Institute of Pharmaceutical Sciences, SAGE University, Indore.
3D printing known formally as Additive Manufacturing began in the late 1980s. It is a digital manufacturing process that creates 3D objects by fusing or depositing material such as variety of polymers, metals, and ceramics in successive layers laid down under computer control. This objects can be of almost any shape or geometry & are produced from a 3D model as defined in a Computer- aided design(CAD). A variety of 3D printing technologies have been developed to fabricate novel solid dosage forms which are among the most renowned & distinct products today. The present review focused on briefing various techniques, applications in Pharmaceutical technology. This review summaries the mechanisms of the most commonly used 3D printing technologies, describes their characteristics, advantages, disadvantages, and applications in the pharmaceutical industry, analyzes the progress of global commercialization of 3D printed drugs and their problems and challenges, reflects the development trends of the 3D printed drug industry, and guides researchers engaged in 3D printed drugs.
In contrast to the traditional manufacturing techniques of “subtractive manufacturing”, 3D printing is an “additive manufacturing” technology, where a model is constructed using computer-aided design software, sliced, and transferred to a printer, and the 3D product is then constructed layer by layer using the principle of layered manufacturing With the research and development of 3D printing technology, many new 3D printing technologies have emerged one after another. As each 3D printing technology uses different materials, deposition techniques, layering manufacturing mechanisms, and final product characteristics, the American Society for Testing and Materials classified 3D printing technologies into seven categories according to their technical principles namely material extrusion, binder jetting, powder bed fusion, vat photopolymerization, material jetting, directed energy deposition, and sheet lamination. Three-dimensional printing technology is widely used in automotive, construction, aerospace, medical, and many other fields. In the pharmaceutical sector, research into 3D printing technology is currently experiencing a global boom . Compared to traditional preparation technologies, 3D printing offers flexibility in the design of complex 3D structures within drugs, the adjustment of drug doses and combinations, and rapid manufacturing and prototyping, enabling precise control of drug release to meet a wide range of clinical needs, a high degree of flexibility and creativity to personalize pharmaceuticals, and a significant reduction in preparation development time, driving a breakthrough in drug manufacturing technology and transforming the way we design, manufacture, and use drugs.The main 3D printing technologies used in pharmaceuticals are BJ-3DP, FDM, SSE, and MED in material extrusion, and SLA .
3D Printing Techniques :
These methods are used to develop innovative drug delivery systems, personalized medications, and efficient manufacturing processes. Below are some of the key 3D printing methods used in pharmacy:
Fused Deposition Modeling (FDM):
Fused Deposition Modeling (FDM) is one of the most commonly used 3D printing techniques, particularly in pharmaceutical applications. It involves extruding a material (usually a thermoplastic) layer by layer to build up a solid object. In pharmacy, FDM is used to create tablets, capsules, and other drug delivery devices. A plastic filament or metal wire is unwound from a coil and supplies material to an extrusion nozzle which can turn the flow on and off. The nozzle is heated to melt the material and can be moved in both horizontal and vertical directions by a numerically controlled mechanism, directly controlled by a computer-aided manufacturing (C.A.M) software package. The model or part is produced by extruding small beads of thermoplastic material to form layers as the material hardens immediately after extrusion from the nozzle. Stepper motors or servo motors are typically employed to move the extrusion head. FDM, a prominent form of rapid prototyping, is used for prototyping and rapid manufacturing. Rapid prototyping facilitates iterative testing, and for very short runs, rapid manufacturing can be a relatively inexpensive alternative.
ADVANTAGES:
Cheaper since uses plastic, more expensive models use a different (water soluble) material to remove supports completely. Even cheap 3D printers have enough resolution for many applications.
Supports leave marks that require removing and sanding. Warping, limited testing allowed due to Thermo plastic material.
Stereolithography is an additive manufacturing process which employs a vat of liquid ultraviolet curable photopolymer "resin" and an ultraviolet laser to build parts' layers one at a time. For each layer, the laser beam traces a cross-section of the part pattern on the surface of the liquid resin. Exposure to the ultraviolet laser light cures and solidifies the pattern traced on the resin and joins it to the layer below. After the pattern has been traced, the SLA's elevator platform descends by a distance equal to the thickness of a single layer, typically 0.05 mm to 0.15 mm (0.002" to 0.006"). Then, a resin- filled blade sweeps across the cross section of the part, re-coating it with fresh material. On this new liquid surface, the subsequent layer pattern is traced, joining the previous layer. A complete 3-D part is formed by this process. After being built, parts are immersed in a chemical bath in order to be cleaned of excess resin and are subsequently cured in an ultraviolet oven. Stereolithography requires the use of supporting structures which serve to attach the part to the elevator platform, prevent deflection due to gravity and hold the cross sections in place so that they resist lateral pressure from the re-coater blade. Supports are generated automatically during the preparation of 3D Computer Aided Design models for use on the stereolithography machine, although they may be manipulated manually. Supports must be removed from the finished product manually, unlike in other, less costly, rapid prototyping technologies.
ADVANTAGES:
Selective laser sintering is an additive manufacturing technique that uses a high power laser (for example, a carbon dioxide laser) to fuse small particles of plastic, metal (direct metal laser sintering), ceramic, or glass powders into a mass that has a desired three-dimensional shape. The laser selectively fuses powdered material by scanning cross-sections generated from a 3-D digital description of the part (for example from a C.A.D, file or scan data) on the surface of a powder bed. After each cross-section is scanned, the powder bed is lowered by one-layer thickness, a new layer of material is applied on top, and the process is repeated until the part is completed. Because finished part density depends on peak laser power, rather than laser duration, a S.L.S, machine typically uses a pulsed laser. The S.L.S, machine preheats the bulk powder material in the powder bed somewhat below its melting point, to make it easier for the laser to raise the temperature of the selected regions the rest of the way to the melting point. Some S.L.S, machines use single component powder, such as direct metal laser sintering. However, most S.L.S, machines use two-component powders, typically either coated powder or a powder mixture. In single-component powders, the laser melts only the outer surface of the particles (surface melting), fusing the solid non-melted cores to each other and to the previous layer. Compared with other methods of additive manufacturing, SLS can produce parts from a relatively wide range of commercially available powder materials.
ADVANTAGES:
Paediatric:
The ability to produce medicines with personalised dosage, flavour, shape and size can provide many benefits to paediatric populations, for whom conventional mass-produced formulations may not be suitable (e.g. owing to poor palatability or unsuitable dosages)??. Several studies have focused on producing child-acceptable formulations using 3D printing, including the production of chewable and even chocolate-based formulations??.
In 2018 study by Scoutaris et al. produced ‘candy-like’ formulations of several drugs, including indomethacin, that imitated Haribo Starmix sweets using FDM?. However, while 3D printing can create formulations that are palatable to children, it is important to balance this against the risk of the formulations being too desirable and creating unintended risks to patient safety.
In 2020, Januskaite et al. evaluated the visual preferences of children aged 4–11 years of placebo printlets produced using four different 3D printing technologies, including digital light processing (DLP), the concept of which is similar to SLA, SLS, SSE and FDM??. Printlets wer
judged based on their familiarity, appearance, perceived taste and texture. Around 62% of children considered DLP printlets to be the most visually appealing, followed by SLS printlets, and FDM and SSE printlets. However, when the children were informed that the SSE printlet was chewable, the majority (79%) changed their original choice, which highlights children’s preference for chewable dosage forms??. In 2019, a world-first clinical study was carried out using a 3D printer to prepare personalised therapies in a hospital pharmacy setting??. This technology was integrated into the Clinic Hospital at University De Santiago de Compostela, Spain, to produce personalised medicines to treat children aged 3–16 years with maple syrup urine disease — a severe metabolic disease that stops the body from processing certain amino acids, causing a harmful build-up of substances in the blood and urine. Chewable isoleucine printlets with six different flavours and colours, and four different dosages, were prepared using SSE, and researchers evaluated isoleucine blood levels as well as the acceptability of each formulation. After six months of treatment, the 3D printed formulations demonstrated more desirable pharmacokinetic profiles of isoleucine and improved medicine acceptability among the participants, compared to standard isoleucine therapy. All of the formulations with different flavours and colours of the printlets were well accepted by patients, but flavour preference differed according to individuals? ?. Research is ongoing at Alder Hey Hospital in Liverpool for the production of personalised 3D printed hydrocortisone preparations for paediatrics.
3D printing technologies pose many benefits to the pharmaceutical industry, especially within early phase drug development?. The time it takes from drug discovery to a marketed formulation is around 10–15 years, costing an average of £1.3bn??. There is an urgent need to reduce time and cost to market to expedite drug development timelines, made evident during the recent COVID-19 pandemic requiring rapid drug development and repurposing trials. During pre-clinical and clinical formulation development, 3D printing could be used as a rapid prototyping tool to evaluate one-off or small batches of differing drug product iterations?. This rapid prototyping could speed up evaluating the impact of different formulation compositions on critical quality attributes (such as drug performance within in vitro and in vivo models). To date, 3D printed formulations have been tested in a wide variety of pre-clinical animal models??. As such, compared with laborious conventional manufacturing technologies, 3D printing could enable an earlier understanding of process and formulation variables, in turn allowing more rapid entry into first-in-human (FIH) clinical trials, reducing the time and cost of development. Moreover, 3D printing could be utilised throughout pre-clinical and early phase clinical trials to produce small batches of dose flexible drug products on demand to evaluate safety and efficacy??. 3D printing could be used as an alternative manufacturing method in the pharmaceutical industry to produce mass customised or personalised medicines. From an economical perspective, it is likely that conventional methods of manufacture for high-volume and low-added value pharmaceuticals (such as tableting or encapsulation) will remain cost efficient in centralised facilities?. However, there is value in 3D printing formulations that require personalisation to improve therapeutic outcomes. Formulations could be mass customised to patient requirements using 3D printing at localised hubs, which is already being done in the healthcare industry; several major manufacturers use 3D printing to produce personalised hearing aids in a scaled up manner (around 1,000 devices per day), each being tailored in shape and size to the patient’s ear canal??Pharmaceutical companies could use 3D printing to formulate medicines on demand in decentralised locations, such as within pharmacies, clinics or even the patient’s home. Furthermore, this could enable pharmaceutical companies to drive down transport costs and overall logistics expenses, in turn reducing the carbon footprint associated with transport and avoiding the need for energy-intensive storage conditions, such as cold-chain storage for thermosensitive drugs??. While the opportunities for 3D printing are still being explored, the integration of 3D printing into industry will require a shift in business model and approach will need to be carefully considered before 3D printing is taken up by pharma on a large scale.
There are many published research papers demonstrating the potential and role of 3D printing technologies for medicines manufacture and patient care?. A timeline of 3D printing in pharmaceuticals and highlights the major milestones of this technology in the sector. Other pharmaceutical printers include Aprecia Pharmaceutical’s ZipDose technology, a scaled-up binder jet printing process to enable the mass manufacture of highly porous and rapidly orally-disintegrating drug products containing levetiracetam for the treatment of epilepsy?. Triastek has also recently launched a scaled-up melt extrusion system that enables the production of unique drug products for clinical trial. Other companies, including DiHeSys, Vitae Industries and Craft Health, are also working towards producing GMP-compliant pharmaceutical printers, but no research has yet been published using these printing systems.
REFERENCES
Puja Kumari*, Garvita Soni, Jaydev Shrivastava, Arvind Jadhav, Nirmal Dongre, Raghvendra Dubey, An Overview on Role of 3D printing in pharmaceutical Sciences, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 2211-2221. https://doi.org/10.5281/zenodo.14498518
10.5281/zenodo.14498518
