For the engineering sector, 3D printing is a well-established technology. However,
it has now begun to be used in the pharmaceutical industry to print drugs, challenging traditional medical manufacturing techniques, which have been based on a standard powder-compaction method. It also promises to push forward innovations that could improve or even transform patient care.
The use of 3D printing technology for pharmaceuticals was thrust into the limelight recently with the news that US pharmaceutical company Aprecia had received approval from the US Food and Drug Administration (FDA) to 3D-print the prescription anticonvulsant, Spritam (generic name levetiracetam). This drug is used in the treatment of partial-onset seizures, myoclonic seizures and primary generalised tonic-clonic seizures in adults and children with epilepsy.
ZipDose Technology
The method that Aprecia developed has been more than a decade in the making. A proprietary manufacturing platform called ZipDose Technology uses 3D printing to produce a porous product that rapidly disintegrates with a sip of liquid in less than 10 seconds. While 3D printing has been used previously to manufacture medical devices such as hips or dental implants, this approval marks the first time a drug product manufactured in this manner has been approved by the FDA.
Tom West, project director and manager of intellectual property at Aprecia, says that the ZipDose technology is at its core a combination of formulation and 3D printing know-how which results in a porous, fast-melt tablet. It also enables the delivery of a high drug load – up to 1,000mg in a single dose.
However, the speed at which the pill dissolves isn’t about making the drug delivery any more efficient, but the comfort of the patient – ensuring that even the highest strengths of levetiracetam can be taken as comfortably as possible, without the need to swallow large tablets.
In addition, no measuring is required as each dose is individually packaged, making it easy to carry the treatment on the go. For example, Aprecia hopes that patients who have to take 2,000 to 3,000mg of the drug per day in two doses for long periods will have a tablet that’s easier for them to manage and stay on.
Powder-liquid printing
Founded in 2003, Aprecia developed ZipDose Technology using a powder-liquid 3D printing technology that originated at Massachusetts Institute of Technology in the late 1980s as a rapid-prototyping technique.
“We use a liquid to bind the powders together,” says West. “This means you don’t have to worry as much about the thermal exposure of the materials as you would for laser or extrusion-based techniques. We’re able to be a lot more gentle thermally with the materials, so there’s a wider palette we can work with.”
While not keen to go into detail, West says the company uses a range of well-known established materials, called excipients. These are inactive ingredients in a pill that can include binding materials, dyes, preservatives and flavouring.
Traditional tablet manufacturing methods will use binding agents that react to compression and hold together in response to physical change rather than wetting. However, the version of 3D printing that Aprecia uses is basically a ‘wet binding’, so it needs binding agents that are liquid-activated, says West.
“If you were looking at a more traditional kind of compressed tablet, made by compacting all of the void, space would have been removed. To be able to re-disintegrate it sometimes takes the addition of different agents that might swell to disintegrate the tablet. We don’t really need to add high-end disintegrants or superdisintegrants, but we can work with them, as they are not necessary to get the fast-melt function that we have.”
Taking the kind of technology traditionally used for rapid-prototyping and using it for drug production hasn’t been without its challenges. Doing so
has also begun to change the way many people now think about the process.
“A lot of people will think of 3D printing as a desktop, prototype-oriented process – you make a lot of single, customised units that change all the time. We’ve essentially taken this process to scale, as we want to help large segments of people. At the same time, we focused it on being able to make small units, uniformly, one after the other. It’s the flip side of what you think of with prototyping and 3D printing.”
To achieve this process, the Aprecia team first looked to scale up the printer and analysing the various steps to ensure that it operates as efficiently as possible.
A key concern, not normally so important for 3D printers, was that the material contact surfaces should be easily cleanable to prevent any residue and cross-contamination in the finished product – in line with FDA regulations.
“Overall, it was much like developing any other pharmaceutical product, where the FDA expects a firm to make a safe and uniform product,” says West. After scaling its 3D printing process, Aprecia’s main focus was demonstrating this safe repeatability to the FDA regulators.
“Essentially, it’s quality by design, just like you have for any other kind of pharmaceutical development,” he says.
Although West is confident about 3D printing’s emerging crucial role in the pharmaceutical industry, he stresses it is still early days. The technique can’t yet compete with high-speed tablet pressers that have had up to 100 years of development, but it’s fast enough to meet commercial needs for differentiated and new products. “If you could meet a need with the lowest-cost tablet, that will still be around,” he says.
“However, not all traditional tablets meet the need of all patients. What we’ve done with this process, and ZipDose, is to better meet what we feel are the needs of segments of patients who have to try to adapt to a tablet or, in some cases, to a liquid. The focus of this technology is the new process which allows you to make different structures with different functions. That’s where the value is – something that didn’t exist before.”
Spritam is expected to be available in the first quarter of 2016, and Aprecia plans to introduce a line of central nervous system products in the near future.
In the UK, developments are also being made in this field, with academics testing and developing additive manufacturing methods for the pharmaceutical market.
Dr Simon Gaisford, head of the department of pharmaceutics at University College London (UCL) School of Pharmacy, along with colleagues Professor Abdul Basit and Dr Stephen Hilton, has developed techniques for fabricating drugs and established a spin-out company to commercialise their work.
The team use fused-filament (drug-loaded polymer strands) and stereolithographic (drug-loaded photo-cured polymers) printers to fabricate tablets and drug-loaded devices to understand and exploit the advantages this technique can bring to drug delivery.
So far, the team has printed tablets containing aminosalicylic acids (for treatment of inflammatory bowel disease) and antibacterial polymers suitable for wound dressings. They have also exploited the printer to explore the effects of tablet geometry on drug dissolution rate, and have designed and developed several multi-faceted tablets and caplets for controlled drug release.
Fused-filament additive manufacturing is useful because it makes it possible to produce pharmaceutical-grade polymer using hot melt extrusion, which can be fed into a 3D printer to fabricate a tablet, says Gaisford. “It’s a common pharmaceutical technique, so this dovetails nicely on to the end of an existing technology.”
The focus for this kind of application is exploring the fabricating method for drugs rather than exploring new kinds of materials, so it’s being applied to drugs that are already well-established, such as Spritam. As such, Gaisford’s team make sure that every polymer they use in the 3D printing process is FDA-approved.
Pros and cons
This approach has been more difficult for stereolithographic printing, which uses a laser to photo-cure a resin (or monomer) to make a polymer, limiting the amount
of materials they can use and making it harder to gain FDA approval. However, the benefit of using a stereolithographic printer is that the resin can be diluted with other liquids, such as water, which makes it easier to introduce the drug solution into the tablet. “You can make things that have high water content, and that, in principle, allows you to get much faster dissolution because your compound is already in solution in the tablet,” says Gaisford.
Despite only having used the stereolithographic printer for a few months, they have been able to produce a tablet with up to 90% water, effectively creating a hydrogel. The UCL team will continue to conduct further tests with FDA-approved photo-curable materials.
In terms of the fused-filament 3D printers, the team had no need to modify them, just adjust the variables already built into the machine, such as the temperature of the printing head and build plate, says Gaisford. This means they can use a range of polymers that melt and solidify at various temperatures.
Once the parameters are dialled in, it’s a reliable process, he says, although Gaisford admits that they have used a trial-and-error approach to find out which polymers work best for the process, occasionally having to take the machine apart when the material solidified too early in the print head. “It’s funny that a technology developed for a different area can be applied in a pharmaceutical context with little modification,” he says.
Another benefit to using the 3D printing process is the software controls, which allow the team to easily scale up or down the basic cylinder tablet designs. The controls also enable the concentration of the drug in the polymer to be kept the same throughout the entire tablet.
The main focus for the team has been on modifying the polymers used for the printing process. “When you incorporate a drug into a polymer, it tends to change the properties of the polymer,” explains Gaisford. “For example, with the addition of small organic molecules most polymers are plasticised, to give them certain properties such as smoothness or flexibility. But what that means is that every time you try to incorporate a new drug into a polymer, you don’t know how it’s going to change the properties of the polymer. It may slow down the dissolution or increase the stability of the drug, for instance – all which is handy, because you can really make a business out of that.”
Proprietary polymers
That is exactly what Gaisford and his colleagues have done, creating a spin-out company called FabRX to begin developing a set of proprietary pharmaceutical-grade polymer blends that can be used in 3D printing. The next step would then be to help companies develop new ways of manufacturing their drugs, using their polymer and 3D printing know-how.
He envisions a time when 3D printing drugs could become a standard practice at pharmacies, where patients could visit, and have a specific size and dosage of drug printed out for them on the spot.
Along with West, Gaisford feels that printing may never replace powder compaction for making tablets, but that the value of the technology lies in its unique attributes. “For me, it’s about drugs that have got a narrow therapeutic index: a specific dose for a specific patient. That’s hard to achieve by mass manufacture.” A current example would be the blood thinner, warfarin. This drug is available in half-milligram strengths, but the dosing is often narrower, so patients may have to take one-and-a-half tablets at a time. Changing the size of the tablet for more accurate dosage would also be useful for immunosuppressants – often used in organ transplant patients, where prescription requirements can vary from person to person and will often be taken for many years.
The fact that 3D printers can also have more than one printer head means that it’s possible to use multiple pharmaceutical polymers to make complex, multi-layered tablets, or a tablet with one drug in its core and a different drug in the outside corona.
“You can play around with the dissolution rates. You can have something where the outside layer dissolves quickly, but the inside dissolves very slowly,” says Gaisford.
This aspect opens up the possibility of creating targeted treatments, particularly for colonic diseases such as ulcerative colitis, where traditional tablets would normally be dissolved and absorbed before reaching the gastrointestinal tract. FabRX aims to develop its own drugs
for targeting diseases along the GI tract in the near future.
“It is also possible to print other biocompatible polymers that dissolve or don’t dissolve, or that release the drug over several years. For example, it’s possible to make drug-loaded implants, contraceptive implants, or chemotherapy agents. These implants could be placed in the body during surgery to remove a tumour, then remain in place and slowly release a drug at the site of action,” says Gaisford.
Simplest succeeds
As it stands, it’s hard to see how 3D printing can compete with powder compaction for the mass manufacturing of drugs. The first thing Gaisford teaches his students is that in pharmaceuticals it’s always the simplest method to get the product to market that succeeds. However, what happens when mass manufacture is no longer the dominant method?
“I like to think is that the pharmaceutical arena is changing,” he says. “Rather than just having a ‘one drug fits all’ approach, we’re all going to be moving to this biopharmaceutical future where drugs are going to be made for specific patients. At that point, mass manufacture becomes irrelevant.”
Spotlight: Chemputer 3D printer
Lee Cronin, chair of chemistry at the University of Glasgow, is working on a configurable robot inspired by 3D printers. He and his research team are exploring complex chemical systems, and one aim is to control the complicated processes needed to make new molecules. Such approaches could be applied to drug discovery. Cronin aims to develop routes to making chemical processes universal, and has conceived a device called the ‘Chemputer’, in an attempt at ‘digitising chemistry’.
In a hybrid system, his team were able to 3D-print test tubes – ‘reactionware’ – and use the 3D printer as an ‘automated bartender’, pouring liquids to allow the reactions to occur. They applied this method to make a simple commercial drug, while also including a purification step in the process.
In future, the team want to develop a universal platform for chemistry that would make manufacturing easier, and perhaps even allow for more personalised medicines.
“We’re trying to do chemical discovery and analysis digitisation, and explore the network of reactions in real space and time,” says Cronin.
Spotlight: 3D printed animal shapes for children
Getting kids to take their medicine can be tricky, but Dr Simon Gaisford, Professor Abdul Basit and Dr Steve Hilton from the UCL School of Pharmacy have a clever solution…
The team’s research suggested that 3D printing might provide a solution by fabricating tablets in a variety of fun shapes, such as animals, to potentially increase compliance for paediatric patients.
Gaisford said: “It is possible, in principle, to ask a child what his or her favourite animal is, and then print a tablet shaped like that animal especially for that child. If the printer were located in a hospital pharmacy, then the tablet could even be printed in sight of the patient.”