Aprecia Pharmaceuticals has become the first company to commercially launch a FDA-approved drug manufactured using 3-D printing technology. So what is behind the technology? DCAT Value Chain Insights (VCI) takes an inside look.

3-D printing is a technology being developed across several industries, but how viable a technology is it for the pharmaceutical industry? Placed in the broader field of adaptive manufacturing, 3-D printing is seen as tool in pharmaceutical research and in related fields, such as medical devices, but is it the wave of the future for the manufacturing of drug substances or drug products? DCAT Value Chain Insights (VCI) examines potential applications.

A technology first 
Aprecia Pharmaceuticals, a pharmaceutical company based in Blue Ash, Ohio, reported earlier this month that Spritam (levetiracetam) tablets, for oral suspension, is now available as an adjunctive therapy in the treatment of partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures, making it the first prescription drug product approved by the US Food and Drug Administration (FDA) that is manufactured using 3-D printing technology. The drug disintegrates in the mouth with a sip of liquid and is designed as a new option for patients, including those who may struggle to take their medicine.

Spritam is formulated with Aprecia's proprietary ZipDose Technology, which combines 3-D printing and formulation science to produce rapidly disintegrating formulations of medications. Manufactured in a regulated commercial-scale facility, the drug is available in four unit-dose strengths, including 250 mg, 500 mg, 750 mg and 1,000 mg.

Aprecia developed its ZipDose Technology platform using the 3-D printing technology that originated at the Massachusetts Institute of Technology (MIT). Using 3-D printing as a catalyst, Aprecia created a novel manufacturing system to produce fast-melt formulations of medicines that exceed the disintegration speed and dose-load capacity of products made by other fast-melt technologies, such as orally disintegrating tablets and oral thin films. The company says that the ZipDose products are also more portable than liquid formulations and have greater dosing accuracy than liquids, which may be more susceptible to measurement errors. The company manufactures them on Aprecia's proprietary equipment. Aprecia holds an exclusive, worldwide license for pharmaceutical applications of this 3-D printing technology. The company says it has the rights to more than 50 patents related to pharmaceutical applications of 3-D printing technology and has filed patent applications to protect its proprietary manufacturing system through 2033.Aprecia is privately owned, with Prasco Laboratories and its parent company, Scion Companies, holding a controlling interest.

The FDA approved Spritam in August 2015, and the drug became commercially available this month. Earlier this year, Aprecia also announced that it is investing $25 million in a 190,000-square-foot manufacturing facility in Blue Ash, Ohio, which will add 150 new jobs. Spritam is the first in a line of products in the central nervous system therapeutic area that Aprecia plans to introduce over the next several years.

Aprecia was founded in 2003. Powder-liquid 3-D printing, a technology that forms objects layer by layer, was originally developed by researchers at MIT in the late 1980s as a rapid-prototyping technique. This technology uses an aqueous fluid to stitch together multiple layers of powder. From 1993 to 2003, this work was expanded into the distinct areas of tissue engineering and pharmaceuticals. While 3-D printing technology rights are currently licensed for a diverse range of industrial fields, pharmaceutical rights to MIT’s 3-D printing process are exclusively licensed to Aprecia. In 2007, after refining the 3-D printing process, the company began developing its orodispersible platform, known as ZipDose technology. In 2008, Aprecia began working with a proprietary forming system that enhances manufacturing efficiency and output in the 3-D printing process, which enabled the company to achieve its initial goal of reaching commercial production rates for its 3-D printing formulations. This initiative continued through 2011, when the company further refined this process to prepare for commercialization and ultimately comply with FDA regulatory standards. In 2011, Aprecia also began operations at its registration and launch facility in East Windsor, New Jersey. After refining and commissioning its first full production line, this operations site became prepared for registration of the initial ZipDose Technology product set. The company submitted its first new drug application for Spritam in October 2014, received FDA approval in August 2015, and launched the product earlier this month.

Using its proprietary, computer-aided, 3-D printing manufacturing process, Aprecia developed the ZipDose Technology platform, which is designed to enable delivery of high-dose medications in a rapidly disintegrating form. ZipDose technology product candidates are assembled layer-by-layer without using compression forces or traditional molding techniques. Thin layers of powdered medication are repeatedly spread on top of one another as patterns of liquid droplets (an aqueous fluid) are deposited or printed onto selected regions of each powder layer. Interactions between the powder and liquid bond these materials together at a microscopic level. The company says that the platform yields highly porous structures even at high loading and doses of drug and can support dose loading up to 1,000 mg.

Potential applications 
The potential value of using 3-D printing technology to produce drug products is the opportunity to customize dosing, further opening up the potential of personalized medicine. To what degree such an approach will begin to be used by pharmaceutical companies has yet to be seen. On a research level, a 2013 review article in the Journal of the American Pharmacists Association summarized the published literature on existing 3-D printing technologies for pharmaceutical manufacturing and outlined the limitations and potential of these technologies (1, 2). A structured search of PubMed and Embase identifed articles published between January 1, 1990 and August 31, 2012. Search terms included drug printing, drug 3D printing, and drug three-dimensional printing. Twenty-one of 511 identified references were included in the review.

The review showed that Inkjet and powder-based printing were the primary printing technologies used for drug development and fabrication. Eleven articles described a powder-delivery system, and 10 identified inkjet printing. These printing technologies allow for certain advantages, such as precise control of droplet size, high reproducibility, complex drug-release profiles, and personalized medication therapy (1, 2).

On a research level, a team led by Simon Gaisford, reader in pharmaceutics at the University College London's School of Pharmacy, applied thermal inkjet printing technology to make personalized-dose oral films of salbutamol sulfate by replacing the paper in the printer with a sheet of polymer film that allowed the drug to be jetted onto the surface (1, 3, 4). A printer cartridge was modified so that aqueous drug solutions replaced the ink. Film strips were cut. Varying the concentration of drug solution, area printed, or number of print passes allowed the dose to be controlled. The printer was used to deposit salbutamol sulfate onto an oral film made of potato starch (1, 3, 4).

On the drug substance side, Professor Lee Cronin, Regius Chair of Chemistry at the School of Chemistry at the University of Glasgow and founder of Cronin Group Plc, a technology discovery company, has offered his vision for 3-D printing technology in chemical production, including pharmaceutical production. He founded the Cronin Group in December 2015 to focus on the discovery, development and manufacture of small molecules and nanomaterials utilizin proprietary chemistry developed at Glasgow University and enabled through the application of 3-D printing and related technologies.

References
1. P. Van Arnum, “The Future of Dosage Forms,” Pharm. Technol. 38 (1), 2014.
2. I.D. Ursan, L. Chiu,and A. Pierce, J. Am. Pharm. Assoc. 53, 136-144 (2013).
3. P. Van Arnum, Pharm. Technol. 37 (5), 58 (2013).
4. S. Gaisford et al., Pharm Res. 28 (10), 2386-92 (2011).