Powder, Pills, and 3D Printing

Despite still being viewed as a niche – or even experimental – technology, 3D printing is increasingly making its presence felt in pharma. You’ll likely be aware of Spritam – the first FDA approved 3D printed tablet. You may also be aware of Merck’s joint efforts with AMCM/ECOS toward producing Good Manufacturing Practice compliant 3D-printed pills for clinical trials, or the CPhI Pharma award won by University College London spinout FabRX for pioneering work carried out using its own trademarked 3D printer, and you may even have heard about the potential applications of 3D-printed medicine for missions into space.

Another company ploughing ahead with this exciting branch of modern technology is DFE Pharma – an excipient solutions company based in Goch, Germany. A recent paper in the journal Powder Technology shared some of the research conducted by DFE Pharma. The result? Another stab at 3D-printed tablets.

Here, DFE’s Senior Product Developer Korinde Van Den Heuvel shares the story of these tablets, the tech that prints them, and which medical and logistical ills they can address.

How did DFE Pharma come to work with 3D printed tablets?

In 2015, 3D powder bed tablet printing emerged from academia. In powder bed printing, the powder’s properties are of the utmost importance and this aligns with DFE Pharma’s core expertise: mechanistic understanding of powder behavior. Therefore, it seemed logical to apply ourselves to 3D printing!

However, the siloed nature of research in this area has contributed to slow progress. I believe the data gap here could be addressed by universities, innovators, and industry working together and sharing research. We believe that developing an understanding of how to use excipients within the 3D printing process is the first step in creating a centralized dataset that would allow us all to truly seize the opportunities on offer. 

How does the powder bed printing work?

The easiest way to grasp this manufacturing method is to break it down into steps.

First, a thin layer of powder is spread on the printing table. Second, a very specific area of the bed of powder is then wetted with ink (which in our case is just a water/ethanol mixture, but can also be a solution containing a binder or API) that solidifies the particles at the points where the ink enters the bed. Third, another layer of powder is positioned on top of the powder bed and a similar circle is wetted. By printing many layers in succession, a three-dimensional tablet can be created. Finally, the tablet can be scooped out of the powder bed. The remaining powder – that which was not in contact with any liquid – remains loose.

Using this technique, ODT, CR, and IR tablets can be produced – and it can also be used for combination products or poorly soluble APIs. The main advantage of 3D printing is that you can produce relatively small batch sizes.

What question or challenge were you setting out to address when you began your research in this area?

Excipient selection for powder bed printing is essential; excipient functionalities known for direct compression and wet granulation are not always comparable to excipient functionality in 3D printing. Unfortunately, there is limited information available in the public domain on excipient selection in relation to functionality in the dosage form.

In a bid to overcome this challenge, DFE Pharma screened more than 20 lactose batches in collaboration with the Netherlands Organisation for Applied Scientific Research (TNO). We investigated the impact of different grades of lactose blends on the critical material attributes for powder bed printing: wettability, flow, and consolidation. The obtained blends were further applied into a medium dosed tablet with either a hydrophilic or hydrophobic drug. And the resulting tablets were tested for hardness and dissolution. We also looked at the impact of factors such as line spacing. 

What were your main findings?

We concluded that the particle size distribution is very important – particularly the d10 value; the d10 value should be larger than 6 μm, and preferably in excess of 10 μm.

Based on the wettability findings, two lactose grades (A+ and B^) with a higher than 10μm d10 value were blended with 10 percent fully pregelatinized starch and measured for 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 a low compressibility. Circular, 9mm tablets with a height of 2.8mm were 3D printed using lactose grades A and B. Both grades resulted in tablets with an acceptable variation in tablet mass, diameter, and height.

Understanding critical (raw) material attributes for 3D powder bed printing is essential to creating a tablet that meets the European Pharmacopoeia and USP specifications. Thanks to the mechanistic knowledge we gained from this study, we can now support customers’ development of 3D printed products.

What challenges did you face along the way?

Since the use of 3D printing remains a frontier in pharma, regulatory bodies are still formulating the relevant guidelines, which can lead to uncertainty among pharmaceutical companies. That said, 3D powder bed printing is the only 3D technique with an approved drug product on the market: Spritam. The technology is therefore proven to be both scalable and acceptable to regulators.

Has COVID-19 had any effect on the field?

COVID-19 made the industry as a whole more aware of the risks of the supply chain status quo, with respect to manufacturing shutdown and international restrictions. 3D printing enables production of smaller batches in country-specific hubs – or even at small-scale, local sites, such as hospitals and pharmacies. During the pandemic, many European academic pharmacies have been investing heavily on 3D printing for small scale production runs of drugs whose supply had been cut off due to COVID-19 restrictions. On-site production capability restores security to the supply chain. However, we have only seen a limited transition from mass to small-scale production so far.

What’s on the horizon for this technology?

Though there is still much to learn about how different grades of lactose can impart various qualities onto tablets, our study demonstrates that it is a suitable excipient for the 3D printing of pharmaceuticals. What’s more, the study contributes to the common evidence base for 3D printing in the pharma industry and highlights the power of collaborative work.

Universities, innovators, and industry are beginning further explorations of 3D printing. The printing of clinical trial formulations will presumably be the first step on this path, and should help the industry and its regulatory bodies become more comfortable with the technology as a whole.

From that point onwards, 3D printing in pharma should be able to expand to economic production of commercial formulations for products of smaller batch sizes. 

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 to pursue research in this area. We intend to invite other organizations to work with us too, making use of our mechanistic knowledge of lactose-based 3D printing blends and our ability to customize lactose to suit each use case.

By pooling knowledge and expertise, we hope to take bigger strides towards delivering patient-centered clinical trials and medicines.