3D Printed Medications Face Hurdles, But Growth Continues

By Julie Deardorff, Ph.D., MPH, Contributing Writer

3D printing of medications that meet regulatory standards is a reality, thanks to Aprecia Pharmaceuticals paving the road with the approval of the first 3D printed medication, SPRITAM (Levetiracetam), in August 2015. Although additional commercial products have yet to be approved, novel products made possible by the unique attributes of 3D printing, including “polypills,” are being developed.

Specifically, using extrusion technology, which allows layering of different medications into the same pill, Clive Roberts’ research group at the University of Nottingham, U.K., has successfully “printed” a polypill that not only contains five unique medications for the treatment of heart disease, but that also successfully allows separate medication-specific release profiles (either immediate or controlled release) within the same pill.

Thus, as Roberts, chair of pharmaceutical nanotechnology and head of the School of Pharmacy at the University of Nottingham, optimistically explains, “Developing 3D printing as a manufacturing tool for medicines is now becoming an engineering problem; the scientific principal has been proven. If it meets a clinical need and there are funds to do it, then as long as there is a will, it can be done.”

This was successfully exemplified by the development team at Aprecia, who found an unmet clinical need that could be uniquely addressed by 3D printing. As explained by Don Wetherhold, Aprecia’s CEO, with their proprietary ZipDose technology, “Aprecia is using 3D printing to make high-dose, ‘fast-melt’ preparations that are easy to take and that deliver medicines that remain unaddressed by other techniques for making fast melts. This approach is directed to ease of administration, regardless of dose.” ZipDose technology allows delivery of doses up to 1 gram that can dissolve in the mouth within 10 seconds. Wetherhold added, “We believe there are numerous populations that can benefit from a ‘fast-melt’ formulation, such as children and the elderly, and those dealing with the complications of stroke, Alzheimer’s disease, head and neck tumors, or certain other neurological disorders that may impact swallowing or self-management of care. Accordingly, we developed proprietary equipment to address that type of production need.”

One of the promises frequently touted about 3D printing is that it allows for the customization and personalization of medications. Furthermore, 3D printing of medications is often seen as an ideal solution for niche clinical-need markets. But how large can these niche markets be? It’s commonly acknowledged that 3D printing in general — not just with medications — is not economically suitable for large-scale production processes. So how will that limitation affect the 3D printing of medications?

Wetherhold agrees that 3D printing processes will remain smaller and more specialized than something like highspeed compression tableting. “But it is already well beyond the bench,” he says. “If your primary goal is making unique strengths for each individual patient (e.g., such as a 90-day supply), then a benchscale process rather than a full-scale production facility may meet the need. And, you can then focus on a different set of challenges such as demonstrating the extent of clinical benefit or clarifying regulatory requirements. We certainly believe 3D printing will have an impact at larger production scales than that. Our goals required considerable scaling of the process as a prerequisite, with a focus on creating value-added dosage forms to better meet the needs of substantial numbers of patients.”

Indeed, the scale of production for SPRITAM is relatively not small. SPRITAM is approved for an indication that affects approximately 1.3 million to about 2.8 million in the United States, of which a significant subset may clinically benefit from the fast-melt formulation. Thus, the benefits associated with this technology can be applied to a larger segment of the population than is often envisioned when discussing the customization of medications. Wetherhold explained that the 3D printing of medications allows the “tailoring of functional attributes to better meet the common needs of certain subsets of patients. In this way, we hope to help larger groups of patients sooner.” As such, Wetherhold added, “For our goals, it made sense to develop and build proprietary equipment that can mass produce our units with standardized dosing.”

Roberts also shares this vision of 3D printing of medications not being limited to small production runs. “Larger production runs, particularly in the presence of decentralized manufacturing (such as production at the point-of-service in pharmacies), will be feasible. Yes, you could make millions of tablets with 3D printing if you distribute the manufacturing. I think it’s very realistic to imagine 3D printers in hospitals controlled by pharmacists that could make thousands of pills a day. I would expect that to happen at some point.” He also pointed out that we need to put the field of 3D printing of medications into perspective. Namely, this field is very much in its infancy. “As such, the technology is being rapidly improved and optimized such that the cost per unit is decreasing, which promises that larger production runs will be increasingly more viable. Furthermore, as manufacturing costs are a relatively small component of the realized drug cost, if the clinical benefit delivered by the customization allowed by 3D printing is of sufficient value, the added manufacturing costs may not be prohibitive.”

"We are at the beginning of the technology adoption curve for 3D printing in our industry."

Don Wetherhold
CEO, Aprecia Pharmaceuticals

THE CLINICAL BENEFITS OF 3D PRINTING

Once we accept that the volume challenges associated with 3D printing can be overcome, we need to consider the potential clinical benefits of this method of drug manufacturing. Various possibilities exist ranging from greater access to medications, especially in developing countries and remote areas due to the decentralized production at the point-of- need, to customized and/or personalized attributes that will ultimately lead to improved treatment adherence. If 3D printing of medications does improve treatment adherence, that will be of significant clinical benefit. Roberts emphasized that one of the primary challenges to successfully treating chronic diseases is treatment adherence. For example, SPRITAM holds the promise of increasing treatment adherence among certain subsets of epileptic patients who have difficulties swallowing pills. One can imagine that personalization of pills could improve the likelihood that children in particular would take their medications. With 3D printing, a child could choose a color, flavor, and/or shape of their pill. Furthermore, personalization of medications may provide particular benefit for patients who have to take multiple pills a day, such as the elderly, by improving the ease of patient use. Polypills such as the one developed in Roberts’ laboratory, which contain five medications, would allow a patient to take only one pill rather than five. These polypills would also deliver personalized doses that can be of considerable benefit, as currently some patients need to cut pills that come in standardized doses in order to receive the correct dose.

Another benefit is the ability to create solid-form medications at patient-specific doses. Currently, numerous medications that have a patient-weight-specific dose must be administered intravenously in a supervised setting. Thus, the 3D printing of medications could reduce the need for such infusions, allowing an improved patient experience and requiring fewer healthcare resources.

THE REAL CHALLENGES FACING 3D PRINTING OF MEDICATIONS
Now that Aprecia has successfully navigated the regulatory hurdles to gain approval for SPRITAM, the regulatory process is not considered a challenge. In Roberts’ opinion, currently the most significant challenge is “the lack of options for the basic materials in the ‘inks’ (e.g., formulated medications). Essentially, there is a very limited dataset at the moment. We need to continue to develop materials that print well and produce suitable dosage forms.” Again, putting things into perspective and emphasizing that the 3D printing of medications is just in its infancy, he points out that it took decades to optimize the inks that are in the inkjet printers currently used today.

Wetherhold feels the largest hurdle for the field right now is focus, as there are so many possible applications. He explains, “We are at the beginning of the technology adoption curve for 3D printing in our industry, and there are multiple versions of the technology that can each be deployed in more than one way. Each faces its own questions regarding regulatory requirements, quality assurance, and cost/benefit for the application. To achieve success, it is necessary to remain focused on clear goals to address the respective requirements and execute through to completion.” It was this type of focus that led to Aprecia successfully developing its ZipDose technology and obtaining FDA approval for SPRITAM, which is made in a centralized manner, in scale, at Aprecia’s own FDA-inspected facilities. The next step, the ability to achieve commercial success with a 3D-printed medication, will soon be put to the test. The field excitedly awaits as Aprecia plans to bring SPRITAM to market in the first half of 2016.

While the field certainly has its challenges, it’s not stopping the activity or buzz associated with the potential for 3D printing of medications. It seems certain that it’s not a matter of if these challenges can be overcome but rather a question of when. Companies — ranging from small startups to large established companies such as AstraZeneca and GlaxoSmithKline — are exploring the applications of applying this manufacturing technology to the creation of new medications. As the knowledge base and experience in this arena continues to grow rapidly, the development and approval of additional 3D medications is something we can expect in the relatively near future.