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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5427_Библиотеки_им_академика_М_И_Перельмана
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332 Z. Rahman et al.
(Fig. 10.1e). The binder can be added in powder formulation and later activated
by the solvent, or it can be dissolved directly in the solvent followed by spraying
over the powder bed. Thus, BJ is not suitable for printing water-sensitive drugs.
Currently available printheads cannot handle highly viscous polymer solutions;
therefore, either polymer concentration should be kept low or an organic solvent
should be used for high polymer concentration or high-molecular-weight polymers.
In the latter case, the printhead should be carefully selected as not all printheads
can handle organic solvents. Drying in an oven at 50–60
◦
C or vacuum is required
to remove the solvent followed by sifting of the support powder from the printlets
(Rahman et al.
2018).
10.2.5 Selective Laser Sintering (SLS)
This method is very similar to BJ, but instead of liquid binder/solvent, it uses heat
and laser sintering for powder fusion. It was invented by Carl Deckard and Joe
Beaman of the University of Texas at Austin in mid-1980 (Rahman et al.
Charoo et al.
2020). Powder components are preheated in the printing platform
followed by powder layering and laser sintering of the selected region of the powder
bed as defined by the printer software. Laser sintering causes softening and melting
of powder components. This is followed by platform downward movement, powder
layering, and laser sintering. This process is repeated till 3D object forms. The
purpose of preheating is that it reduces the laser power requirement needed for
sintering and melting of the powder components (Fig.
10.1f). Unlike other 3D
printing methods (SLA and BJ), SLA does not require post-processing steps such
as drying or UV curing. This method, like FDM and MED methods, is limited to
thermally stable components and also requires thermoplastic polymer to bind the
powder components. Additionally, laser-absorbing agents such as dye are required
to aid in sintering process since pharmaceutical powders are white in color that are
inherently poor light absorbers (Charoo et al.
2020).
2018,
10.3 3D Printed Drug Product Development Considerations
10.3.1 Excipient Selection
Excipients play a critical role in providing framework and essential properties
to traditionally manufactured dosage forms. These agents function as diluents,
binders, disintegrants, lubricants, glidants, extended-release agents, etc. The FDA
lists excipients that can be used in drug products in the IIG and GRAS databases
(Rahman et al.
data for new excipients proposed for use in drug products (FDA
also provide the skeleton to 3D printed dosage forms. However, 3DP processes may
need additional or specialized classes of excipients that are not typically required in
traditional pharmaceutical manufacturing.
2018, Charoo et al. 2020). The agency requires extensive safety
2005). Excipients
10 Regulatory Perspective of Additive Manufacturing in the Field . . . 333
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In SLA printing process, liquid excipients are incorporated into the delivery
system by photopolymerization, initiated by UV light. The liquid formulation
contains photoinitiators and oligomers besides other components. Photoinitiators
absorb incident UV light and trigger the formation of free radicals that react with
the oligomers, thus promoting the development of chemical bonds between polymer
chains. Key characteristics such as solubility, stability, absorption spectrum, molar
absorptivity, and efficacy in generating free radicals are essential properties that
should be considered while selecting photoinitiators. Photoinitiators used in drug
delivery are Irgacure 819, phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide,
diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide, ethyl(2,4,6-trimethylbenzoyl)
phenyl phosphinate, etc. (Xu et al.
2021). Oligomers serve as precursors of
photopolymerization. They are synthesized by including vinyl group into the
backbone of natural or synthetic polymers via chemical modification with acrylates,
methacrylates, fumarates, and vinyl esters. In this regard, the reactivity of acrylates
is highest among all the oligomers. Examples of monomers/oligomers used in
pharmaceutical applications are tert-butyl acrylate, di(ethylene glycol) diacrylate,
(methacryloxypropyl)methylsiloxane, poly(mercaptopropylmethylsiloxane-codimethylsiloxane), vinyl terminated polydimethylsiloxane, Pluronic F127
dimethacrylate macromonomers, soybean oil epoxidized acrylate, methacrylated
vanillin, acrylated waste cooking oil, methacrylic anhydride, methacrylated vanillin,
glycerol dimethacrylate, etc. (Xu et al.
2021). So far, the FDA has not approved any
photoinitiator or oligomer for drug product. One of the reasons is their safety. The
majority of photoinitiators and oligomers do not polymerize completely, leaving
residue in the delivery system that may be released after ingestion and can produce
undesirable adverse effects (Pereira and Bártolo
2015,Xuetal. 2021).
Thermal processes such as HME and spray drying are commonly used to
prepare amorphous solid dispersion. Polymers, preferably thermoplastic forms,
are required to convert crystalline drugs into amorphous forms. FDM and MED
thermal processes can utilize currently available polymers with known safety profile
and thus avoid regulatory hurdles. Polymers investigated for drug delivery using
FDM process are polyvinyl alcohol, polyvinylpyrrolidone (PVP), polycaprolactone,
Eudragit
ypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate
(HPMCAS), Kollidon
®
, polylactic acid, polyethylene glycol, hydroxypropyl cellulose, hydrox-
®
, Soluplus ® , Polyox ® , and ethyl cellulose. Additional excipients such as plasticizers, diluents (mannitol, lactose, tricalcium phosphate), and
disintegrants (sodium starch glycolate, croscarmellose, crospovidone) may also be
required to modulate the process and attain the desired release profile (Cailleaux et
al.
2021). Similarly, Eudragit ® , HPMCAS, and Kollidon ® VA 64 polymers have
been reported for MED process to provide zero-order release delivery systems
(Zheng et al.
2021).
BJ process is similar to traditional wet granulation process where solvent or
binder solution is added to the powder bed to bind the particles, resulting in
an increase in particle size and density and an improvement in dose uniformity.
Excipients that have received FDA approval for human use are useful in wet
granulation process. They can also be used in BJ process removing any safety and
334 Z. Rahman et al.
regulatory concerns. BJ requires various excipients including diluents, flow promotors (lubricant, glidant), binders, humectants, and surfactants. High-dose drugs may
constitute a significant portion of the formulation. For example, Spritam
®
contains
250–1250 mg of levetiracetam. Lactose, mannitol, sucrose, dextrin, microcrystalline
cellulose, and pregelatinized starch have been investigated as diluents for the BJ
process (Yu et al.
2009, Tian et al. 2019, Wilts et al. 2019). HPMC, sodium
carboxymethylcellulose, ethyl cellulose, and PVP have been explored as binders
in both solvent systems and powder mixtures (Yu et al.
Kozakiewicz-Latała et al.
2022). Glidants/lubricants (magnesium stearate, talc, and
2009, Tian et al. 2019,
colloidal silicon) facilitate the uniform spread of the powder mixture over the
building platform and are used in low percentage (Yu et al.
2009, Hong et al. 2021).
The solvent system can be aqueous, organic, or hydro-organic. Organic solvent
allows the use of a high percentage of binder in the solvent system. However, not all
BJ printers are equipped to handle organic solvents, and additionally, presence of
the residual organic solvents in final printed dosage forms would impact quality
and safety. Water and ethanol are commonly used solvent systems for BJ. BJ
process may need additional excipients such as humectants and surfactants. Both are
typically added to the binder/solvent system. Humectant prevents/slows down the
evaporation rate of binder in the printhead and powder bed and keeps the powder bed
in a non-dried condition so that it can fuse with successive layer to an appreciable
level. Glycerin is used as a humectant in Spritam
®
tablets. Surfactants are usually
required in low concentration and also added to the binder system/solvent system
to reduce surface tension and thus prevent clogging of the printhead. Commonly
used surfactants are Tween 80, polyethylene glycol 400, and sodium dodecyl sulfate
(Tian et al.
2019, Kozakiewicz-Latała et al. 2022). Like in the case of BJ process
seen above, excipients commonly used in wet granulation can also be used in SSE
process. SSE involves the extrusion of a paste mixture containing a drug, excipients,
and binder (Seoane-Viaño et al.
2021).
Similar to FDM and MED, HME thermoplastic polymer can also be used in the
SLS process. Additionally, excipients such as lubricants/glidants form an important
part of the formulation composition to facilitate uniform powder spread (Hamed
et al.
2021a, b). Fusion of particles takes place by the synergic action of heating
and laser scanning. Initial heating of powder raises the temperature just below the
melting point of the powder bed. Laser scanning causes sintering and melting of
powder components depending upon their melting point. Thus, the laser provides
additional heat to raise the temperature of selected regions of the powder bed. SLS
process needs a new class of excipients not used in conventional pharmaceutical
manufacturing called laser-absorbing agents. These agents are typically coloring
agents and are used up to 3% level. FDA-approved FDC dyes (metal oxide or lake
dyes or synthetic dyes) can be used in the SLS process. Candurin
®
gold sheen
(silicon dioxide coated with ferric oxide) is the most commonly reported laserabsorbing agent in the literature for printing dosage forms by the SLS process
(Charoo et al.
2020, Hamed et al. 2021a, b).
10 Regulatory Perspective of Additive Manufacturing in the Field . . . 335
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10.3.2 Drug Properties
Various drugs have been printed into immediate- and extended-release systems.
Physicochemical properties of a drug influence the selection of excipients as
well as the printing method and process parameters. Among the physicochemical
properties, stability is of paramount importance. Ideally, a drug should be stable
against all external factors such as temperature, oxidation, light, and solvent
(Rahman et al.
However, a drug may rarely exhibit stability against all risk factors; as a result,
a process is chosen to ensure that the drug retains its stability characteristics. FDM
and MED are not suitable for thermally labile drugs. Similarly, SLA printing process
requires that a drug possesses stability against UV light. Both thermal and light
stability are required for drugs intended to be printed using the SLS process. BJ and
SSE processes expose the drug candidate to solvent-mediated hydrolysis. Another
property to consider in process selection is solubility of the drug in oligomer,
especially in the case of SLA printing as liquid oligomer is printed into dosage
forms. Solubility of drugs in the oligomer and photoinitiator solutions would ensure
uniformity of drug content in the final printed dosage forms. Insoluble drugs are not
ideal candidates for the SLA process (Rahman et al.
et al.
2021).
2018, Charoo et al. 2020).
2018, Charoo et al. 2020,Xu
10.4 Process Design and Process Understanding
Product design is dictated by 3DP process and material attributes. Furthermore, each
3DP process adds distinct features to the printed delivery system. For example,
BJ printed dosage forms are usually very porous and dissolve instantly without
water or a sip. The first FDA-approved 3DP product was a high-dose product
that disintegrated in 2–11 s. On the other hand, FDM, SLS, MED, and SLA
printed dosage forms will have moderate-to-high mechanical strength compared to
BJ printed products. Generally, all the 3DP methods are amenable to developing
sustained-release delivery systems, except BJ. In addition to the above-listed factors,
designing a dosage form also depends upon the components of the formulation such
as drug, excipients, and polymer attributes besides process parameters (Rahman et
al.
2018, Charoo et al. 2020).
Development of quality 3D printed products depends upon the understanding of
critical material attributes (CMAs) and critical process parameters (CPPs) and how
their interactions impact critical quality attributes (CQAs) of printed dosage forms.
ICH guidance documents that Q8 and Q9 can be used as a framework during product
development. These guidelines emphasize on built-in quality rather than testing drug
product for quality. Quality by design (QbD) is an approach to build quality into the
product (ICH
and manufacturing processes should be investigated, and control strategy should be
developed to consistently produce a quality product. In general, CMAs and CPPs
are identified through an assessment of the extent to which their variation can have
2005,ICH2009). Attributes of drug substances, excipients, polymers,
336 Z. Rahman et al.
Table 10.1 Critical material attributes and process parameters of various 3D printing processes
3D printing process Critical material attributes Critical process parameters
Stereolithography Viscosity, surface tension, etc. Layer thickness
Fused disposition
modeling
Binder jetting Powder: Particle size distribution,
Selective laser
sintering
Filament dimeter,
amorphous/crystalline ratio,
elasticity, plasticity, viscosity,
melting point
bulk and tapped densities, shape,
size, cohesiveness, moisture
content, porosity, flow behavior,
wettability, etc.
Liquid: Surface tension and
viscosity
Particle size distribution, bulk and
tapped densities, shape, size,
cohesiveness, porosity, moisture
content, flow behavior
Laser exposure time/speed
Laser angle
Laser spot diameter
Orientation
Curing depth
Hatch spacing
Fill cure depth
UV wavelength
Post-cure time temperature
Extrusion temperature, extrusion
speed
Layer thickness
Number of printheads
Percentage fill
Print pattern
Print nozzle diameter
Print-bed temperature
Raster thickness
Raster gap width
Raster angle
Build orientation
Rate of cooling
Number of printheads
Spraying mechanism
Bed temperature
Binding jetting pattern
Binder delivery rate
Powder spread speed
Layer thickness
Post-processing heat-curing
parameters (curing method,
temperature, and time)
Laser energy density
Laser spot diameter
Laser angle
Bed temperature
Layer thickness
Hatch distance
an impact on the CQAs of the drug product. CMAs and CPPs vary with the 3DP
process and dosage form being printed. CMAs and CPPs of 3DP are listed in Table
10.1. Various tools are available to understand CPPs, CMAs, and CQAs (Barakh Ali
et
al. 2019). These are formal experiment design and process analytical technology
(P
AT).
Formal experiment design and process monitoring tools can be employed to
f
asten product development. Both components are part of the QbD approach
10 Regulatory Perspective of Additive Manufacturing in the Field . . . 337
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advocated by the FDA. Formal design of experiments allows understanding of
the impact of CMAs and CPPs on CQAs. PATs are process monitoring tools
for understanding, monitoring, and controlling the process. It is defined as the
system for “designing, analyzing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical quality and performance attributes
of raw and in-process materials and processes, with the goal of ensuring final
product quality” (FDA
2004). The term “analytical” means chemical, physical,
microbiological, mathematical, and risk analysis conducted in an integrated manner.
The objective of PAT measurement is to enhance understanding and control of the
manufacturing process. PAT tools are commonly used to monitor unit operations
of traditional pharmaceutical manufacturing processes such as mixing, milling,
granulation, hot-melt extrusion, tableting, coating, and spray drying (Zidan et al.
2010, Markl et al. 2013, Kim et al. 2021). These tools allow monitoring of each
individual process unit to ensure that the end point of the process has been achieved
before transferring in-process material into the next unit operation, e.g., mixing,
granulation, or drying. Additionally, these allow real-time release of the batch
subject to mandatory validation requirements having been fulfilled. PAT tools can
also be used for 3DP processes. Monitoring of 3DP process is required since the
process is continuous in nature as there is no feasibility for in-process material
sampling. However, challenges remain as to how PAT sensors can be installed to
monitor 3DP process. 3DP is a dynamic process as the dimension of the dosage
form continuously changes during the manufacturing, which further complicates
monitoring and data analysis. Interference between sensor and printhead such as
laser/UV scanning is likely to be encountered in 3DP. The software would need to
be programmed in such a way that there would be a delay or time gap between layer
scanning and monitoring. In contrast, in traditional manufacturing, multiple sensors
can be installed in a unit operation without technical difficulty or interference. The
most commonly used PAT tools are near-infrared sensors and Raman spectroscopy
(Fig.
10.2). These PAT tools can provide useful information on physical and
chemical transformations occurring during the printing process including particle
size, moisture content, assay, impurity, polymorphic transformation, etc. (Zidan et
al.
2011, Rahman et al. 2013a, b). In the case of 3DP, spectra of each layer can
be linked to the CQAs of the dosage form. Off-line sensors have been reported for
monitoring the quality of the printlets and amorphous-to-crystalline quantification
(Hamed et al.
2021a, b).
10.5 Challenge in 3D Printing Processes
10.5.1 In-process Sampling
Traditional processes are multistep processes where discrete unit operations are
performed in a systemic order. At the beginning of each unit operation, processed
material from the previous unit operation is tested before proceeding to succeeding
operation. For example, water content is tested in dried granules before lubrication
338 Z. Rahman et al.
Fig. 10.2 3D printing process monitoring by PAT sensors
unit operation. On the other hand, in-process sampling and testing are not feasible
in 3DP process, as finished dosage form is formed in a single-unit operation in
a continuous fashion. However, filament, paste, or powder mixture consisting of
drug(s) and various excipients can be tested before and after printing to ensure
that there is no change in the quality attributes of raw material during the printing
process. This will provide some confidence about the quality of the printed dosage
forms.
10.5.2 Recycling
Not all raw formulation composition is utilized in printing dosage forms. For
example, powder mixture in SLS and BJ processes provides support to the printed
dosage forms and is retrieved at the end. In the case of SLA, the printed dosage
form is printed in vat that contains liquid mixture, i.e., drug dissolved in initiator and
oligomer. However, some 3DP processes print all the raw formulation composition
and hence prevent material loss. Examples of such 3DP processes are FDM,
MED, and SSE. Unprinted powder presents challenge in reutilizing it in printing
subsequent dosage forms as processing can adversely affect CQAs of the powder
formulation. In BJ process, the binder/solvent spread with subsequent diffusion over
the powder bed. Solvent/binder may spread laterally beyond the desired region of the
powder. Similarly, laser light may stray and scan undesired region of the powder in
the case of SLS. In the case of SLA process, UV-mediated polymerization may also
change the composition of liquid. The CQAs of unprinted powder or liquid mixture
that may change after exposure to process cycles include change in impurities,
10 Regulatory Perspective of Additive Manufacturing in the Field . . . 339
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particle size distribution, moisture content, polymorphic transformation, and change
in polymorphic content. These changes may or may not have a significant impact
on the CQAs of the printed dosage if used as such. The unprinted raw material can
be discarded, reused, or recycled. If reused, its effect on the CQAs of the dosage
forms should be evaluated prior to its use. Another option is to recycle it in such
a way that exposed raw material can be mixed with the virgin powder in a certain
proportion. However, caution should be exercised while empirically determining
the number of reuse cycles for powder or percentage of exposed powder that can be
mixed with virgin powder while still producing dosage forms meeting their CQAs
(Rahman et al.
the literature on this subject. Recently, Khuroo et al. (
2018, Charoo et al. 2020). There is not much information available in
2022) demonstrated a change
in powder mixture characteristics after exposure to SLS process.
10.5.3 Stability
As mentioned earlier, drugs or excipients that can be processed via 3DP must
possess certain physicochemical characteristics. For instance, thermal stability is
required for FDM, MED, and SLS, while aqueous/solvent stability is required for
BJ and SSE processes. Likewise, photostability is required for printing dosage
forms using the SLA process, while SLS process requires drugs and excipients
to exhibit adequate thermal and photostability. Heat, laser, and/or solvent may
induce chemical and/or physical transformation in drugs and excipients that may
be reflected in the change in quality attributes of the printed dosage forms. Khuroo
et al. (
2022) reported no change in CQAs of isoniazid printlets after exposure to
◦
C/75% RH in a pharmacy vial (Khuroo et al. 2022).
40
10.5.4 Amorphous-to-crystalline Transformation
Most of the drugs exist in crystalline form, and very few drugs are present in an
amorphous form in their native state, e.g., vancomycin hydrochloride (Rahman
et al. 2013a, b). Amorphous form is preferred for biopharmaceutical reasons
due to better dissolution and bioavailability. However, the amorphous form is
thermodynamically unstable and may revert to stable crystalline form when exposed
to high temperatures and humidity (Dharani et al.
Unlike traditional manufacturing methods, many 3DP methods provide a single-step
process to fabricate amorphous solid dispersion dosage forms, e.g., FDM, MED,
SLA, and SLS. Heat or laser converts crystalline drug in situ into an amorphous
form, which is stabilized to a certain extent by the polymer matrix (Rahman et
al.
2018; Charoo et al. 2020). Depending upon the drug properties and excipients
present in 3D printed dosage forms, drug may or may not transform back into
crystalline form on exposure to temperature and humidity. Hamed et al. (
reported less than 5% crystalline conversion of amorphous printlets of lopinavir after
exposure to 40
◦
C/75% RH for a month in pharmacy vials (Hamed et al. 2021a, b).
2021, Hamed et al. 2021a, b).
2021a, b)
340 Z. Rahman et al.
10.5.5 Regulatory Nomenclature
Dosage forms’ name is typically derived from the manufacturing process. For
example, a compressed dosage form is called a tablet, and granules or powder filled
in hard gelatin capsules is categorized as a capsule dosage form. These terms are
accepted by all regulatory agencies. However, there is no regulatory consensus on
an acceptable term for 3DP printed dosage form. Spritam
®
did not get a special name
that would indicate that it is fabricated by the 3DP process. Its label says “tablet for
oral suspension.” Not all health professionals are aware of the advantage offered by
Spritam
®
over the traditionally manufactured dosage forms of levetiracetam due to
its unique manufacturing method. On the other hand, literature uses different terms
for 3DP dosage forms. The most commonly used term is printlets, but this is not a
regulatory acceptable term (Hamed et al.
2021a, b).
10.5.6 Volume
Thousands of capsules and tablets can be manufactured in an hour using traditional
manufacturing methods. Even though 3DP processes involve fewer manufacturing
steps compared to the traditional manufacturing methods, current 3DP methods
allow the manufacturing of only a few hundred dosage forms in an hour. Although
production volume can be increased by increasing the number of printheads, still
production volume cannot compete with the traditional manufacturing methods.
Currently, 3DP processes are therefore more suited for printing specialized dosage
forms where volume is not a critical consideration, such as implants, anticancer
drugs, or orphan classes of drugs (Rahman et al.
2018, Charoo et al. 2020).
10.5.7 Quality Defects
Quality defects in a dosage form arise due to formulation- and/or process-related
factors. Most of the defects are cosmetic in nature, which means that they will not
impact in vitro and the clinical performance of the dosage forms. Defects reported
for tablets include sticking, mottling, delamination, etc. Similar to traditional dosage
forms, many defects are reported for 3D printed dosage forms. These include corners or elephant’s foot, shrinkage, warping or bending, coffee stain effect, staircase
effect/layer shifting, delamination/Z-layer separation, balling, weight variation, etc.
Weight variation and delamination may impact CQAs where patients may not get
the required dose. These defects are attributed to the poorly designed formulation
and/or process parameters (Rahman et al.
2018, Charoo et al. 2020).
10 Regulatory Perspective of Additive Manufacturing in the Field . . . 341
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10.5.8 Packaging
3DP process manufactured dosage forms can be packed in either blisters or HDPE
bottles. However, packaging printlets presents a challenge especially if they are not
mechanically strong. Huge losses may result during packaging. Furthermore, the
dosage forms may break during transportation and in-use conditions. Consequently,
patients may not receive the correct dose, particularly if they are bulk packed in
HDPE bottles. On the other hand, although patients may receive the full dose of
printlets packed in blisters provided that broken pieces are consumed too, fragmented pieces may indicate a quality defect which can not only impact the release
and stability characteristics, but also cause patient noncompliance for obvious
reasons. Moreover, packing of these tablets requires specialized infrastructure where
the dosage form is spread out over the conveyer belt and robotic arms place the
individual tablets in the pockets of blisters rather than using conventional blister
packing machines (Rahman et al.
2018).
10.5.9 Good Manufacturing Practice Compliant
Current GMP compliance is a must for the manufacturing of drug products intended
for human consumption. However, there is a paucity of GMP-compliant 3D printers
intended for drug product manufacturing in the commercial space. This is one of
the reasons for the lack of wider acceptability of the technique in drug product
manufacturing. The fact that Spritam
GMP compliance requirements is an encouraging development (Rahman et al.
2018).
®
manufacturer used their 3D printer to meet
10.6 Regulatory Aspects
The FDA encourages pharmaceutical companies to adopt innovative methods
in manufacturing. However, novel manufacturing methods present technical and
regulatory challenges to the agency that may cause delays in application submission
and eventual approval as the reviewers would require time to familiarize with new
technologies and then determine how best to handle it within the existing regulatory
framework. The FDA/CDER office of pharmaceutical quality (OPQ) created the
Emerging Technology Program (ETP) in 2014 to address these issues. It is a
collaborative program where industry representatives can meet with ETT members
to discuss, identify, and resolve potential technical and regulatory issues regarding
the development and implementation of a technology before filing an application to
the FDA for review. It comprises members from OPQ, CDER Office of Compliance,
and the Office of Regulatory Affairs. ETT is applicable to IND (Investigational New
Drug), original or supplemental BLA (Biologic License Application) or NDA (New
Drug Application), ANDA (Abbreviated New Drug Application), and applications
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