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Printing medicines: a new era of dispensing and drug formulation?

Advances in printing technology have been predicted to turn manufacturing upside down. Could a similar revolution happen in pharmacy? Lin-Nam Wang finds out

By Lin-Nam Wang

Advances in printing technology have been predicted to turn manufacturing upside down. Could a similar revolution happen in pharmacy? Lin-Nam Wang finds out

3D printers are all the rage in design and manufacturing circles right now. And the general media seem to be enamoured of this technology too, with reports of 3D printers being used for anything from cutting the costs of prototype production to making pizzas for astronauts. But the evolution of printer technology has also touched the world of pharmacy: a team at University College London School of Pharmacy has taken the humble inkjet printer, purchased for just £29.99 from Argos, and used it to produce co-crystals of drugs such as carbamazepine.

Simon Gaisford, reader in pharmaceutics at UCL, said: “Newer drugs are typically poorly soluble so an option is to choose to produce them in a crystalline form”. He described co-crystals as metastable structures formed from two drugs or a drug plus excipient. Their potentially weaker bonds, compared with pure drug crystals, mean better dissolution and better bioavailability, he said.

Fundamentally the procedure involves replacing the ink in a printer cartridge with a drug solution and jetting it onto a substrate, typically acetate. “We get very rapid evaporation and can see the crystals growing on the acetate sheet. We think it’s because of this very rapid evaporation, that we can produce metastable forms,” he explained.

Such novel use of printer technology could help new medicines reach patients quicker by making drug development faster and easier. For example, Dr Gaisford, who is also a pharmaceutical scientist member of the Royal Pharmaceutical Society, explained that, conventionally, screening for crystal forms would be done in a 96-well plate.

The drug would be dissolved in solvents of different polarities and the researchers would look at what had crystallised. His team is developing the inkjet system so that the same thing can be achieved by printing different solutions. “The process should be a lot faster — we get evaporation and crystallisation within seconds. In principle, it should be possible to have completed that screen within an hour or two, reducing time and cost,” Dr Gaisford said.

Applying the technology a step further UCL, in collaboration with the University of Strathclyde, has also produced a crystal structure of carbamazepine predicted to exist by computer but whose isolation had, until then, eluded researchers. This was achieved by first printing a dihydrocarbamazepine solution onto the substrate because it was known to crystallise in the desired form.

This layer acted as a “seed crystal” onto which the carbamazepine solution was then printed. In effect, it directs the second solution to grow with the same crystal structure, a process which Dr Gaisford calls “crystal templating”. This could benefit drug development because it is a method of making computer-modelled structures of interest. Dr Gaisford suggested that inkjet printing might even, in future, enhance the development of monoclonal antibodies, which can be difficult to crystallise.

“The principle is demonstrated. Now we need to develop it as a method,” Dr Gaisford said. He revealed that last month his team secured a £1.25m grant from the Engineering and Physical Sciences Research Council, the main UK government agency for funding research and training in engineering and physical sciences, to take the work further. “[It] will be used to look at how we can vary parameters, such as solvent, temperature and substrate type,“ he said.

Personalised dosing

Pizzas for astronauts might seem a bit of a gimmick but “printed medicines” have the potential to solve a number of pharmaceutical problems. One day, instead of counting tablets into a bottle or ordering a special, pharmacy staff could be loading a cartridge into a printer and printing active pharmaceutical ingredients (APIs) onto a dosage form to give to their patients.

Dr Gaisford’s team has already shown that doses can be printed onto film made of starch which dissolves in the mouth (much like Listerine breath strips) and the next project that he is looking to get funded is the use of printer technology to achieve personalised dosing, he told The Journal.

“In terms of personalised dosing and why [printer] technology is useful relative to other techniques, it comes down to the very fine control of the volume which is being jetted,” Dr Gaisford said. He explained that because each droplet is typically between 7 and 24 picolitres the inkjet is capable of printing minute doses — so printer technology could be used to make safer the administration of extremely low dose, highly potent, narrow therapeutic index drugs, especially for children.

“The technology of an inkjet printer is so far ahead of what we need in pharmaceutics, we’re almost taking a backwards step,” he said. However, the tiny droplet size also limits the number of drugs suitable for printing because the maximum dose the team has been able to print is 35µg per cm2.

So far, they have been working with tacrolimus. Squares of film (or “oral wafers”) could be printed in weekly batches for a particular patient. The idea is that you can vary the dose patient to patient by, for instance, jetting a different concentration of solution, a different area on the film, or you can put the film through a number of times, building up the number of layers that you are printing. You could even print each film with a day of the week, with the drug contained in the text, Dr Gaisford suggested.

Another “jettable” drug might be clonidine, used off-label for epilepsy. The added benefit of a film is that it could be used during an attack of epilepsy because it does not have to be swallowed, he added.

Challenges

“The next stage is to develop hardware which allows some sort of translation into the clinic. So, for example, the cartridge content needs to be manufactured under good manufacturing practice standards. It needs to be robust and, most importantly, there needs to be a way of checking how much dose has been deposited each time. Those are the technical challenges that we need to overcome,” Dr Gaisford said.

Despite the accuracy of inkjet printing, quality control is still a big challenge, according to Dr Gaisford, particularly how you would typically assay doses when batch sizes are so small. He said that his primary concern is that one of the printer nozzles could get blocked, which would not be seen.

“In a typical assay, let’s say you’ve manufactured 500 million tablets, you sample those tablets. You’d dissolve them and assay them, typically with an HPLC method. In this instance, we’re talking about individually producing a dosage form for each patient, so that’s not an option [if] we’ve only got seven films. We could print eight and sacrifice one, but the statistics aren’t working in your favour at that point,” he explained, although he added that this problem is true for all personalised medicine.

He went on to say that what would be needed is in situ quantification of the dose. “This will be difficult unless the drug itself is fluorescent [in which case] you could have some sort of fluorescence monitor. So we’re proposing that we can add a second component, typically a food dye that can be jetted alongside the drug, and we would assay that with an in situ spectrometer and we’d have to demonstrate that the drug was always there in the same proportion.That’s one of the areas that we need to work on, to demonstrate that that’s a valid assumption,” he said.

However, he believes that, overall, printing medicines could also make quality assurance procedures faster because it follows the “quality by design” ethos, which involves understanding how changes in each step in the process affect the final product.

“What that means is that by controlling the process we shouldn’t ever need to assay the product at the end because we’re guaranteeing that the quality is in the product. I’m not saying you don’t test at the end but, in principle, you should never have a batch that fails because you know at all points if something went wrong and, you’d know what the knock-on consequence was,” he said.

3D printers in medicine

3D printers work by extruding a melted material to build an object layer by layer, directed by computer-assisted design software. This additive manufacturing technology is already being harnessed in the fields of prosthetics and dentistry to produce bespoke items. For example, Glasgow Caledonian University is using 3D printers to make insoles and splints at a faster rate and to a new degree of precision, and scientists in North Carolina are using the technology to produce scaffolding to grow human cells into organs.

Last year saw the establishment of a National Additive Manufacturing Innovation Institute in the US and the announcement of an intention to invest in the research and development of 3D printing technologies in the UK.

Could additive manufacture be applied to the production of medicines? Polymer-drug blends could be used to print tablets and the dose could be varied by varying the volume [ie, tablet size] printed, according to Simon Gaisford, reader in pharmaceutics at University College London.

However, new technologies intended to benefit society can come with a flipside. For example, 3D printers being used to make guns have grabbed recent headlines. Could printer technology be exploited for illicit drug manufacturing? “There’s nothing to stop people from using tablet presses now. Using 3D printers may be slightly harder. They would need to know what is an extrudable polymer,” Dr Gaisford says.

Other challenges in the application of this printer technology are likely to be shelf-life and patentability. “The short shelf-life of a metastable crystal may be because that crystal may convert to the stable crystal. In that sense it loses its bioavailability but it hasn’t changed the chemistry, just the physical structure and so we’ve lost product performance. If a drug’s in solution, it may well chemically degrade — there is no physical structure in solution — and then we have a problem because we’ve got less drug there than we thought we did,” Dr Gaisford said.

“Patentability is a grey area but I think that the co-crystal would be deemed to be a different active than pure carbamazepine. So you need to decide that you’re going to use your co-crystal early in development because all your clinical trials are going to have to be run with it,” he commented.

On the horizon

The UCL/Strathclyde team are not the only ones interested in the potential of printer technology in pharmacy. Scientists from Leeds and Durham universities have worked in collaboration with GlaxoSmithKline on “printing” APIs onto tablets.

A press release from 2010 stated that GSK had already developed a process — now coined “liquid dispensing technology” — but it only worked for 0.5 per cent of APIs (those being drugs which were highly water soluble). The aim of the collaboration was to make the process suitable for 40 per cent of APIs, with proposed benefits including faster production, more precise dosing and the ability for more than one drug to be printed onto a single tablet.

A GSK spokeswoman updated The Journal on the now patented technology. She said: “Liquid dispensing technology is a novel manufacturing technology developed by GSK for producing low dose, high potency tablets . . . with an unprecedented degree of dose accuracy. The drug is prepared in liquid form and the solution is then dosed on inert carrier tablets with dose verification of every tablet manufactured.

"[This] allows for content uniformity and the concentration of the dosing solution to be continuously measured. In addition, high speed imaging can accurately measure the volume of every drop. Combined, the known drug concentration and calculated drop volume means that the actual drug content can be determined for every single tablet manufactured to a high level of accuracy.”

After working on this innovation for over 10 years, GSK has now installed the technology and industrial scale machinery at a manufacturing site in Barnard Castle, County Durham. According to the company, several GSK compounds are in clinical development.

So, it looks like this technology is not that far removed from practice. “I can envisage a hospital pharmacist printing medicines on a handheld printer. This is probably feasible in the next 10 years. But there’s no reason why this wouldn’t reach community pharmacies too,” Dr Gaisford predicts. “The technology is there, all you need is a pharmacist to buy into the concept,” he said.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11122986

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