3D printing offers drug research and development professionals a world of possibilities, but only with the right materials and formulations. Korinde van den Heuvel, senior product developer with DFE Pharma, shares perspective as well as findings from the company’s recent research into 3D powder bed printed tablets.
OSP: The COVID-19 pandemic has had a significant impact on most of the pharma sector. How has it impacted the excipients market?
KVDL: The coronavirus pandemic has indeed had a significant impact on the pharmaceutical industry and the pharmaceutical excipients market. COVID-19 will prompt a range of changes in the use of medicines, demand for new vaccines and therapeutics as well as shifts in demand for existing therapies and changes in patient behaviors.
This too has its impact on the excipient market. In DFE Pharma, we have seen an increased demand for excipients used as binders and fillers in tablets. We have also seen an increased demand in lactose-based excipients used in inhalation medicines – normally used for the treatment of COPD and asthma but now also for COVID treatments.
Disruptions in the supply chain caused due to a halt in global operations are also projected to have an adverse impact on the market. Our customers – pharma companies from across the globe – have an urgent need for reliable supply. At DFE Pharma, we have been able to offer security of supply due to our global spread of manufacturing facilities and double sourcing of raw materials among others.
OSP: Please tell us about the interest in and use of 3D printed tablets for pharma. How has this relatively new field evolved in recent years?
KVDL: Tablets need to adapt to the demands of 21st-century healthcare. They must be easier to make, easier to take, and easier to personalize. 3D printing of tablets creates great opportunities including dose flexibility, taste masking, solubility enhancement, shape modifications, easy-to-swallow tablets, and multi pills with multiple APIs.
Next to this, 3D printing enables patient-tailored medicine to be “printed” on demand in pharmacies or hospitals, making it particularly useful for orphan drugs and personalized medicines. On top, it holds huge potential in the clinical trial space, which has a constant demand for bespoke, small-scale batches.
COVID-19 has also created additional interest in 3D printing. Many countries realized the potential challenges in supply and transportation and the need for having worldwide stocks. 3D printing is a technology that allows local production of tablets to have security of supply all over the world. This can be established by local 3D printers receiving recipes for the production of a specific medicine, instead of one large facility for worldwide supply like we do with other production processes.
OSP: What are some challenges and questions 3D printed tablet producers have to consider that conventionally produced tablets don’t necessarily encounter?
KVDL: When selecting excipients for a 3D printed formulation, it is important to realize the importance of critical material attributes. Whereas for conventional tablets compaction behavior is of utmost importance, for 3D printing (using powder bed printing technology) characteristics like flowability, wettability and consolidation are the main characteristics.
On a regulatory aspect, producers have to consider the acceptance by regulatory authorities and the validation and registration of 3D-printed products. Typically, the overall approach still requires a risk assessment, followed by evaluation and validation of critical parameters. Due to the limited experience with 3D printing, however, these steps could be a bit more challenging. Here powder bed printing has the advantage that it has been commercialized and FDA approved (Spritam, Aprecia).
OSP: Specifically, what considerations exist around excipients when planning 3D printing of tablets?
KVDL: To date, we know that powder bed printing can result in significant dust formation during the process and high friability in the resulting tablets. DFE Pharma researched the use of lactose as an excipient for 3D printing in collaboration with TNO (an independent research company in the Netherlands).
Despite lactose being a well-known, well-established, and widely used pharmaceutical excipient, its use in the 3D printing of pharmaceuticals is rare – possibly because it isn’t easy without the right expertise and access to materials.
The research team tested 20 lactose grades, all with varying morphology, and explored their effects on selected criteria, such as hardness, friability, and disintegration. The primary objective was to develop a lactose with sufficient flow, wetting, and binding to be used effectively in the powder bed 3D printing of pharmaceuticals.
With the initial selection of excipient grades and the range of printer settings tested, we achieved 3D printed tablets with properties that, while not yet equal to traditional pills, are approaching the industry standard for hardness and friability (i.e. <1%). Ultimately, lactose works. It’s worth noting that 3D printed tablets will always look more irregular and have a rougher surface area than those produced using traditional methods.
OSP: Why did you decide to take a deeper look into 3D powder bed printed tablets?
KVDL: We noticed there is a gap in data research and we believe the whole sector benefits from the creation of a centralized database that unites industry, innovators, and academia in the common aim of providing patient-centered care.
Key to addressing the data gap is developing an understanding of how to use excipients, as different substances will affect the powder parameters that are central to the success of the 3D printing process in different ways. We need to build the knowledge of how excipients impact these parameters in 3D printing before we can begin to understand the most appropriate materials or techniques for each use case.
Next to studying individual excipients, it is important to study the interaction between various excipients and their effect on different types of APIs (hydrophobic and hydrophilic). A repository of excipient usability and applicability, along with their impact on powder parameters and those of the resulting tablet, would provide investigators of all backgrounds with an invaluable tool.
OSP: Could you please share some of the most notable findings from your research?
KVDL: We used 20 grades of lactose and starches to produce various powder blends for 3D powder bed printing of tablets. The powders were assessed on wettability, flowability, and consolidation and printed into tablets.
The resulting tablets were tested for hardness, friability, and disintegration. We also examined the impact of factors such as line spacing, print direction, and rotation. Formulations with acetaminophen and diclofenac sodium were printed. The study showed how hydrophilic/hydrophobic APIs can be successfully formulated into 3D powder bed printed pharmaceutical tablets.
- Wettability: In order to study the impact of particle size distribution (PSD) on powder bed printing, wetting tests were performed by printing a single layer with different line spacings. The findings concluded that the d10 value should be larger than 6μm, and preferably in excess of 10μm
- Flow: Blends of two lactose grades with a higher than 10 μm d10 value were blended with 10% fully pregelatinized starch and measured on flowability, density, and particle size. Both blends had a flow function (FFC) above 10 and a compressibility index below 15. This is an indication of excellent flowability and low compressibility.
- Consolidation: Circular, 9mm tablets with a height of 2.8mm were 3D printed using lactose grades as mentioned above. Both grades resulted in tablets with an acceptable variation in tablet mass, diameter, and height.
OSP: How do you expect the findings of this study to impact future 3D printing of tablets?
KVDL: This study demonstrates that lactose is a suitable excipient for the 3D powder bed printing of pharmaceuticals. What’s more, it contributes to the common evidence base for 3D printing in the pharmaceutical industry and highlights the power of collaborative working in this space.
We are taking the tentative first steps towards creating the centralized dataset that we believe is the key to accelerating progress, and we will continue our research in this area. We would invite other organizations to work with us, our knowledge of 30 types of lactose, and our ability to customize grades to suit each use case so that we can all find out more.
By pooling the knowledge and expertise of industry, innovators, and academia, we can truly move the dial on 3D printing in pharmaceuticals, and in doing so take huge strides towards delivering the person-centered clinical trials and medicines future. This is something we take very seriously.
OSP: What advice would you have for pharma professionals and their R&D partners when considering 3D printing for their tablets?
KVDL: As 3D powder bed printing proves to have a lot of potential for the manufacturing of medicines, we invite pharma professionals to get in touch to further discuss constructive collaborations.
At DFE Pharma we have a dedicated researcher who is committed to driving development in this space. We also have strong relationships with institutions such as TNO (the Netherlands) and respected academic centers like Deakin University, Australia. To find out more about possible collaborations or to request full details on our lactose in 3D printing study, get in touch on firstname.lastname@example.org
OSP: Anything to add?
KVDL: Perhaps good to note that we, as DFE Pharma, refer to zip-dose (drop-on-solid) technology when we talk about 3D printing. This is the only commercially proven technology.