Additive manufacturing, which includes three-dimensional printing (3DP), offers many potential benefits to drug makers, including more efficient continuous production of complex drug products with more straightforward formulations that overcome poor solubility and bioavailability issues. Easy scalability and real-time monitoring allow production of medicines tailored to individuals, as well as larger clinical and commercial quantities. Melt-extrusion deposition (MED®), a type of 3DP technology that continuously converts powder feedstocks into softened/molten states followed by precise layer-by-layer deposition to enable challenging drug formulation and delivery with mathematical precision, is one of the most efficient and diverse 3DP technologies in pharmaceutical design, development, and manufacturing, It enables applications of polymeric excipients with different thermomechanical properties — for example, Parteck® MXP polyvinyl alcohol — and also offers fast prototyping of products that combine multiple APIs with different release rates and modes in one tablet.
Numerous Advantages to 3D Printing
Interest in three-dimensional (3D) printing of pharmaceuticals has risen steadily since the U.S. FDA approved Aprecia’s Spritam® (a levetiracetam tablet) in July 2015. That interest is driven by the potential advantages that this manufacturing technology offers, many of which derive from the digital nature of the technology and the possibility of using it for commercial production of both blockbusters and highly personalized medicines.
Additive manufacturing involves using digital models to dictate the deposition of materials in very thin layers with fine control. For pharmaceutical products, that translates to the ability to incorporate process analytical technologies (PAT) for continuous real-time monitoring. In addition, 3DP can facilitate rapid prototyping and thus accelerate drug development. As a continuous process, it also offers flexibility to meet both clinical and commercial needs and enable rapid responses to changing market demands.
Furthermore, while 3DP can be advantageous for active pharmaceutical ingredients (APIs) that do not suffer from solubility or permeability issues, layer-by-layer construction affords the potential to create novel structures that may solve important challenges in drug delivery, such as poor solubility and drug absorption. Additive manufacturing provides more versatility with respect to establishing the pharmacokinetics (PK) and the timing and location of API release to optimize bioavailability and targeted delivery.
For instance, amorphous solid dispersions (ASDs), which are known to enhance the bioavailability of poorly soluble APIs, can be readily generated using 3DP with flexible structure design to achieve desired release profile. This approach may also present the opportunity to formulate APIs that would not be processable using existing manufacturing technologies.
The digital nature of 3DP, in addition to allowing the formation of unique product designs, involves the generation of large quantities of process data that can be analyzed using artificial intelligence and machine learning tools to allow continuous process optimization, as well as the prediction of release kinetics for enhanced formulation development. As such, 3DP fits well within the Pharma 4.0 paradigm.
Advanced Manufacturing Plays an Important Role in Production
A key current trend in the pharmaceutical industry today is the introduction and implementation of advanced manufacturing concepts. Continuous processing is a primary example that is becoming increasingly important across all aspects of drug production. The evolution toward continuous manufacturing, which by its nature also leverages advanced digital technologies, will enable standardized processing.
3DP — as a highly digitalized, continuous process — fits well into this narrative. It will initially find use for dedicated manufacturing where classical approaches cannot fully serve market needs. With the ability to scale out rather than up, 3DP will be valuable where production flexibility is needed at a minimal initial capital expenditure level, with the ability to manufacture medicine in clinical, commercial, and personalized quantities.
This technology can provide solubility enhancement, enable formulation of completely new drug substances, and accelerate the drug development process via a versatile, data-driven, and efficient manufacturing process that can be replicated in multiple geographies, addressing challenges in development, formulation, and the supply chain. Therefore, once existing technology and regulatory roadblocks are surmounted and newer, more advanced 3DP processes are implemented for GMP drug production, more people within the industry will rapidly come to realize its benefits and versatility.
Industrial-Scale and Personal Solutions Possible
The scalable nature of 3DP means that it can be applied not only for clinical and commercial manufacturing but also to produce personalized medicines with dosing and release profiles tailored to individual patients. In fact, 3DP solutions for pharmaceutical production are evolving along two distinct pathways.
Advanced technology companies like Triastek are providing 3DP solutions for use in new dosage design and early prototyping as well as in large-scale manufacturing. They work closely with companies such as MilliporeSigma, which contributes the development of tailored excipients and formulation application support.
There is also significant movement toward the use of 3DP to produce personalized medicines. Developing such solutions requires that people with wide-ranging expertise, such as engineering, pharmaceutical development, programming, and regulatory, work together to develop the necessary raw materials, equipment, and processes. There is high demand for further advancing the technology, as well as understanding the required polymer attributes. Collaborations between industrial partners and universities assure a fundamental understanding of the complex attributes to enable future industrial application. The PolyPrint Consortium, for instance, brings together universities and industrial partners with the goal of defining the requirements for 3D-printed personalized medicine, such as for polymers and printer designs.
The PAT and precision capabilities of 3DP are also significant when it comes to the production of highly personalized medicines. Rapidly switching tablet geometries and dosing levels for printed products requires demonstration that the target geometry and weight are achieved for each product to ensure patient safety. The intention is to bring these personalized, small-scale technologies closer to the clinic and the patient for more targeted use.
Several 3D-Printing Technologies Explored
Additive technologies used and investigated in the pharmaceutical industry for drug and device manufacturing can be classified into three groups: powder-based, liquid-based, and extrusion-based systems. Powder-based technologies include drop-on-powder (DOP, also referred to as binder jetting) and selective laser sintering (SLS). Liquid technologies include drop-on-drop (DOD) deposition and stereolithography (SLA). Extrusion-based systems include fused deposition modeling (FDM) of solids, pressure-assisted syringe technologies that use semi-solid forms and the melt-extrusion deposition (MED®) technology developed by Triastek.
Aprecia’s Spritam® is produced using powder-based technology, and therefore, powder-based systems have been a focus within the industry, and significant progress has been achieved as a result, particularly with respect to realizing industrial-scale solutions. Aprecia and others are also working to add more functionality, such as leveraging multi-particulate and nanoscale technologies.
SLS allows the creation of 3D structures through the fusion of powder particles using a laser system. It is attractive because no solvents are involved and there is no need to spray any liquid, as is the case with traditional spray-dried formulations.
Extrusion technologies have recently begun to attract attention, particularly those that have their foundations in hot-melt extrusion (HME), which, along with spray drying, is an established method for generating ASDs. Two approaches of particular interest are advanced melt drop deposition and MED®.
An Ideal Excipient for 3D Printing
As with traditional manufacturing approaches, excipients play an important role in the performance of 3D-printed drug products. The key is to understand the properties of the API so that the critical quality attributes of the drug substance can be defined early in development. For instance, some compounds are not limited by intrinsic dissolution but rather by the dissolution rate. Distinguishing the relevant characteristics is important in order to provide the appropriate formulation development guidance.
Our SAFC® polyvinyl alcohol (PVA) solubility enhancement platform was initially developed for HME and is also widely applicable for 3DP technologies, particularly when using extrusion-based processes. The platform comprises a range of products with different molecular weights/viscosities and percentages of hydrolyzed acetate groups (and thus hydroxyl groups), generated via the controlled, partial hydrolysis of polyvinyl acetate. The amphiphilic structure facilitates solubility enhancement while also inhibiting precipitation of the API upon release, thereby improving the bioavailability of the drug substance.
Focus on Melt Extrusion Processes
In HME, an ASD is formed that is then subjected to milling to reach a specific particle size, and the resulting granules/powder are combined with other formulation ingredients (e.g., binders, disintegrations, lubricants) and formed into tablets or filled into capsules.
With extrusion–based 3DP processes, the final dosage form is created directly with no need for milling, formulation, and tableting. This benefit is in addition to the capability of designing the tablet structure for optimum release kinetics, even including pulsating devices that can be difficult to generate using classical tablet manufacturing. In addition, 3D-printed formulations are often simpler, because many of the additional excipients required to facilitate the tableting process are not needed. As a result, there are fewer compatibility issues, and 3D-printed tablets generally exhibit long-term stability.
Advanced melt drop deposition follows the principle of Arburg plastic freeforming (APF). The polymer excipient and API mixture is melted in a heated plasticizer barrel, and then the material is transported to the nozzle tip via screw rotation. The pressure generated due to the translational movement of the screw causes a homogeneous discharge of droplets, which is controlled using a piezo actuator.
In melt-extrusion deposition (MED®), which was developed by Triastek, a powder feedstock is continuously converted into a softened/molten state, and this material is then precisely deposited layer by layer to produce objects with well-designed geometric structures. Using powders as starting materials rather than other 3DP approaches like fused deposition modeling, this technology doesn’t rely on filaments, and the process can take place at lower temperatures. No organic solvents are required for the process, making this sustainable technique safer, environmentally friendly, and easier to implement.
The digitalization properties of continuous manufacturing and MED® 3DP technology enable a flexible structure designed to achieve various release profiles, fast prototyping, and accelerated clinical and commercial supply and, in doing so, improve the safety and efficacy of the drug products, remaining FDA compliant. These advantages enable solutions for insoluble drugs, gastric delay, colon targeting, as well as product lifecycle management. Continuous real-time monitoring using advanced PAT technologies with full data traceability to each tablet ensures complete quality control. Easy scalability makes MED® suitable for the manufacturing of clinical, commercial, and personalized quantities.
The platform Triastek developed for formulation development is called 3D printing formulation by design (3DFbD®). Once the target PK profile is defined, it can be translated into the corresponding release profile that can then be used to design tablet structures and identify appropriate polymeric materials and excipients to fabricate the prototype. A wide range of amorphous and crystalline polymers are compatible with the process. The technology allows for simple particle dispersion, as well as molecular dispersion and the generation of ASDs.
In addition, the array design enables mass production using multiple materials to fabricate complex structures. Tablet structures can be designed to enable delivery of low-solubility APIs, programmatically release APIs at targeted locations in the gastrointestinal tract with the right rate and the right dose, and enhance the oral absorption of biologics.
Furthermore, MED® has the capability to create products that combine multiple APIs with different release rates and modes in one tablet, giving full play to the advantages of Triastek’s highly differentiated drug delivery platforms. Each API can be printed into a separate compartment, with each compartment having a structure, surface area, and delayed-release layer designed to meet the onset time, location, release kinetics, and gastric retention for the specific API that it contains. By combining extended release and pulsatile release, multiple APIs with markedly different PK profiles can be incorporated into a single tablet with once-a-day dosing.
MilliporeSigma/Triastek Joint Research Project
Our SAFC® Raw Material team collaborated with Triastek on a joint research project to demonstrate the applicability of the PVA solubility enhancement platform for 3DP using MED® technology. A particular focus of the project was to achieve the continuous printing of a poorly soluble drug.
First, the printability of formulations containing PVA series, including Parteck® MXP excipient, was demonstrated at a temperature of 200 °C. Next, the feasibility of tablets containing felodipine as a model Biopharmaceutics Classification System (BCS) Class 2 API with poor solubility and PVA was explored. Success at this stage led to investigation of the 3DP of an ASD of felodipine using PVA. The API was found to be amorphous at a concentration of 40%. Notably, felodipine acted as a plasticizer of PVA, lowering the processing temperature.
In general, Parteck® MXP excipient was easy to process and worked well with a range of compounds in addition to felodipine, including plasmids. It is also stable at high temperatures and therefore may be suitable for use with poorly soluble, high-melting APIs — which are often not easy to formulate using existing delivery technologies.
Due to MED® technology’s advantages in pharmaceutical formulation development and continuous manufacturing, especially in solubility enhancement, Triastek established a cooperative partnership with MilliporeSigma’s SAFC® Raw Materials team.
Overall, the collaboration revealed significant synergies between Triastek’s MED® technology and MilliporeSigma’s PVA solubility excipient. By combining the knowledge of the two companies, it is possible to fine-tune release kinetics with designed structures, such as a core-shell structure, multi-compartment structure, or honeycomb/weave structure.
Innovation Still Needed to Fully Realize Pharma 3D Printing
Widespread implementation and adoption of 3DP cannot take place without further innovation in several areas. Achieving that innovation will require more collaboration across the industry. The combination of different technologies is also needed to enable the development of different structures that use different materials and thus allow for a wider range of administration routes. With such an approach, it will be possible to process not only solids but also liquids and larger molecules, such as peptides and RNA.
Smart manufacturing solutions that leverage advances in digitalization tools are also needed to enable further progress in the 3DP of pharmaceuticals. Ideally digital design and calibration of tablet structures will make it possible to achieve programmed release profiles, while digital manufacturing solutions will enable real-time product release, increasing process efficiency and reducing cost. Incorporation of microelectronic controls could improve targeted delivery and controlled drug release. The ultimate result will be high-precision manufacturing to produce high-quality, safer, and more reliable products.
There is anticipation that the significant advances in additive manufacturing within the plastics and metal industries will help designers of pharmaceutical 3DP equipment and processes make rapid improvements. Meanwhile, material suppliers are focused on addressing the shortcomings of existing polymeric excipients with respect to material quality attributes.
As part of our SAFC® Raw Materials portfolio, MilliporeSigma is investigating new polymer excipients that meet the specific requirements of different 3DP technologies. This work is particularly important, because access to effective excipients is key to the success of all drug formulations, including those generated via additive manufacturing. This effort includes gathering input from experts in the many fields applicable to 3DP to ensure the development of optimal excipient platforms.
Triastek is looking forward to evaluating any new excipients within our SAFC® Raw Materials portfolio developed by MilliporeSigma. MilliporeSigma is also exploring the printing of specialized products, such as child-friendly products, including not only tablets but also chewables with different flavors.
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MilliporeSigma is the life science business of Merck KGaA, Darmstadt, Germany.