et al.
Korte and Quodbach
2018; Nukala et al. 2019). One can also extrude crystalline
drug embedded filament to impart FDM-based supersaturation (Bandari et al.
Buyukgoz et al.
2021) in the printed dosage form. Chitosan was included in
2018) or collapsible structure (Arafat et al. 2018;
2021;
one of the formulations to increase permeation and buccal adhesion of the film
(Eleftheriadis et al.
2019). Orally disintegrating films (ODFs) with high surface
area have also been used advantageously. Using FDM, low soluble APIs have been
converted into ASD and loaded onto these films.
1.3.2.2 SLS
The first SLS printing in pharmaceutical field was performed in 2017 (Fina et al.
2017) by Fina et al. using two types of thermoplastic polymer (Eudragit RL and
Kollicoat IR) to create to different release properties of paracetamol in a 3D printed
dosage form. Based on the expected lack of absorption of directed energy by the
API and excipients (required to obtain adequate binding via SLS), a pharmaceutical
grade colorant (Candurin Gold sheen) was incorporated in the formulation and has
been used for pharmaceutical SLS ever since (Fina et al.
Januskaite et al.
2020; Thakkar et al. 2021a, 2021b; Trenfield et al. 2022). The
2017; Fina et al. 2018b;
function of thermoplastic polymers in SLS is similar to their application in FDM
process that is as matrix former by melting and cooling/fusing to embed APIs by
kinetic trapping. Unlike FDM, very few thermoplastic polymers have been explored
so far. However, based on the published studies, one can fabricate IR or ASD-based
dosage forms via SLS by using Kollidon
®
VA64 (Allahham et al. 2020; Davis et al.
2021; Fina et al. 2018b; Thakkar et al. 2021a; Trenfield et al. 2022), Kollicoat IR
(Januskaite et al.
2020), HPC (Trenfield et al. 2022), HPMC E55 (Fina et al. 2018b).
Apart from the excipients above, SLS can incorporate process aids such as silicon
dioxide as glidant (Davis et al.
2021) or mannitol as disintegrant (Allahham et al.
2020).
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 15
(continued)
Fanous et al. (2021)
IR stable formulation formed with hot melt
extrusion and printed in stable form
(2021)
Kissi et al. (2021), Than
and Titapiwatanakun
ASD-stable formulation formed with hot
melt extrusion and printed in stable form
VA 64-matrix
®
ASD (drug and kolli) loaded ODF (PEO) Cho et al. (2020)
VA 64-matrix
®
Sadia et al. (2018)
IR with perforated channels (minimal
disintegrant effect observed due to
perforated channels)
starch glycolate
grant
Buyukgoz et al. (2021)
Supersaturated by FDM induce
Amorphization
ASD (mix of all) IR 80% in 45 min Saydam and Takka (2020)
VA64-matrix former
48/16-solubility enhancer
®
®
copolymer-Eudragit EPO-Matrix
Technology API (BCS Class) Key Excipients Dosage form Reference
FDM Lumefantrine (IV) Butylated methacrylate
Tab le 1 .2 Use of AM with BCS II and IV compounds involving BA enhancement
former
hydrophilic xylitol-plasticizer
maltodextrin-pore former
(80% released in 50 min no pore
Naproxen (II) Kollidon
formers)
Olanzapine (II) Polyethylene oxide
Kollidon
poloxamer 407
poloxamer 188-plasticizers
triethyl citrate-plasticizer tricalcium
phosphate-non-melting filler
Eudragit E-matrix
Disinte
Croscarmellose sodium
Crospovidone
Sodium
Hydrochlorothiazide
(IV)
protection
hydroxypropyl cellulose-matrix
Rufinamide (II) HPMC
Griseofulvin (II) Kollicoat protect-moisture
Ketoprofen (II) polyvinyl alcohol (PVA) channeled tablet IR Nukala et al. (2019)
Soluplus
Kollidon
Gelucire
Triacetin -Plasticizer
16 K. Sen et al.
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Davis et al. (2021)
ASD
Printing process parameters such as hatch
spacing was tweaked to fully amorphized the
drug
®
Thakkar et al. (2021b)
Thakkar et al. (2021a,
IR stable formulation formed with Twin
screw granulation and printed in stable form
blend ASD-stable formulation formed with
®
VA 6 4
VA64 Candurin
®
2021b)
Trenfield et al. (2022)
Allahham et al. (2020)
twin-screw granulation and printed in stable
form
ASD-stable formulation with proper
excipient
ODF-provides quick disintegration and
quicker drug release
VA64-matrix
®
Lopez-Vidal et al. (2022)
Seoane-Viaño et al.
(2021b)
Chen et al. (2021)
loading (~50%w/w) provides fast release of
poorly soluble drug
SR-maximizing drug connection at onsite of
action with lipid-based excipient
Core-shell system SR where floating
property of the tablet increases the residence
time
Li et al. (2018)
Johannesson et al. (2021).
Emulsified lipid-based formulation for
thermolabile compound and to be absorbed
with lipid outer core
Candurin-absorbent
Silicon dioxide-glidant
Technology API (BCS Class) Key Excipients Dosage form Reference
SLS Ritonavir (II) Copovidone VA64-matrix
Tab le 1 .2 (continued)
Candurin
Indomethacin (II) Kollidon
Indomethacin (II) Kollidon
Candurin
Kollidon
Candurin
Itraconazole (II) HPC 3 grades
Ondansetron (II) HPBCD-tase masking
Mannitol-disintegration
SSE Albendazole (II) PEG 1500/propylene glycol Fast release nano crystal with high drug
and coconut oil
EC
Poloxamer
Tacrolimus (II) Gelucire 44/14 or Gelucire 48/16)
Clarithromycin (II) HPMC
PVP K30
Nano-caco3
Triglyceride
Tween 85
Fenofibrate (II) Glyceride
Kolliphor EL
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