Made to fit: 3D-printed medicine

Additive manufacturing, or 3D printing, is a fundamentally different way of making things compared to traditional manufacturing processes.

“This novel approach, which involves adding material one layer at a time to build an object, is opening a range of new opportunities across the health-care industry,” explains Christoph Huels, founder of OneZeroMed™ Additive Manufacturing of Tablets.

The process starts with a digital 3D model, which is then sliced up into ultrathin digital layers and turned into a set of instructions for the printer to follow. Some 3D printers will melt the starting material into “glue” which is then directed through a precision nozzle onto the preceding layer. Alternatively, a laser or electron beam is used to selectively melt thin layers in a bed of powdered material. As the materials cool or are cured, they fuse to form a 3D object.

Since the release of the first 3D printer in 1987, the technology has advanced at a staggering pace [4]. In 2018, there were 1.42 million 3D printers sold globally, and this is projected to exceed 8 million by 2027 [1]. Additive manufacturing is already in extensive use across a range of heavy industries – such as the automotive, electronics, aerospace, and health-care sectors. Some predict that one-half of all manufactured goods will be made using 3D printing by 2060 [2].

In the health-care sector, 3D printing is now being used to build custom-made prosthetics, dental implants, and other medical devices. And researchers are exploring other applications for this revolutionary technology, such as “digital pills” or to create artificial living human tissues to help accelerate drug development.

Millions of people around the world take prescription pills or tablets every day. These are traditionally manufactured by compressing a powder formulation containing active ingredients and helper constituents (excipients) into a solid form.

“This is an established process that’s been used for many years,” states Kipping. “It’s very efficient for the large-scale production of a single formulation to produce billions of pills – such as paracetamol or acetylsalicylic acid.”

But the approach is not ideal for making smaller batches of experimental drugs, which are usually needed during clinical development. In early clinical trials, for example, dose-escalating studies are usually carried out to determine the best and safest dose for patients – which require access to different formulations with varying amounts of the active ingredient.

Additive manufacturing has the potential to revolutionize the way that tablets are produced – moving the industry toward digitalization. In 2015, the first 3D-printed prescription drug was approved by the US Food and Drug Administration (FDA) for the treatment of epilepsy, opening the door to the development of customized pills [4].

“It offers much greater flexibility during the early stages of drug development; we can easily make changes to the characteristics of a pill – such as its shape, size, dosage, or release profile – just by making a few changes to the digital file,” explains Kipping.

As well as helping to get new medicines to patients faster by speeding up clinical trials, 3D printing could also benefit patients with rarer conditions – and help to deliver personalized medicine by opening new possibilities for making bespoke pills with a precise dosage tailored to a patient’s needs.

“You can imagine having small batches made for groups of patients,” predicts Kipping. “But the ultimate goal would be the customized 3D printed ‘polypills’  that combine different medications to meet specific individual needs.”

Additive manufacturing could also lead to the decentralization of drug production, which could help to secure the supply chains and make it easier to adapt formulations to comply with regional regulatory requirements. In the future, it may even be possible to deploy 3D printing technologies in pharmacies, enabling on-demand manufacturing of small-volume products.

“Currently, there may only be one or two manufacturing centers for a pill that is then shipped to different countries,” says Kipping. “In the near future, 3D printing will enable tablets to be produced locally, where they are needed, and according to different market requirements.”

Other researchers are exploring the potential of 3D bioprinting. This involves applying the technology to print a biomaterial, such as gelatin or collagen, combined with living cells, into layers on laboratory dishes.

“You can print with different cartridges, so you might have one with collagen and one cell type and another with a different material mixed with another type of cell,” explains Petra Macht, a senior scientist in our Analytical Services Department. “You can then combine them into a very defined structure using the bioprinter.”

Although the technology is still in its infancy, it offers exciting opportunities to build laboratory-engineered complex tissues. For example, our skin has different layers, opening the possibility of printing each layer using different cell types.

“The holy grail of bioprinting is organ regeneration, such as skin grafts using the patient’s cells,” says Macht. “It’s still a very long way off, but it would be a total game-changer.”

The development of advanced cell-culture models created using 3D bioprinting also has the potential to improve drug development. Traditionally, 2D cell cultures are used in the early stages of drug discovery to select which compounds to progress. But these models do not provide an accurate reflection of human physiology.

“Cells grown in monolayers are not in their correct 3D environment,” says Macht. “In the body, a tissue contains many different types of cells that will interact with each other.”

This can be a challenge in early drug discovery. Around 86% of drug candidates entering clinical trials will never gain approval [5], and it takes an average of 12 years for an experimental drug to enter the medicine cabinet [6]. Selecting the wrong compounds during early laboratory testing is likely to play a part in this high failure rate.

“Developing better laboratory models that mimic how cells normally grow and function in the body would help rule out unsuitable compounds early on,” says Macht. “This should increase the chance of success of experimental drugs that progress into clinical trials.”

The pharmaceutical industry is now taking the first steps towards realizing the benefits of 3D printing in drug development. Many pharmaceutical companies are investigating how these technologies could help find solutions for ongoing challenges in manufacturing solid-dose formulations.

“It’s an additional tool for drug formulators – providing options to produce formulations for potential drugs that may otherwise have been abandoned,” says Kipping. “There will be scenarios where 3D printing of drugs will offer advantages over standard manufacturing approaches, especially where you need advanced functionality.”

We have assembled interdisciplinary teams of experts from across our business who are supporting different drug companies to take advantage of these novel technologies to improve their capabilities in drug production.

“It’s a fast-moving technology – and to succeed you need to apply knowledge from across several different fields,” says Kipping. “We can offer our combined expertise across diverse areas of research including engineering, excipient manufacturing, and formulation technologies – as well as providing insights in quality and regulatory aspects to ensure that new medications are thoroughly evaluated and will in the future also be safe for patients.”

We are also aiming to develop 3D bioprinting for drug testing applications. Like any new system, the technology will first require extensive validation – and currently, reproducibility is a major challenge.

“We need to print lots of very small structures into tiny wells to enable the testing of many drug substances at different concentrations,” describes Macht. “And these must be identical – so the first well needs to be the same as the hundredth.”

But despite these challenges, 3D bioprinting is an exciting technology to work on.

“It’s a unique technique because you have the cell biology, the printing technology, and the material – and also the unlimited possibilities of how you change it,” says Macht. “And just seeing how the cells behave in a different environment, that’s fascinating for me.”

Progress in the development of 3D bioprinting is set to disrupt experimental drug testing and regenerative medicine.

“It’s fun to try something different – it’s always exciting!” enthuses Macht.

^{[1] https://www.3dhubs.com/guides/3d-printing/#basics
[2] https://www.grandviewresearch.com/industry-analysis/3d-printing-industry-analysis
[3] http://www.3ders.org/articles/20171003-ing-says-3d-printing-could-account-for-half-of-manufactured-goods-by-2060-wiping-out-25-percent-of-global-trade.html
[4] https://www.nature.com/articles/nbt1015-1014a
[5] https://www.centerwatch.com/articles/12702-new-mit-study-puts-clinical-research-success-rate-at-14-percent
[6] https://www.medicinenet.com/script/main/art.asp?articlekey=9877}