Innovative approaches to develop pharmaceutical dosage forms can lead to drug products that exhibit unique properties. These new approaches can also speed up the drug development process, resulting in significant savings of time and money and allow new medicine to reach patients sooner.
Three-dimensional printing (3DP) is one such approach that allows dosage forms to be built in layer-by-layer fashion while controlling size, shape and composition at levels difficult or impossible to attain with conventional processes. Moreover, 3DP of pharmaceuticals provides an opportunity to speed the drug development process, either by rapid prototyping of candidate formulations or by potentially facilitating on-demand production of clinical trial supplies.
Binder jetting technology, which combines powder and liquid input materials in controlled fashion, has been used successfully to produce an U.S. Food and Drug Administration (FDA)-approved pharmaceutical product, Spritam, demonstrating the commercial feasibility of 3DP-based pharmaceutical production system. Controlled binding of active pharmaceutical ingredient (API) with excipients, enabled by the 3DP process resulted in a unique combination of very high dose levels of API with rapid dispersion, an elusive feat using prior “fast melt” techniques such as soft compaction or freeze drying. In addition to commercial production, this process lends itself to small batch production and can be used to rapidly iterate product designs without tooling changes usually associated with conventional pharmaceutical technologies. This agility to provide different doses and dose combinations provides an opportunity to accelerate drug development in both clinical trial and life cycle extension of pharmaceutical products.
There are several different 3D Printing or additive manufacturing technologies being advanced for potential application within the pharmaceutical industry. We can look at the various technologies as fitting into three broad categories based on bulk input material:
With respect to binding powder, one approach is to use an inkjet printer to deposit precisely programmed droplets of binding agent onto a bed of powder. This process is referred to as binder jetting as categorized by ISO/ASTM52900-15, an attempt to standardize terminology for additive manufacturing. Another way to bind powder is to use a laser, electron beam or heat to selectively fuse regions of one powder layer to another powder layer in a laminar process, hence the ASTM terminology powder bed fusion.
Material extrusion processes involve the use of pressure activated syringes or heated nozzles to extrude layers of paste-like material or thermoplastic filaments to build an object. The most common form of extrusion is fused deposition modeling (FDM). Due in part to availability of inexpensive, compact equipment, extrusion-based approaches enabled a series of exploratory work on pharmaceutical dosage form printing, with the bulk of the investigations originating from academic institutions.
Lastly, resin-based processes rely on photopolymerization, often activated by UV light to build 3D objects. This can occur in a vat with layer-by-layer introduction of uncured resin (i.e., vat polymerization) or via inkjet printing of photocurable resin (i.e., material jetting), each drop selectively placed via computer control, followed by UV curing. While some researchers have demonstrated feasibility to prepare dosage forms with these approaches, lack of proven pharmaceutically acceptable material system (i.e., monomers, photo initiators, inhibitors, etc.) presents a significant hurdle for their adoption. The in situ reaction must not compromise stability of the active pharmaceutical ingredient (API), and residual reactants must be below acceptable levels.
In contrast, powder-based 3DP technologies offer access to a wide range of pharmaceutical excipients already familiar to formulation scientists and regulators alike, removing a key barrier to the technology adoption. In the binder jetting formulation platform, pharmaceutical products are assembled layer-by-layer from a pharmaceutical powder blend without using compression forces and molds. This gentle layering process eliminates the potential for disrupting drug particles or particle coatings used for taste masking or modified release. Spreading of thin layers of powder and depositing pre-programmed patterns of liquid droplets onto selected regions of each layer is carried out repeatedly until tablets form. With flexibility in powder and liquid flow, the process affords tremendous control of tablet hardness in whole or regionally within the tablet. Taste masking, dispersibility and overall form and shape of the tablet can all be dictated by the controlled interaction between powder and liquid during the 3DP process which binds the layered materials together.
Binder jetting 3DP techniques allow control and flexibility of the internal and external geometry and spatial control of tablet composition. For example, multiple printheads can be used in Binder Jetting process to selectively deposit ingredients that can affect key characteristics of dosage forms such as dissolution rate, appearance, stability, etc. This opens up the opportunity for entirely new dosage forms with unique properties and or combinations of functionalities that could previously not be achieved. For example, a highly porous matrix can be made which includes particles engineered for controlled release, resulting in a dosage form that disintegrates rapidly, exhibits taste-masking while in the mouth, and releases the drug in a controlled release fashion. Likewise, dosage forms with ultra-low levels of API may be achieved by precisely metering API in a solution form via printheads (instead of struggling to achieve a homogenous blend of very low concentration of API in a powder). Alternately, a combination therapy of two or more APIs could be achieved by combining the APIs in powder blends, or both in the powder blend and the liquid form, to be printed through nozzles. Enhanced permeability and absorption is also possible for products targeting pre-gastric, gastric or alternative delivery sites by incorporating functional excipients into the formulation.
As with any new technology and system there are opportunities for improvement. Significant developments are underway for future forming systems that will address barriers to adoption, such as the relatively low throughput in comparison to conventional tableting technologies that had the benefit of decades of refinement.
With the tremendous flexibility afforded by binder jetting technology, early stage formulation and development work can be done to assess feasibility of finished prototypes. In early clinical trials, when API availability is limited and there is a high level of uncertainty around appropriate human dose strengths, the agility to produce small batches of exploratory formulations can eliminate significant delays and costs from the already long and expensive development programs. The ultimate vision is that clinical trial material can be created on-site and on-demand, minimizing stability program requirements and product waste while facilitating adaptive clinical trial protocols. Flexible dosage forming reduces the need to make compromises over required dose loads needed during the study. All of these opportunities can lead to earlier decisions on finished dosage form and dose load, titration decisions, and patient preference, thereby getting the innovative medicine to patients faster.
Breakthroughs beget expectations of more breakthroughs. News of the FDA’s approval of Spritam in 2015 was followed by speculations of future state in which every medicine will be 3D printed at home. That future remains distant due to many technical, regulatory and economic challenges still to be overcome. However, a plethora of opportunities exist where unique dosage forms can replace the less effective or convenient ones in order to improve patient care. Moreover, 3DP can serve as a tool to accelerate the development of new products, bringing improved medicines to patients sooner.
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