Integrating 3D Printing and Additive Manufacturing into Personalized Medicine for Pharmaceuticals: Opportunities, Limitations, and Future Perspectives

Abstract

Over the last decade, additive manufacturing (AM) has been widely investigated for developing on-demand, patient-centric, and personalized medications. Among various AM techniques, fused deposition modeling (FDM), semi-solid extrusion (SSE), inkjet printing, binder jet printing, stereolithography (SLA), and selective laser sintering (SLS) have been most widely studied for developing simple and complex pharmaceutical medications. Implementing the AM platform enables decentralized manufacturing of medications at the hospitals and clinical sites. The dose and release profiles of the dosage forms can be tailored based on patient needs, providing flexibility to the physician. In fact, streamlining the AM process into a continuous manufacturing process equipped with process analytical technology (PAT) tools will ensure the manufacturing and delivery of safe and efficacious medications to the patient population. Complex medications, such as polypills, which are complex and time-consuming to manufacture using traditional manufacturing techniques, can be printed quickly using the AM approach. The pediatric patient population can be attracted to medication by printing the dosage forms with a geometry of interest. The AM platform can be integrated with artificial intelligence (AI) and health records to accelerate drug development and tailor medications based on patient conditions. Despite the various advantages that the AM platform brings to the pharmaceutical field, a few limitations, such as scalability, material innovation, secondary processing, and regulatory evolution, need to be addressed. This review article compares the advantages and limitations of the existing AM techniques along with a note on the recent advancements and future perspectives.

1. Introduction

Additive manufacturing (AM) is a computer-controlled process that involves fabricating an object by depositing material layer by layer until the input geometry and dimensions are printed. The AM process differs from the traditional subtractive process, which involves eliminating excess material for designing the object [1,2,3]. AM has been extensively used in the automotive and aerospace industries for rapid prototyping and manufacturing accessories involving complex geometries. In recent years, the feasibility of AM has been explored widely in pharmaceutical and biomedical domains. AM provides the flexibility of fabricating complex designs that cannot be manufactured using traditional platforms. Various types of AM platforms, such as fused deposition modeling (FDM), semi-solid extrusion (SSE), stereolithography (SLA), selective laser sintering (SLS), and inkjet printing, are being investigated for developing pharmaceutical medications [4,5,6].

Implementing AM platforms in the pharmaceutical industry will provide the flexibility to manufacture complex medications and enable the delivery of tailored medications based on patients’ disease conditions and needs [7,8,9]. AM will also offer the flexibility of controlling the drug’s dose, size, geometry, and release profile from the medications. The AM process will also address difficult-to-manufacture medications, such as polypills, compared with traditional platforms. Manufacturing efficiency can be improved by employing AM to minimize process waste [10,11]. The approval of the first AM-based product, Spritam^® (Levetiracetam) by Aprecia Pharmaceuticals (Mason, OH, USA), has set a precedent for the acceptance of regulatory agencies and the pharmaceutical industry [12,13,14].

Since 2010, a tremendous increase in publications focused on AM in developing pharmaceutical medications has been noticed. Pharmaceutical industries have invested in research and development (r&d) to evaluate the suitability of the AM platform for industrial settings. A lot of interest has been seen in academia in exploring various AM techniques and assessing the suitability of materials [15,16,17]. Investigating AM in bioprinting and tissue engineering has gained much attention in regenerative medicine. Even the regulatory agencies have expressed interest in the AM by initiating quality control and validation discussions. A detailed evolution of AM technology within the pharmaceutical sector has been tabulated in

Table 1. Detailed evolution of the additive manufacturing for developing pharmaceuticals.

Timeframe	Stage	Key Findings	Milestones
2000–2014	Early concept and prototyping	Evaluated the feasibility of an additive manufacturing platform for printing simple proof-of-concept dosage forms	Demonstration of 3D printed tablets using FDM and inkjet printing techniques
2015–2020	Innovation phase	Evaluated the feasibility of complex geometries such as polypills FDA approval of the first 3D printed product, Spritam® Increased academic research	Commercialization of Spritam® Investigation of SSE and binder jet printing for oral disintegrating tablets (ODTs)
2020–2025	Specialized applications	Next generation materials Improved control of the process, product characterization, and performance Focus on personalized medicines and orphan diseases Integration of PAT tools	Evaluation of the AM process for polypills, pediatric medications, and alteration of the release profiles. Pilot-scale manufacturing at the hospitals
Next 15 years	Future outlook	Industrialization, scaling, and continuous manufacturing Decentralized manufacturing Expansion of the excipient portfolio Successful integration of artificial intelligence (AI)	On-demand manufacturing at clinical sites and hospitals Evolution of the regulatory framework for 3D printed medications

.

The AM platform enables the development of patient-centric medication for all age groups of the patient population, from pediatrics to geriatrics. It provides the flexibility of on-demand manufacturing, reducing the footprint of digital pharmacies, and even the release rate of a drug from 3D-printed pills can be controlled and adjusted by altering the design attributes [18,19,20]. Implementing AM within clinical settings will reduce the timelines, accelerating the drug development. The dose of the medications can be adjusted easily based on the safety, efficacy, and pharmacokinetic profile at subsequent doses [21,22]. Like any other manufacturing platform, despite various advantages, the AM process also has limitations that must be addressed at this early stage of evolution. The availability of suitable materials, scale-up, lack of a proper regulatory framework, and quality control of the 3D-printed medications are a few of the limitations the advanced manufacturing platform faces [23,24,25,26]. As mentioned earlier, any process has a few limitations; however, the advantage that the AM platform brings to the pharmaceutical sector compared with the traditional manufacturing platforms is of utmost importance. Various review articles have been published on developing pharmaceutical medications using AM platforms [27,28]. However, all these articles focused mainly on the advantages of AM technologies.

The focus of the current review article is to provide a basic overview of the various AM technologies, such as FDM, SSE, SLA, SLS, and inkjet printing, along with their applications in the pharmaceutical sector. The article also summarizes various advantages, limitations, and future perspectives. By summarizing the advantages, future trends, and limitations, this review seeks to inform the researchers and regulatory bodies about the potential gaps that need to be addressed before the successful implementation of the AM platform within an industrial setting.

2. Overview of Additive Manufacturing Technologies

The feasibility of various AM techniques for developing simple and complex pharmaceutical medications has been evaluated to date. FDM, SSE, SLS, SLA, and inkjet printing have been most widely studied among multiple technologies. All the AM techniques generate a digital design fed into the 3D printer software. STL file. The 3D printer software slices the design into individual layers and sends the signal to the printer layer by layer until the desired geometry and size are printed. Each technique has advantages and limitations regarding printing speed, resolution, curing, and post-processing steps. One major challenge faced by all the AM techniques is the availability of pharmaceutical-grade materials suitable for developing 3D medications. However, over the last decade, researchers from academia have mainly focused on evaluating the feasibility of existing pharmaceutical-grade excipients from various manufacturers.

FDM 3D printing involves feeding drug-loaded polymeric filament, followed by melting and deposition onto the build platform layer by layer until the object is entirely printed. The process consists of applying thermal energy to melt the polymeric filaments [29,30,31]. The drug-loaded polymeric filaments are usually manufactured using a hot-melt extrusion process. Another way of loading the drug into off-the-market polymeric filaments is called “impregnation”, where the filament is soaked in a solvent consisting of dissolved drug. Selecting a suitable solvent is crucial to avoid damage and the dissolution of the filament. The mechanical properties of the filament play an important role [32,33,34]. The filaments, which are brittle and soft, are not suitable for this process. The drawbacks of this approach are the application of thermal energy during the extrusion and printing process, the limited availability of thermally stable polymers at high processing temperatures, and the need for polymer combinations to achieve better mechanical properties. The FDM approach is unsuitable for processing heat-sensitive active pharmaceutical ingredients (APIs) [35,36,37,38].

The process of SSE is also referred to as pressure-assisted micro-syringe (PAM). The name semi-solid extrusion indicates that the process is suitable for extruding semi-solid materials. The instrumentation of the SSE 3D printer looks similar to a syringe setup, where the semi-solid processing material is filled into the barrel and is extruded through the nozzle by applying pressure using the piston [39,40,41]. The extruded material is deposited on the build platform layer by layer. Depending on the nature of the processing material, the piston can be replaced with a rotating screw, which is ideal for highly viscous materials. Preparing a semi-solid paste of the processing materials requires solvents that can dry quickly, reducing the product curing time. The use of hydro-alcoholic solutions is very recommended, but results in a longer curing time [42,43,44,45]. A solvent-based system is ideal for processing heat-sensitive materials and preparing a semi-solid paste. In addition, to avoid using solvents and for thermally stable materials, the barrel can be mounted with thermal heaters to heat and melt the processing material. The molten material can be extruded through the barrel nozzle by applying pressure. Thus, the approach of SSE is ideal for the processing of heat-sensitive and thermally stable materials [46,47]. The FDM and SSE techniques are usually categorized as extrusion-based or nozzle-based AM approaches. The extrusion-based AM techniques are discussed in detail, along with the critical process and material attributes, in one of our recently published articles by Nyavanandi et al. [48]. The detailed instrumentation of FDM and SSE 3D printers are shown in Figure 1.

The other AM techniques based on liquid deposition are inkjet printing (IP) and binder jet printing. The inkjet printing process, also called drop-on-demand (DOD), involves spraying the drug and binder solution on top of a build platform layer by layer until the object is completely fabricated [2,49,50,51,52]. Between printing each successive layer, a lag time is needed for the liquid vehicle to evaporate, leaving the dried solid mass behind on the build platform [23,53,54,55,56]. Binder jet printing, also known as drop of powder (DOP), involves spraying a drug or binder solution on top of a layer of powder bed composed of general pharmaceutical excipients [2,54,57]. Following the spraying of the solution, a new layer of powder is spread, binding the two layers together. Across DOD and DOP techniques, the viscosity of the spray solution and the stability and solubility of the drug in the liquid vehicle must be considered [55,58,59,60,61]. The first commercial product manufactured using the additive manufacturing technique, Spritam^® (2015), utilized the DOP approach to develop orally disintegrating tablets (ODTs). The approval of a commercial product shows the interest of pharmaceutical industries and encouragement from regulatory bodies, along with the feasibility of an additive manufacturing platform for commercial-scale manufacturing with reliability and reproducibility [62,63]. The detailed instrumentation of inkjet and binder jet 3D printers is shown in Figure 2.

Additional AM techniques that have been widely explored include stereolithography (SLA) and selective laser sintering (SLS) [19,64,65,66]. The SLA process involves the solidification of photopolymer resin dissolved in a drug solution. The photopolymer resin solidifies in the shape of the 3D design on the build platform with the help of ultraviolet (UV) light. The sensitivity of the drug to UV light and the solubility of the resin within the solvent need to be considered [67,68,69,70,71,72]. Following the printing of the 3D object, a post-cleaning and curing process is required. The SLS type of AM involves the utilization of a powdered formulation blend with the drug and excipients and laser light [73,74,75,76]. The process involves spreading a thin layer of powder on the build platform, and then a high-energy laser heats a specific area of the powder bed, fusing the particles [77,78,79]. Later, the build platform moves downward, spreading a new layer of powder and sintering the powder particles with laser energy. The process repeats until the entire 3D object is fabricated. The sensitivity of the processing materials to the heat and the laser energy needs to be evaluated [80,81,82]. A detailed comparison of commonly used additive manufacturing platforms for developing pharmaceutical medications is shown in

Table 2. A detailed comparison of commonly used additive manufacturing platforms for developing pharmaceutical medications.

3D Printing Platform	Mechanism	Materials	Advantages	Limitations	Common Applications
FDM	Drug-loaded polymeric filament is melted and extruded layer by layer	Polymers such as HPMC, HPC, Eudragit, PEO, PVA, PVP	Low cost, user-friendly Amorphous solid dispersions Solvent-free process	High processing temperatures Slow process Limited materials are suitable for high temperatures	Solid dispersions Immediate release and modified release dosage forms Polypills
SSE	Semi-solid material is extruded through a nozzle and deposited on the build platform layer by layer	HPMC, Poloxamers, Lipids, Starch paste	Suitable for thermally sensitive and poorly soluble drugs	Not suitable for solvent-sensitive drugs Requires a secondary drying step	Oral disintegrating tablets Pediatric medications Buccal films
Inkjet	The fine droplets of formulation solution sprayed onto the build platform layer by layer	Formulation materials dissolved in aqueous/organic solvents	Fast process Suitable for microdosing	Requires low viscosity solutions Nozzle clogging Requires a drying step	Oral dispersible films Polypills Microdosing
Binder jet	The fine droplets of binder solution are sprayed on top of successive powder layers	Binder solution sprayed onto common powder excipients such as microcrystalline cellulose and starch	Suitable for heat-sensitive drugs Fast process	Low hardness Requires a de-powdering step	High-dose tablets Oral disintegrating tablets
SLS	The powder particles are fused with the application of a laser in the shape of a 3D design	Polymers such as PVP, Eudragit, and PVA	No binders are needed Solvent-free process Can generate high-porosity tablets	Risk of drug degradation Powder recovery is needed Energy intensive	Porous pills Controlled-release tablets
SLA	The drug solution, consisting of photopolymer resin, is cured in the shape of a 3D design with the application of UV light	Methacrylate, PEG diacrylate resins	High resolution Complex geometries	Slow process Limited availability of materials Risk associated with unreacted monomers	Implants Complex geometries Microneedles

. The instrumentation of SLS and SLA 3D printers are shown in Figure 3.

3. Advantages of Additive Manufacturing

3.1. Simple Manufacturing Process

Compared with the traditional manufacturing techniques, AM involves a simple manufacturing process with reduced unit operations. The traditional methods, such as direct blending, high-shear wet granulation, dry granulation (slugging and roller compaction), drug layering (Wurster coating), and top spray granulation, involve several unit operations involving the characterization of various in-process materials, resulting in longer production times and increased product cost [83,84,85]. In fact, the failure of the batch to meet the pre-established specification will delay the product release into the market, which might not only affect the industry but also impact the patient population experiencing emergency conditions. Manufacturing pharmaceutical medications using AM techniques will accelerate the development times, contributing to reduced processing steps and testing [22,86]. Even the product’s failure to meet the acceptance criteria might not significantly affect the timelines, considering the faster manufacturing of another production lot. Even compounding pharmacies can accommodate 3D printers with a smaller footprint for the fabrication of medications using the feeding material supplied by the pharmaceutical industries.

3.2. Improved Bioavailability

Improving bioavailability has been an ongoing effort by the pharmaceutical industry for decades. The majority of the drug substances within the developmental pipeline are claimed to be poorly soluble, belonging to Class II (Poor solubility and High permeability) or IV (Poor solubility and Poor permeability) of the biopharmaceutical classification system (BCS) [24,87,88]. Much research is still ongoing to explore and evaluate the feasibility of novel approaches for improving the solubility and bioavailability of drug substances. Traditional techniques such as salt form, cocrystal, lipid-based formulations, and amorphous solid dispersions (ASDs) have been successfully implemented within the industrial setting for commercial manufacturing [89]. However, in the case of BCS class IV compounds, the enhanced solubility might not ensure improved bioavailability due to the limitation of poor permeability—unless any permeation enhancers are incorporated into the formulation. By employing additive manufacturing, solubility enhancement can be achieved. Using the FDM approach, the amorphous drug-loaded filaments can be extruded using a hot-melt extrusion process and printed into tablets for any desired dose, shape, and infill density [26,90,91]. Within the SSE type of 3D printing, the drug can be dissolved in a suitable solvent or dissolved in a lipid carrier and loaded into the cartridge to print the dosage forms. The drug can be dissolved in a suitable solvent and sprayed onto the powder carrier within inkjet and binder jet printing. The incorporation of a small amount of polymer will aid in retaining the solid state of the drug in amorphous form. In the SLA and SLS types of AM techniques, the conversion of the drug into an amorphous form for solubility enhancement needs to be further evaluated. To date, FDM 3D printing has been most widely explored for generating 3D-printed pills with amorphous drug, focusing on solubility and oral bioavailability enhancement.

3.3. Easily Portable

Compared with all the equipment used within the traditional manufacturing techniques, the footprint of the 3D printers is small enough that they can be easily moved within and between sites. The qualification of the 3D printers is simple, and the equipment can be brought into operation quickly. In the current market, all the AM 3D printers have a benchtop footprint, which will be easily accommodated in the r&d labs and clinical pharmacies. In the future, the concept of mobile pharmacies can also be made possible using the AM techniques, where the pharmacy can be taken near the patient population for the on-demand manufacturing and at-home dispensing of medications [17,23,92]. Using the AM techniques, there is an opportunity to establish digital pharmaceutical industries within a smaller footprint.

3.4. Easy to Scale

The scale-up of traditional manufacturing is critical, attributing to various scale-dependent and scale-independent process parameters that need to be optimized. Establishing a controlled space for the robust manufacturing of the pharmaceutical medications remains time-consuming and challenging. In most situations, the make, model, and geometry of r&d-scale equipment cannot be transcribed to the commercial scale [93,94]. The capacity of the equipment will limit the batch size, requiring the manufacturers to make multiple sub-lots to meet the supply chain demands. With the implementation of the AM techniques, the scale-up of the process remains straightforward. In most AM platforms, the critical process parameters involve temperature, printing speed, nozzle diameter, cooling rate, laser or UV power, droplet size, etc. The commercial-scale equipment is mounted with increased printing heads across all the AM techniques, thereby scaling the production. The process parameters employed within the r&d-scale prototype development can be directly transcribed for the commercial manufacturing [95,96,97]. The commercial-scale equipment successfully implemented within the automobile industry can be modified slightly to be suitable for pharmaceutical manufacturing. A list of key process parameters and typical operating conditions for additive manufacturing techniques for developing pharmaceutical medications is shown in

Table 3. List of key process parameters and typical operating conditions for additive manufacturing techniques for developing pharmaceutical medications.

Platform	Key Process Parameters	Typical Operating Conditions	Solid State of Drug
FDM	Extrusion and printing temperature Nozzle size Printing speed Infill density Layer height Cooling rate Build platform temperature	Extrusion and printing temperature (150–250 °C) Nozzle size (0.2–0.6 mm) Layer height (100–300 μm)	Based on extrusion and printing temperatures, the drug can be converted into an amorphous form
SSE	Extrusion pressure Nozzle size Printing speed Material viscosity Drying/curing conditions Build platform temperature	Low/ambient printing temperatures Nozzle size (0.1–0.6 mm) Extrusion pressure (0.1–0.5 MPa)	At low printing temperatures, the drug remains in crystalline form In the presence of lipids/solubilizers, the drug gets dissolved and converted into an amorphous form
Inkjet	Droplet size Solution viscosity Nozzle size Spray frequency Platform temperature	Droplet size (1–100 pL) Nozzle size (20–50 μm)	The drug remains in crystalline form
Binder jet	Droplet size Solution viscosity Nozzle size Spray frequency Powder layer thickness Drying/curing conditions	Drying (40–60 °C) Layer height (50–200 μm)	The drug remains in crystalline form
SLS	Laser intensity Scan speed Particle size distribution Bed temperature	Laser intensity (2–15 W) Scan speed (100–2000 mm/s) Layer height (100 μm) Bed temperature (40–80 °C)	The applied laser might result in partial amorphization of the drug
SLA	Resin viscosity UV/laser intensity Exposure time Layer thickness	UV (355–405 nm) Layer thickness (25–100 μm)	Based on the solubility of the drug in the resin solution, the drug can be in amorphous or crystalline form

.

3.5. Continuous Manufacturing

In recent years, continuous manufacturing has attracted many researchers from academia and the pharmaceutical industry. The implementation of end-to-end continuous manufacturing will significantly reduce manufacturing time and ensure product quality. The process can be scaled easily by increasing the run time of the continuous manufacturing line. The manufacturing line used for developing a prototype can also be used for commercial manufacturing [98,99,100]. Product quality can be continuously monitored by equipping suitable process analytical technology (PAT) tools. In the event of a discrepancy, the unprocessed material can be saved, limiting the wastage and reducing the production loss. With PAT tools, the number of quality control tests can be reduced, releasing the product faster into the market [21,101]. Continuous manufacturing lines can be established using the AM platforms with PAT tools to monitor product quality. The most used PAT tools include near infrared (NIR), Raman, thermal infrared, high-speed cameras, and micro-computed tomography. A detailed list of PAT tools with respect to their role in the characterization of products manufactured by additive manufacturing is shown in Figure 4. Among all the AM techniques, binder jet and inkjet 3D printing techniques seem more feasible for continuous manufacturing. The FDA-approved 3D-printed product Spritam^® was manufactured by binder jet printing, confirming the feasibility of AM techniques for transforming into a continuous manufacturing line.

3.6. Dose Personalization

With the traditional manufacturing techniques, such as tablet compression and encapsulation, there is no flexibility to adjust the dose. Even physicians must prescribe the doses studied and established by the pharmaceutical industries. By employing AM techniques, the dose can be adjusted before the fabrication of the medications in the clinic or the compounding pharmacy. It is well-known that the doses established by the pharmaceutical industries are suitable for a broad age group of the patient population [75,102,103]. However, in reality, one dose will not be ideal for all age groups of the patient population. Each patient might need a different dose and a different pattern of drug release from the medication, depending on the age, sex, race, and disease condition. Implementing the AM platform will give physicians excellent flexibility.

3.7. Patient-Centric Design

Another limitation of traditional manufacturing is the shape or geometry of the medication. Modifying the dosage form’s shape using the traditional tablet compression process requires additional studies and resources, delaying the drug development. In the majority of cases, the geriatric patient population tends to skip the medication due to the large pill size, which makes it difficult to swallow [18,104,105]. In such cases, the shape of the medication is of the utmost importance. Implementing the AM platforms will provide flexibility in changing the shape of the dosage form based on patient needs. In fact, geometries such as a donut shape or a gummy bear can be printed to appeal to pediatric patients. Various studies have been conducted to date, where a minimal difference in the performance of the medications with different shapes has been noted, showing the AM platform’s suitability for developing patient-centric medications [106].

3.8. Complex Geometries and Release Profiles

The demand for medications is increasing each year, with an increasing patient population. In today’s world, a geriatric patient must administer multiple medications daily, attributing to several disease conditions. Patients who have Alzheimer’s might skip a few medications in a day due to forgetfulness [18,75,103]. In such situations, developing fixed-dose combination medications will be helpful, where all the medications can be taken as a single pill. Developing such medications using traditional approaches can be achieved by developing multiple-layered tablets, which is a challenging and time-consuming process. Complex dosage forms, such as gastro-retentive and colon-targeted, can also be fabricated using AM techniques. The release profiles of the drug from the printed tablets can be controlled and altered by adjusting the infill densities. In the case of traditional manufacturing, the entire formulation needs to be adjusted to alter the release profiles [107,108]. Thus, AM offers more advantages to manufacturers, physicians, and the patient population than the traditional route.

3.9. Accelerated Development Timelines

The traditional drug product developmental process is slow and time-consuming. To make an r&d batch, the manufacturing process will involve multiple processing steps, from formulation planning to the characterization of the samples [21,102]. With the implementation of the AM platform, the number of unit operations can be reduced to three steps: design, print, and testing, saving a significant amount of time. Another benefit of implementing an AM platform is reduced material waste [109,110]. In the early stages of development, material availability is limited and expensive. The AM techniques would need a minimum amount of material to generate prototypes. Instead of waiting for the clinical batches, the AM process can be established in the clinical site. The doses can be personalized on demand, and the release profiles can be modified by adjusting the infill densities. This will save the pharmaceutical industry significant amounts of time. The benefit of changing the release profiles using infill densities of the 3D printlets would eliminate the need for traditional functional coatings. In fact, the AM platform can be integrated with in silico tools such as artificial intelligence (AI) and physiologically based pharmacokinetic (PBPK) models for inputs and rapid prototype generation, eliminating the need for formulation planning [111,112,113,114,115]. Thus, the AM platform would benefit the pharmaceutical industries and help the patient population with the availability of novel therapy in a shorter time.

3.10. Reduction in Material Waste

Unlike the traditional batch manufacturing process, the AM techniques would need a few grams of material to fabricate the prototypes. Depending on the scale of the r&d equipment, the traditional manufacturing would need a few hundred grams to generate the required prototypes for testing [116,117]. During traditional batch manufacturing, any discrepancy will affect the entire batch, resulting in the discard of the batch. However, within the AM process, the whole batch material will not be exposed to risk, and the unprocessed material can be preserved, reducing the material waste. Integration of the AM techniques with the PAT tools will aid in monitoring the quality of the printing process and the printed products, reducing the number of destructive tests and saving material [93,96,101].

3.11. On-Demand and Decentralized Production

Compared with traditional manufacturing, another significant advantage of AM platforms is the on-demand and decentralized manufacturing of medications. The AM platforms can be established in clinics and pharmacies, where medications can be printed on demand based on patient needs. The performance of the medicines can also be altered based on patient physiology and disease state [22,85,118,119,120]. The AM process provides the flexibility of manufacturing small-scale batches. In contrast, the equipment size determines the batch size within traditional manufacturing. Instead of the product being manufactured at a single site, the AM process will allow the manufacturing to be decentralized to pharmacies and hospitals. Even in emergencies, the medications can be fabricated at military bases, space stations, and rural areas. The AM process involves the creation of a digital design file, which will be sent to the printer software for the fabrication of medications. The digital files can be transferred anywhere within a few minutes, rather than shipping the medicines, which would take longer [17,23,24,26,88]. The doses of the drugs can be adjusted based on patient age, sex, race, and body weight at the clinic, providing physicians with more flexibility in offering better treatment opportunities.

3.12. Artificial Intelligence (AI) and Machine Learning (ML)

The integration of AI and ML with the additive manufacturing platforms will provide a significant advantage for understanding the process, for improving the quality of the printed medication, and for adjusting the dose and performance of the medication using the patient historical records. Utilizing AI/ML for evaluating the printing process will benefit the identification of the critical process parameters (CPPs) and critical material attributes (CMAs). AI/ML also play an important role for the prediction of porosity, degradation and incomplete polymerization. Integration of AI/ML within continuous manufacturing along with PAT tools will improve the efficiency of process control and will adjust the process parameters to limit the variability between the printlets and the batches. Implementation of AI will accelerate the drug development process by limiting the number of research and development (r&d) trials and will also propose the optimized geometry designs based on the patient profile.

4. Limitations and Challenges

Along with the advantages, any manufacturing process will also have limitations. However, compared with traditional manufacturing, the advantages that the emerging technologies introduce to the pharmaceutical industries are of utmost importance and value. As time evolves, these limitations can be addressed, and alternate approaches can be identified. There will be a few limitations that cannot be resolved, and the process needs to be considered unsuitable in cases where the quality of the product is compromised. In this section, a few high-level limitations that need to be further addressed are discussed.

4.1. Limited Materials

AM technology has been introduced into the pharmaceutical sector over the last decade. However, the pharmaceutical-grade excipients used for traditional manufacturing are unsuitable for all AM techniques. For FDM 3D printing, the quality of the filaments depends mainly on the nature of the polymers. Most polymers must be processed at high temperatures, which might degrade the thermally sensitive drug substances [24,121]. In a few instances, it would be difficult to process high-melting-point drugs (>250 °C), where the polymers will degrade at such high temperatures. There is a need for the excipient manufacturers to introduce next-generation polymers suitable for the additive manufacturing process that can withstand high processing temperatures. Even the excipient manufacturers have to prove the toxicological safety of the materials to the regulatory bodies before making them available to the industries. In the SSE type of AM process, materials with low melting points and viscosity are more suitable for processing. In recent years, much research has been conducted to evaluate the feasibility of existing excipients for inkjet, binder jet, and SLS types of AM techniques [24,122,123]. Limited pharmaceutical-grade materials are available for the SLA type of 3D manufacturing process. The lack of materials will result in the failure to utilize the AM capability to the fullest. The support of excipient manufacturers is much needed in collaboration with the researchers to advance the AM process for developing on-demand and patient-centric medications. A detailed list of available pharmaceutical-grade materials, strengths, and limitations for additive manufacturing platforms is shown in

Table 4. Detailed list of available pharmaceutical-grade materials, strengths, and limitations for additive manufacturing platforms.

3D Printing Technique	Commonly Used Materials	Strengths	Limitations
FDM	PVA, HPC, PEO, PLA, PEG-based polymers, PVP, HPMC	Suitable for solubility enhancement and for developing controlled release formulations	High processing temperatures limit the platform for thermal-sensitive drugs Limited polymers for the processing of high-melting-point drugs
SSE	Glycerin-based gels, starch gel, poloxamer gel, Carbopol, cellulose-based excipients	Can be processed at ambient or low temperatures	Requires low viscosity materials Poor mechanical properties
Inkjet	HPMC and PVP-based solvent solutions	Suitable for nano to micro range dosing	Requires low viscosity materials Nozzle clogging occurs if the materials are not fully dissolved Not ideal for solvent-sensitive drugs
Binder jet	Lactose, mannitol, cellulose-based materials, PVP	Can be processed at ambient or low temperatures, suitable for thermally sensitive drugs	Poor mechanical properties
SLS	Lactose, mannitol, PVP, PVA, Eudragit	Suitable for complex geometries and partial drug amorphization	Powders with poor flow are not suitable
SLA	Polyethylene glycol diacrylate, polycaprolactone diacrylate	High resolution and ideal for developing implants	Toxicity from monomers Very limited pharmaceutical-grade resins

. Additionally, with the advancement of the additive manufacturing technology, there might be growing interest in the manufacturing of specialized materials with thermal, rheological and mechanical properties suitable for different additive manufacturing platforms. For the manufacturing of specialized materials, the excipient manufacturers might end up needing advanced manufacturing technologies such as controlled hot-melt granulation and precise particle size engineering to ensure batch to batch consistency. While the implementation of specialized manufacturing technologies might increase the upstream manufacturing cost, the overall cost of the finished product depends on the scale of manufacturing, regulatory pathways, and intended application. Additive manufacturing brings significant benefits to the patient population such as dose personalization, as well as patient-centric and on-demand manufacturing, which might outweigh the additional product cost being introduced due to the usage of specialized materials.

4.2. Material Degradation

The AM techniques involve the application of thermal energy, UV light, or solvents. The sensitivity of the materials processed within the AM platform must be thoroughly studied. Within FDM and SLS, there is a high risk of thermal degradation of materials, making the process unsuitable for thermally sensitive materials. The material sensitivity to UV light intensity needs to be studied within the SLA type AM process. The materials sensitive to solvents need not be processed through binder jet and inkjet AM techniques. The SSE type of AM process can be carried out by applying heat or using solvents. Based on the sensitivity of the materials, the type of AM process suitable for developing stable and robust drug products needs to be selected. A detailed list of risks associated with the degradation of material with respect to each of the additive manufacturing techniques is shown in

Table 5. Detailed list of risks associated with the degradation of material and mitigation strategy with respect to each of the additive manufacturing techniques.

3D Printing Technique	Primary Degradation Risk	Root Cause	Impact on Drug Product	Risk Mitigation Strategy
FDM	Thermal degradation	High extrusion and printing temperature Longer residence time	Affects the solid state of the drug Formation of degradants Altered release profiles	Use of low-glass-transition-temperature polymers which can be processed at low temperatures
SSE	Hydrolysis and microbial degradation	Moisture uptake during storage Prolonged drying High water content in gels	Shorter shelf-life Microbial risk	Inclusion of preservatives and desiccants Optimizing drying time and storage humidity Utilization of non-aqueous solvents
Inkjet	Crystallization and chemical degradation	Light or oxidation exposure Solvent sensitivity Drug recrystallization	Affects the solid state of the drug Inaccurate dosing	Incorporation of antioxidants Printing under inert conditions
Binder jet	Hydrolysis and binder instability	Solvent evaporation affects binder solution viscosity Exposure to moisture	Low hardness of tablets Affects drug release profiles	Incorporation of moisture resistant binders Proper control of environmental humidity
SLS	Thermal and oxidative degradation	High-energy laser-induced degradation	Degradation of the drug Recrystallization	Optimization of laser power and scan speed Incorporation of thermal stabilizer Utilization of thermal resistant polymers Printing under inert atmosphere
SLA	Unreacted monomers or photodegradation	Incomplete polymerization Overexposure to the laser	Impacts drug release profiles Drug degradation	Storage of printed tablets in light resistant containers. Optimizing light intensity and exposure time. Selection of biocompatible and stable photopolymers

.

4.3. Stability and Shelf-Life

The stability and shelf life of the in-process material and the finished product are paramount for any medicinal product. Quality and safety are the major requirements for developing any medication that must be proven to the regulatory agencies for their efficacy. In the case of FDM and SSE types of additive manufacturing, the filaments (FDM) and the pre-filled cartridges (SSEM) can be prepared in the manufacturing site and transferred to the clinical sites or pharmacies for the fabrication of on-demand medications [124,125]. However, the stability and shelf-life of the filaments and cartridges need to be thoroughly studied and established. Other AM techniques, such as inkjet, binder jet, SLS, and SLA, involve no intermediate materials that can be transferred between the sites. However, stability and shelf life must be established for finished products manufactured using any AM technique. Utmost caution needs to be provided to the patient population for more sensitive drugs, which are degraded rapidly upon exposure to light or humidity. The compatibility of the drug product with the container closure system also needs to be evaluated. Much research is required to establish the beyond-use date for the medications manufactured by 3D printing and dispensed to the patients. The quality of the medicines should not be compromised within the established shelf-life. Since the AM techniques involve the application of heat, UV light, and moisture, the sensitivity of the materials needs to be carefully considered. The solid state of the drug might be affected when exposed to heat, humidity, and pressure during 3D printing, which needs to be considered to preserve the quality of the medications [85,126]. The AM process is still emerging, and the availability of long-term stability data is limited. The drug products printed using AM techniques result in greater surface area and porosity, where the moisture sorption needs to be controlled, which might result in recrystallization of the amorphous drug. A list of potential stability challenges with respect to the additive manufacturing techniques is shown in

Table 6. List of potential stability challenges with respect to the additive manufacturing techniques.

3D Printing Technique	Stability Challenges	Implications
FDM	Recrystallization of an amorphous drug Thermal degradation	Incorporation of recrystallization-inhibiting polymers will enhance stability Data needed to be generated to prove long-term stability
SSE	Microbial growth Hydrolysis Short shelf-life	Freeze-drying improves shelf-life More suitable for on-demand manufacturing
Inkjet	Moisture uptake Recrystallization Oxidation	Suitable for on-demand manufacturing Protective packaging with an inert atmosphere will enhance stability
Binder jet	Porous tablets Low mechanical strength Hydrolysis	Protective packaging is needed for a longer shelf life
SLS	Oxidation Thermal degradation Recrystallization Porous tablets	Blister packing or the addition of desiccants will improve shelf-life
SLA	UV-induced degradation	Long-term stability data needs to be generated

.

4.4. Risk of Product Liability

Product liability is the major non-technical hurdle within the AM process. Compared with traditional manufacturing, new players such as 3D printers, software, hospitals or clinics, and pharmacists are involved, making assigning risk accountability challenging. Within the traditional manufacturing, the pharmaceutical industry holds the liability [127]. Meanwhile, within AM platforms, the pharmaceutical industry owns the drug formulation, the 3D printer and the software are owned by the equipment manufacturer, and the medications are printed in the hospital or clinical sites by the pharmacists. If the 3D-printed medication results in a safety concern, it is unclear which function will take responsibility. Due to differences in the printer calibrations, environmental conditions, and pharmacist skills, a lot of variation will be introduced into the printed medications, resulting in a certain level of risk [128,129]. The current International Council for Harmonization (ICH) and Good Manufacturing Practices (GMP) published guidelines focus on centralized batch manufacturing. However, with the implementation of 3D printing, if the manufacturing is decentralized, the responsibility of ensuring compliance will be the biggest concern for the regulatory authorities. Considering the current level of risk, the pharmaceutical industry will be reluctant to introduce the AM process [130]. To mitigate the risk associated with pharmaceutical additive manufacturing, well-defined characterization methods such as content uniformity (USP <905>), dissolution (USP <711>), and residual solvent testing (USP <467>) need to be implemented. The Quality by Design (QbD) should detail the critical material and process parameters for each of the additive manufacturing techniques. The regulatory agencies and the manufacturers should collaboratively discuss the data sharing and accountability for product quality oversight.

4.5. Cyber Risk (Fake Pills)

Compared with the traditional manufacturing process, AM is a digitally driven process, where cyber risk is another primary concern. The 3D designs of the medications to be printed are saved as digital files. The tampering of the digital files will result in the fabrication of fake pills, which will affect the patient population. Compared with traditional manufacturing, identifying counterfeit pills manufactured with AM techniques is difficult unless proper PAT tools are installed to monitor the quality of the printed product. Any variation in the quality of the product, if noticed, should be reported and investigated [131,132]. With decentralized manufacturing, the 3D printers will be installed in various sites. Compromising any site for cyber risk will impact all other sites. The regulatory agencies will recommend the proper implementation of cyber safeguarding. The drug manufacturer will be liable for any cyber tampering. Due to the existing level of risk associated with a cyber-attack, the pharmaceutical industry will delay the implementation of AM techniques until a robust safeguarding practice is in place. The cyber risk can be minimized by implementing end-to-end encryption and authentication [133,134]. The information, such as file origin, print history, and modifications, must be tracked regularly. The database consists of digital files that need to be locked by the drug manufacturers, and the signatures on the digital files need to be verified before submitting them for printing. The design files need to be stored in validated GMP-compliant servers with login access. Implementing role-based access to the printers, design files, and servers will reduce the level of cyber risk. Additionally, virtual private network (VPNs) should be implemented for remote access. The manufacturing network should be isolated from the public internet and the software’s need to be updated on a regular basis. The 3D printers, software, and plugins need to be purchased from validated and certified vendors. Limited physical access to the printers and the server rooms will limit the risk of cyber-attack. All the manufacturers should ensure to conduct a cyber risk assessment as part of quality risk management (ICH Q9). Implementing all the preventive measures and periodic reassessment will benefit both the manufacturer and the patient population.

4.6. Safety and Efficacy

Safety and efficacy are two essential aspects of the drug development process. The pharmaceutical industries spend 10–15 years developing new treatment regimens to prove the drug candidate’s safety, efficacy, and quality. The AM techniques will induce a certain level of risk in terms of safety and efficacy. Within FDM and SLS techniques, the applied heat might degrade the processing material, resulting in safety and toxicity concerns [135,136]. Within the SLA process, the photopolymer needs to be completely cured. The incomplete curing of the photopolymer results in unreacted monomers, which result in cytotoxicity, inflammation, and carcinogenicity. Additionally, any residual solvents within the printed dosage forms will affect the safety of the patient population [137]. Variation in the printing process parameters, resulting in under- or over-dosing, affects the safety and efficacy. Implementing decentralized manufacturing will result in the cross-contamination of medicinal products if proper cleaning procedures are not implemented.

4.7. Regulatory Landscape

The current ICH and GMP guidelines, which have been published, are mainly focused on traditional manufacturing platforms and on centralized, large-scale manufacturing. The AM approach introduces the decentralized, on-demand, and small-scale manufacturing of medicines, for which the regulatory authorities do not have any standards [138,139]. Minimal excipients suitable for the AM process are currently available. New materials have to go through the regulatory review and approval process, and they should also be proven safe by toxicological evaluation, which might delay the innovations. Within manufacturing, the regulatory agencies would like to see a robust manufacturing process that can reproduce a similar product each time a batch is manufactured. The AM process needs to be validated, similar to traditional manufacturing, and the control space for the manufacturing process needs to be established. Within the regulatory guidelines drafted in the future for the AM process, the regulatory body should describe the responsibilities of each stakeholder involved in the process [140]. The regulatory agency has approved only one commercial product developed using 3D printing. Any products being created in the future using the AM process might required a longer approval time for the regulatory body to understand the end-to-end process before authorizing the commercial launch. A detailed list of analytical and quality testing requirements for manufacturing drug products using additive manufacturing techniques is shown in Figure 5. Additionally, the BCS-based biowaivers are well-established for the medications manufactured by traditional approaches. However, the biowaiver for the 3D-printed medications needs to be further evaluated before its implemented. Though the composition of the 3D-printed medications remains the same, its geometry, internal printing structure, and hardness might vary, which might influence the dissolution and in vivo performance. Currently, the regulatory agencies have not tailored any guidelines specifically for the 3D-printed medications. However, a 3D-printed medication with a highly soluble and permeable drug substance might still qualify for a biowaiver with a more detailed understanding of in vitro and in vivo correlation (IVIVC). With the implementation of dissolution modeling, a thorough in vitro characterization and the usage of PAT tools will play an important role in establishing the equivalence for the 3D-printed medications. For 3D-printed dosage forms, identifying a reference standard to establish bioequivalence is essential. The current standard and regulatory-aligned practice within traditional manufacturing is to use a commercially available product with the same drug substance, dose, and release profiles as a reference. For 3D-printed products with no commercial products in the market, identifying an alternate reference standard is essential. For the reference standard, a traditionally manufactured drug product with a similar dose can be utilized or a 3D-printed product which is fully validated and being used as an internal reference standard as a comparison for the future production runs can also be utilized.

4.8. Post-Processing

Irrespective of the AM platform, the 3D-printed medications fabricated using all the AM techniques require a secondary processing step, such as curing, drying, depowdering, coating, and solvent washing. The AM process is meant to be a single-step continuous manufacturing process, but including a secondary step will impact the efficiency of the process compared with traditional techniques. The FDM process requires coating the medications to prevent the recrystallization of the drug [141,142,143]. The dosage forms printed using SSE and inkjet printing require drying to remove the solvents, which might be harmful. The medications fabricated using SLS require solvent washing to remove unreacted monomers. The SLS and binder jet printing process involves a depowdering step for removing excess powder that might have adhered to the printed medications. The inclusion of the secondary cleaning step needs to be validated and documented according to GMP requirements. The secondary processing step is manual; scaling the process would be critical. The inclusion of a single unit operation in the manufacturing process would add a certain level of risk to the product quality. The secondary processing steps will affect the surface and porosity of the dosage form, impacting the drug release profiles [144,145]. The secondary processing steps will require additional equipment such as a coater, a dryer, and curing stations, adding cost to the manufacturing.

4.9. Mass Production

Mass production is the primary barrier across all AM techniques compared to traditional manufacturing. The AM techniques are more suitable for on-demand, small-scale, and prototype manufacturing. The FDM and SSE types of AM techniques are slow and print one dosage form at a time, layer by layer [146,147,148]. The inkjet and binder jet types of AM techniques are rapid but require secondary processing steps, such as drying to remove solvents. Among AM techniques, the SLS and SLA types are slow, and they take minutes to hours to fabricate medicines, requiring secondary processing steps [149,150]. The need for a secondary processing step will increase manufacturing time, affecting the production rate. For mass production, the manufacturers should implement several 3D printers, which would affect the production cost. The implementation of multiple printers will result in variation in the quality and performance of the dosage forms and also require increased sampling and testing [151,152]. The traditional manufacturing remains superior based on the current manufacturing constraints for the AM techniques. A detailed comparison of additive manufacturing with traditional manufacturing platforms is shown in

Table 7. Detailed comparison of additive manufacturing and traditional manufacturing.

Parameter	Additive Manufacturing	Traditional Manufacturing
Production speed	Slow (few minutes/unit)	Fast (hundreds/minute)
Batch size	Small scale	Large scale
Scalability	Limited	Depends on equipment capacity
Cost efficiency	High cost, minimal to no waste	Low cost
Quality consistency	Vary between printers	Highly consistent
Flexibility	Flexible to adjust dose and geometry	No flexibility

. In addition, the additive manufacturing platform can also be coupled with the traditional manufacturing technique called hybrid manufacturing, which enables the personalized and mass manufacturing of medicines. The 3D-printed pills can be coated using traditional a pan coating process, which provides an additional protective layer to the tablets. During the early stages of drug development, the additive manufacturing techniques can be implemented for developing the prototype medications for rapid evaluation and, based on the preliminary clinical data, the manufacturing can be scaled using traditional processes. The medications printed using additive manufacturing can be placed into the capsule shells for providing additional protection or for clinical blinding. The 3D-printed medications which require curing can be placed into the traditional tray dryers.

5. Recent Advancements

Since the time that the AM platforms have been introduced to the pharmaceutical sector, a lot of advancements have been seen in terms of equipment design, process improvements, pharmaceutical-grade materials, and formulation design [22,24,153,154]. Within the FDM 3D printing approach, improved drug loading and the stability of amorphous drug formulations have been noted. Implementing PAT tools to monitor the process parameters and quality of the medication has been successful. In fact, much research has been conducted focusing on developing polypills and split dosage forms to support the dose titrations within the clinical studies [155,156,157]. Various pharmaceutical-grade inks and gels have been developed to suit the SSE process. Pharmaceutical inks were successfully developed, and the feasibility of hydroxypropyl methylcellulose (HPMC), polyethyleneoxide (PEO), and starch has been evaluated. The pharmaceutical inks recently developed for SSE have demonstrated improved rheology and the enhanced stability of oral solid and semi-solid medications. In fact, the SSE printing could be processed at low temperatures, and the drying of the 3D-printed medications was made more efficient, reducing the risk of microbial growth and thereby enabling the opportunity to print sterile and biological medications. The SSE 3D printing was also successfully explored to fabricate transdermal and microneedle patches. The printing process has been fine-tuned to control the atomization of the spray and the rate of drying for the inkjet type of 3D printing [158,159]. In fact, the dosage forms with nano- and micro-levels of drug were successfully incorporated using the inkjet process. The pharmaceutical inks possessing low viscosity for the efficient printing of the medications have been developed. Within the binder jet printing process, more efficient binder solutions and powder feed stocks have been studied and optimized for developing stable dosage forms. In addition to optimizing binder solution and powder feed stock, the binderjet printing was optimized for the densification of the printed objects to improve the mechanical properties. Within the SLA type of AM processes, more advancements have been achieved for the secondary processing of the printed objects to remove the unreacted monomers, which are toxic. For the SLS technique, a reasonable amount of work has been conducted for optimizing the laser energy and for the generation of partially amorphous drug products. In fact, the role of printing process parameters was studied to control the porosity of the printed dosage form, which governs the drug release profiles [160,161]. Despite the advancements, several unaddressed limitations exist for each AM technique that must be resolved as research progresses. A detailed list of recent advancements within the additive manufacturing platform (2023–2025) is shown in Figure 6.

6. Future Perspectives

Over the last decade, the AM approach has evolved from proof-of-concept manufacturing to on-demand and patient-centric manufacturing. However, many future directions must be addressed before implementing AM technology within the commercial setting. One significant aspect that needs to be improved within the AM technology is scalability and industrialization [162,163,164]. The equipment manufacturers need to develop more advanced 3D printers with multiple nozzles that can be operated quickly. The production rate needs to satisfy the pharmaceutical industry and meet the demands of the patient population. In the case of FDM 3D printing, the continuous manufacturing line coupled with HME needs to be established along with appropriate PAT tools. The excipient manufacturers should work with the researchers to design and develop novel excipients. The next generation of excipients needs to be processed easily and should preserve the stability of the 3D-printed medications [22,88,165,166]. In the case of FDM 3D printing, the materials should withstand the high processing temperatures and preserve the drug substance’s solid-state properties. The viscosity of the polymers is also essential within the HME-coupled FDM process, where the high viscosity of materials results in the need for high processing temperatures. Within the SSE approach, low-melting-point materials are preferred to avoid using solvents and drying steps. The inkjet printing process requires materials that can result in low-viscosity printing inks for the efficient spraying and for fine atomization of the solution [167,168,169,170]. The binder jet printing also requires low-viscosity binder materials, which can be sprayed on top of the powder bed. The SLA approach requires powder materials that can withstand laser intensity and protect the drug from degradation. The SLA process requires novel photopolymer materials that are non-toxic to the patient population. More research is warranted to identify efficient PAT tools for monitoring the process conditions and quality of the medications. Implementing PAT tools will ensure the quality of the medications and reduce the number of testing requirements [20,171,172,173,174]. The AM process can be integrated with AI and health records to tailor the medication design based on the patient’s history. Appropriate downstream processing methods must be developed and validated to minimize the time and make large-scale manufacturing more efficient. The regulatory agencies need to work closely with the researchers from academia and industry to design and develop guidelines suitable for the AM platform [175,176]. The decentralized manufacturing process at the hospitals and clinical sites needs to be refined to ensure the delivery of safe medicine to the patient population. Future perspectives of additive manufacturing in pharmaceuticals are depicted in Figure 7.

7. Conclusions

Over the last decade, the AM has evolved from benchtop prototype manufacturing, providing significant benefits to the pharmaceutical industries in manufacturing on-demand and patient-centric medications. The AM techniques, such as FDM, SSE, SLA, SLS, inkjet, and binder jet printing, have demonstrated superior advancements in process control, materials, and controlling the product performance. In fact, the AM platform can be integrated into a continuous manufacturing line along with PAT tools to improve the production rate and ensure the quality of medication being delivered to the patient population. Despite various advantages, a few unanswered challenges regarding materials, large-scale manufacturing, reproducibility, and regulatory evolution must be addressed. Integrating AI with the AM platform will provide an advantage of offering tailored medications. Still, much research is warranted across the AM techniques for evaluating the long-term stability of the 3D-printed medications. The complex medications, which are difficult to manufacture using traditional manufacturing techniques, can be easily fabricated using AM techniques. Implementing the AM platform will accelerate the developmental timelines, where the medications can be printed on demand in the hospitals and clinics, eliminating the centralized manufacturing approach. If the current challenges are addressed, the AM platform can be implemented as a core manufacturing technology, enabling on-demand, patient-centric, and decentralized manufacturing platform.