Why Would We Think About 3D Printing Pharmaceuticals?

A few months ago coming home from a conference, the cardiac physician queued alongside me to board the flight back to the US was skeptical about the merits of 3D printing pills. Why, he asked, would anyone do that, what benefits could it offer? Answering his own questions, he reasoned that decentralized production may be a benefit, but that the raw materials would still need to get there; the specialty nature of those active ingredients limits suppliers and the need to ship them could reduce the benefits of local manufacture. Customized formulations didn’t sway his thinking either, as compounders do a steady business in personalized pharmaceutical manufacture. As we boarded the flight and the conversation ended, he went back to his home hospital unconvinced that 3D printing might expand beyond a pharmaceutical novelty anytime soon.

That Philadelphia-based doctor is not the only one asking why 3D printing might be applicable to pharmaceuticals. After all, when you have a hammer, every problem starts to look like a nail, as they say. A hammer, though, is also an incredibly versatile tool and isn’t just used for its best-known one brute force application; similarly, 3D printing can indeed extend into finesse applications, and pharmacists are increasingly taking notice. Dr. Clive Roberts is the Head of School at the School of Pharmacy, University of Nottingham; he presented his thoughts recently on 3D Printing Manufacture of Medicines at this month’s International Conference on 3D Printing and Additive Manufacturing.

“We have oral delivery pharmaceutical tablets; so why would we think about 3D printing them?” Roberts put to the gathered attendees. “I’ll try to convince you there are clinical needs.”

In the abstract for his presentation, Roberts explained that the process for producing tablets — “the dominant form of medicine taken by patients” — hasn’t changed much in the last century and, despite generally serving their purpose, are faced with limitations addressable via 3D printing. Key among these are the creation of complex dosage forms and bespoke (personalized) medicines for a given individual or sub-population. His discussion touched on both the potential of and the challenges faced by 3D printing in medicine manufacture. For example, while 3D printing may enable novel architectures that control drug release, scaling up production and meeting regulatory requirements provide tangible challenges on the path to commercializing these methodologies.

He pointed first to the fact that the work in pharmaceutical 3D printing started at MIT in the late 1990s, using powder bed printing technology, and that both the interest and the breadth of technologies have broadened since then. While those attending the AM Conference were all well-informed regarding a good deal of additive manufacturing applications, the technology’s use in pharma applications isn’t quite as well known as that in, say, jet engines or hearing aids, and so Roberts put forth a bit of background to the topic.

“If you’re thinking there’s no way regulators will allow this, that there’s no reason for this, well there is one; there’s an FDA-approved one on the US market,” Roberts said, referencing epilepsy drug SPRITAM from Aprecia Pharmaceuticals, which received its FDA approval back in August 2015 and became commercially available in March 2016.

“Will it be commercially successful? We’ll see.”

To broadly underscore the viability of 3D printing in commercial manufacture, Roberts pointed to a large-looming example of mass manufacturing announced earlier this year as Carbon announced its partnership with adidas to use 3D printing in the scale production of shoes. Obviously, he noted, 3D printing wouldn’t be used to prototype pharmaceuticals, but to create patient-ready pills; the production capabilities of 3D printing, beyond prototyping, are in focus with work such as that from Carbon, with its well-known tag line, “Stop prototyping. Start producing.”

Turning back specifically to pharmaceuticals, Roberts looked to some of the issues and concerns most commonly raised. Regarding personalized medications, and addressing distributed manufacture, he pointed out that that is already a long-existing practice.

“A pharmacist is able to make medicine for you now; a compounding pharmacist can make personalized medications. The concept of making a medicine close to a patient, mostly by hand, is there. There is no regulatory problem on that end,” he explained.

Compliance is a large issue in pharmaceuticals, as Roberts noted research reporting that fully 50% of people in the UK do not take their medications correctly. Some of this comes down to the sheer volume of pills taken among an aging population — indeed, this pill burden is a common problem in the US as well, where elderly individuals often have a handful of pills to pop on a daily basis, and it can be all too easy to forget one or two of them. 3D printing has been used to create complex formulations combining several active drugs, with research last year showing the possibility for 3D printing one pill containing a full day’s medication. Customized dosages like this also reduce the likelihood of mismanaging drug concentrations through imprecise measures like cutting a pill in half to try to halve a typical dose, ensuring delivery of the right amount of active ingredient for a specific individual.

Among the types of 3D printing technologies Roberts noted as being most relevant to pharmaceuticals are:

• Inkjet printing
• FDM
• Powder bed
• Extrusion based

His team at the School of Pharmacy has shown precise control of dosing with inkjet 3D printing, while FDM technologies allow for the creation of a specialized filament that can be extruded. University College London spinoff FabRx, for example, has told us before about their use of several different 3D printing technologies for their personalized 3D printed Printlets. Powder bed technology is used in Aprecia’s 3D printed pill, which offers a unique fast-dissolving delivery method. Of this, Roberts explained:

“If you were a pharmacist, you’d have your mouth open right now, that’s amazing. This is delivered in a massive dose very quickly. Very, very useful dosage form. Made by powder bed form, inkjet and powder. The pill has a very porous structure that falls apart very quickly. Haven’t made use of the more exotic capabilities of 3D printing… that’s what I’m interested in. Like all things in pharma, that development was about 12 years from design to making. That 12-year roadmap contains a lot of decisions.”

Development of a new drug is, indeed, a fraught process steeped in regulatory hurdles — generally regarded as a good thing for those who will be relying on the medications. Roberts’ team has come up with a few proofs of principle to demonstrate their work, including tablets created via extrusion-based technologies that “produced a perfectly viable tablet, good enough to publish in a journal.”

“Let me show you a sexy tablet, this is really sexy stuff,” he said, pointing to another development. “This is a tablet with two different pockets, with three different drugs. The drugs are in different pockets, you don’t have to be worried about drugs interacting. This takes about 30 minutes to print. If you were in hospital, would you be willing to wait 10 minutes for your personalized medication to be printed up?

Next, here is a five drug polypill designed for cardiac treatment. There is absolutely no way you could have made that pill using traditional methods.”

A challenge in having pharma pick up 3D printing, Roberts explained, is that “Pharma will not allow you to introduce new materials that have not been approved.” They have thus been among those looking at changing the architecture of pills for a better design, rather than starting from scratch with unapproved materials as such work remains in relatively early days. Some of their work was recently accepted to the journal Pharmaceutics, showcasing the world’s first solvent inkjet printed formulations. Of these, he noted that, “It doesn’t look like much but it’s taken a long time for us to get to that point.”

“These are our sexiest hot inkjet tablets,” Roberts said. “They have different honeycomb structures. What you’re doing here is controlling the surface area of the tablet. Though the dosage is the same, the surface area is changed, changing the release without changing the formulation.

You get a different release only by changing geometry. What you change with 3D printing? Geometry.

We know where the drug is, as long as we know how quickly the drug is coming out we can model. Start to predict what the drug release would be if I designed it differently.  Model quite accurately predicting release from those structures.”

Roberts wrapped up his session with a few key takeaway points summarizing his views on the development and eventual commercialization of 3D printing in pharmaceuticals:

• There are a number of varieties of 3D printing proven to be able to manufacture solid dosage forms
• These approaches offer prospects for personalised medicines manufacture at a reasonable scale
• There are many wider applications in healthcare, some already in use, expect to see many more in the future
• Extrusion 3D printing is able to exploit current approved pharmaceutical excipients. Other types may require new ‘inks’
• New business models and new thinking on regulatory matters is required for some of the potential applications
• Technology is developing rapidly, we do not want to be bound by what is possible now in our thinking
• There are potentially some significant applications for Pharmacy and Pharmacists
• Future needs to be driven by clinical need guided by sound business opportunities. Regulators are generally on board in supporting this

With the commercial entrance of SPRITAM to the market, we saw what might mark the beginning of a new era in pharmaceutical manufacture, one with more personalized care. Ongoing work at the University of Nottingham and many other institutions and organizations will continue to explore the possibilities.

For those still asking why we might use 3D printing in pharma, the answers are becoming ever clearer as more supporting research is able to back up claims of benefits and efficacy for use in the creation and distribution of certain medications.

Share your thoughts in the 3D Printed Pharmaceuticals forum at 3DPB.com.

[All photos: Sarah Goehrke / Slides: Clive Roberts/University of Nottingham]