The FDA approval of the first 3D printed drug for public use signals changes ahead for the pharma manufacturing sector
The development of 3D printing is coming on apace and is making waves in pharmaceutical manufacturing. In August last year the US Food and Drug Administration (FDA) approved a 3D-printed dissolvable tablet called Spritam (levetiracetam) produced by US-based Aprecia Pharmaceuticals, which treats certain types of seizures caused by epilepsy.
The company says a lack of high-dosage rapid dissolvable tablets on the market spurred the creation of Spritam. Its 3D printing system can manufacture potent drug doses of up to 1,000 milligrams in individual tablets. The company plans to launch Spritam in the US in the first quarter of 2016.
Significant segments of patients in the CNS therapeutic area would benefit from having a new dosing option
‘Our initial pipeline includes a set of four high-dose, highly-prescribed molecules used for treating central nervous systems (CNS) conditions,’ said Tom West, Project Director and Manager of Intellectual Property at Aprecia. ‘We believe that high-dose medicines remain largely unaddressed by prior “fast-melt” technologies, and that significant segments of patients in the CNS therapeutic area would benefit from having a new dosing option that is premeasured and does not need to be swallowed intact.’
To create Spritam, Aprecia employs what it calls ZipDose Technology, a platform that uses the powder-liquid three-dimensional printing (3DP) technology developed at the Massachusetts Institute of Technology (MIT) in the late 1980s as a rapid-prototyping technique. This simple technology uses an aqueous fluid to stitch together multiple layers of powder, instead of using compression forces or traditional moulding techniques.
First, the 3D printer spreads a powdered medicine into a thin deposit, and then drops a liquid onto it to bind the particles together in a thin, porous layer. This process is repeated a specific number of times to add more layers based on the dosage, building the product from bottom to top. ‘To me, this is a great breakthrough,’ said Dr Shyh-Dar Li, an associate professor of nanomedicine, pharmaceutics and biopharmaceutics at the University of British Columbia (UBC), in western Canada. ‘Previously, making dosage forms was a very long and complicated process, but now, they can use a computer and a very simple machine to print tablets. It will change a lot of things in the pharmaceutical industry.’
With FDA approval in the US, experts predict that it is just a matter of time until similarly produced drugs are made available in other locations, including Europe.
The rapid-dissolve tablet fills a void that is currently underserved by existing technology
The rapid-dissolve tablet fills a void that is currently underserved by existing technology, according to West. ‘In the US market, for example, we have found that nearly all the prescription orally-disintegrating tablets have dosage strengths under 200mg, with the majority under 50mg – hence the largest tablets to swallow are essentially unaddressed. In contrast, for our product, Spritam, all four strengths (250mg, 500mg, 750mg, 1,000mg) are above the dosage thresholds mentioned above,’ he explained.
Spritam was made specifically to benefit patient groups who need strong doses of medicine and have difficulties swallowing traditional compressed pills. ‘During a seizure, it’s very difficult to give people drugs in oral formulations because it requires them to swallow, and that’s not always possible,’ explained Michael J Cima, a professor of materials science and engineering at MIT who also works at the David H Koch Institute for Integrative Cancer Research. ‘Having tablets like this, which it is possible for a person having a seizure to take, is something that can help these patients. These rapid dissolving tablets also benefit other groups, like elderly patients, Parkinson’s patients, and children, who have trouble swallowing.’
The first 3-D printed dosage form approved by the FDA
In terms of production, Cima identifies two areas that could benefit significantly from this innovation. One is precisely controlled release technology. ‘As the tablet dissolves, you can get different release rates and you can be very precise about it. For example, if you wanted to have multiple release rates over the course of one tablet, this method of manufacturing makes this possible. You could make it so a tablet releases medicine in the first hour after it’s consumed, then it could stop for an hour, then turn on again,’ he suggested.
The other area Cima mentions is micro-dosing, where the amount of drug given is measured in micrograms, for example. He says it is difficult to use conventional technologies to manufacture tablets like this because of how they are made. ‘Conventional methods are where you take a drug in powder form and mix it with an excipient or filler, then use a pressing machine to make tablets. What you’ll find is that some tablets will have two micrograms of drug, but other tablets will have zero,’ Cima said. ‘With Aprecia’s technology, you could print one droplet of drug into each tablet, and the content uniformity would be very precise.’
This could even open up the possibility of dual dosing two different drugs in a single tablet, he continued. ‘Most drugs are not physically or chemically compatible in the same dosage form, but this technology could allow us to print one drug into one area and another in a different area in the same dosage form.’
This technology could allow us to print one drug into one area and another in a different area in the same dosage form
UBC’s Li says that one of the biggest advantages of Aprecia’s technology is that it will help small- and mid-sized companies to compete with the bigger pharmaceutical corporations. 3D printing devices are relatively cheap, and eventually this will reduce the cost of manufacturing tablets, he explained. ‘If we look at the traditional way of making tablets, the compression machinery is very expensive and only big companies can afford that. Right now, the working model is that small- or mid-size companies generate pharmaceutical ingredients, and then sell these to big companies to continue the process. In the future, 3D printing technology, to some degree, will allow companies to produce their own dosage forms in-house and not just the active ingredients,’ he said.
This is new technology and new technology requires higher prices because of the patent and innovation involved
However, Li explained that while the basic production process is cheaper with 3D printing, patent costs are one factor that could buoy the price of drugs manufactured in this manner. ‘In terms of manufacturing, the traditional way of making tablets is much more expensive, but if we count the patent into the final product cost, I’m not sure how much cheaper this will be.’
He added: ‘This is new technology and new technology requires higher prices because of the patent and innovation involved.’
While 3D printing is not guaranteed to make drugs cheaper for consumers, Dr Stephen Hilton, a lecturer on pharmaceutical and biological chemistry at University College London’s School of Pharmacy, said 3D printing has especially been cheaper in the testing and trial process of new drug forms, which could have positive future implications.
‘While carrying out trials, we’ve discovered we can save huge amounts of money in laboratories. [3D printing] allows us to be more efficient… and it means we can try things out that we were never able to before,’ he explained. ‘Looking at different tablet shapes and formulations, which is what we’re focusing on now with 3D printing, it would have cost a fortune before so we probably would have only tested one or two examples. Now, we can try 30 or 40 different permutations in one day.
‘That’s where 3D printing makes a difference. It gives you far more data and far more time to try things out, which wouldn’t have been possible before.’
3D-printed drugs have been touted as a personalised option for drug delivery. Hilton believes that, paired with technology such as health applications on mobile phones, drugs can be tailored specifically to a person’s needs. He told Manufacturing Chemist that apps that record health factors such as a person’s weight, body mass index, and medical history, could be a guide for dosages in the future.
‘It’s a very exciting time for medication and I think it’s the evolution of technology that is key. This is the way of the future – people want personalised treatments. Just like we customise our cars to suit our needs, medicine is quickly following. It’s the dawn of individualisation,’ said Hilton.
The new technology is not making new medicine: it is just changing how it is manufactured by altering how medicine is deposited
Lee Cronin, the Regius chair of chemistry at the University of Glasgow’s School of Chemistry, nonetheless stressed that the new technology is not making new medicine: it is just changing how it is manufactured by altering how medicine is deposited. ‘It opens up the concept of personalisation and from that point of view, the excitement is justified because that will allow manufacturers to tailor drugs and their outcome,’ he said. ‘But really, the chemistry is already long done.’
Li also remains slightly sceptical of the innovation and its foreseeable implications. There have been discussions on pharmacies having 3D printers in-house and printing drugs for patients based on the collection of personal data and a doctor’s prescription. But Li questions this scenario, wondering how quality can be maintained and assured.
Traditional methods of making tablets and pills require a lot of quality insurance and quality control during and after the manufacturing process to ensure every product for the market is the same, he pointed out. ‘But how can we make sure that the tablets produced in pharmacies by a 3D printer are the same?’ he asked. ‘Pharmacies wouldn’t have the instruments needed to check quality. This personalised approach is a good sell from the company as a commercialisation strategy, but as an academic, it’s not as practical as they propose.’
Another issue raised by the media is whether people at home can get their hands on 3D printers and print their own drugs, particularly illegal drugs. But Hilton says this talk is nonsense. ‘There are chemical precursors that you need [to make drugs], but these are controlled substances. These precursors aren’t readily available to people, and if you can’t buy the basic ingredients, you can’t make the drugs as a result,’ he said.
Additionally, Cima adds that there are so many easier ways to make illicit drugs, he can’t think why anyone would want to use this method.
Now that Spritam has received FDA approval, Aprecia’s West says the company has plans to expand 3D printing production into other product platforms, including controlled-release or multiphasic-release products, and fixed-dose combinations, but he could not disclose a timeframe.
‘Yes, we expect to apply ZipDose Technology to other types of drugs in the future. We believe it is compatible with a wide range of active ingredients. We believe there are similar opportunities to apply ZipDose Technology in therapeutic areas outside CNS, and we expect to pursue some of those either ourselves or with partners in the future,’ he stated.