How a researcher at the University of East Anglia is using Arburg's Freeforming Process in the additive manufacturing of personalised medicine.
Life expectancy is increasing worldwide due, in large part to advances in prevention, medical treatment and new pharmaceutical technologies. According to a 2019 report (US Pharm. 2019;44(7):33- 36), around 44% of men and 57% of women over the age of 65 take five or more drugs each week, with 12% of this age group taking at least 10. The majority of these pharmaceuticals are made with generic dosages of active ingredients and release patterns that do not necessarily address the individual patient’s needs. This can lead to over- or under-medication and unwanted side effects, and is seen as a problem by many patients.
Similarly, a 2016 report from the National Health Service in England, entitled “Improving Outcomes through Personalised Medicines,” found that tailored treatment that matches the individual patient’s makeup and response to pharmaceuticals is far more effective than symptom-driven, one-size-fits-all approaches and results in fewer side effects.
Dr Sheng Qi, a scientist at the University of East Anglia (UEA) School of Pharmacy, one the leading pharmacy schools in the United Kingdom, has been researching this problem and developing techniques that allow dosages and release rates for active ingredients to be adapted to the specific needs of individual patients. This personalised medicine approach is believed to be able to provide faster and more effective treatment when it is applied in combination with “point-of-care manufacturing,” where small-batch production occurs either on-site or at convenient local hubs.
One of the technologies that seemed to hold the most promise in achieving these objectives, Dr Qi says, involves additive manufacturing or 3D printing. The Arburg Freeforming Process (AFP), developed by the German manufacturer of plastics injection moulding machines, has unique features for printing medicine in comparison to other thermal-based 3D printing replying on filament feeding. See Figure 1.
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Figure 1: The freeformer and the Arburg Freeforming Process works highly precisely and results can be repeated.
Personalised Medications
To date, personalised pharmaceuticals have only been available to a small number of hospitalised patients and patients undergoing cancer treatment. And yet, such personalised treatment could enhance acceptance among patients, minimise repeated hospitalisation and provide improved therapeutic outcomes in general.
Dr Qi’s objective, therefore, has been to broaden the availability of personalised treatments, while standardising and simplifying pill production. Her approach involves compounding active pharmaceutical ingredients (APIs) into a polymer that would dissolve/degrade after being ingested by the patient, thus releasing the drug. She envisioned the drug being compounded into the polymer at a fixed ratio, so there is only one feedstock regardless of patient-specific needs. Then the pills would be 3D printed with different sizes and densities (porosities) so as to precisely match the personalised dose and drug release rate requirements of the patient. See Figure 2. The smaller the pill size, the lower the quantity of the drug would be delivered in a given pill. Then, by controlling pore density and the shape and alignment of the pores, it would also be possible to control the release rate of the given dose. See Figure 3.
Figure 2. Pills can be 3D printed with different sizes and densities (porosities) so as to precisely match the personalized dose and drug release rate requirements of the patient.
Additive manufacturing is already an important production method in the healthcare sector. Applications such as custom-made titanium prostheses and implants already make frequent use of 3D printing. This seemed like an ideal approach, but there would still be a number of technological restrictions to overcome.
In 2015, Dr Qi and her team at UEA started to actively investigate conventional 3D printing, which involves the use of polymer compounds in the form of long strands or filaments, a process called filament deposition modelling or FDM. The possibility to create brand new pill geometries and structures was a key element in this research work. However, she quickly realised that the market for 3D printers was limited with respect to the materials that could be used. Many manufacturers only supply their own consumables for their devices. Others offer more flexible platforms, but with poor reproducibility of the printing quality of pharmaceutical materials. Another restriction stems from the fact that many filaments made from the pharma-grade materials are not flexible enough to be processed by traditional FDM printing.
Still another problem was that, to make the conventional FDM process work with medicinal materials, the API would need to be thermally processed twice. First, the active pharmaceutical ingredients must be mixed with the matrix polymer and formed into filaments. This involves hot-melt processing in an extruder and then cooling of the compounded filaments. Then, during the 3D printing process, the filaments would be melted again and discharged through a hot nozzle to form the desired pill shape. This is far from ideal, as many drugs and polymer excipients have relatively poor thermal stability and do not react well to heat-processed twice.
“We benchmarked several 3D printers and were dissatisfied with all of the results,“ said Dr Qi. “We needed an alternative, robust solution offering high levels of precision and accuracy.“ The scientist hit upon this in 2019 when she conducted trials with the Arburg freeformer, which can also process pharmaceutical materials, not normally available in 3D filament.
Figure 3. The behaviour of the pill can be modified by changing not only the porosity of the pill, but also the pore length, shape and alignment.
ARBURG’S OPEN PROCESS
The APF technology and freeformer are designed as an open system, making use of conventional plastic pellets identical to those used in other plastics processes, rather than filaments. In fact, the freeformer design is based on injection-moulding technology. Pellets are melted in a screw/barrel plasticating unit and then tiny droplets are metered out in a programmed sequence to create the desired shape. While other additive plastics processes are limited to a relatively narrow range of available polymer filaments, the freeformer can handle many standard pellets, including common pharmaceutical polymers.
To create 3D-printed pills, the active pharmaceutical ingredients are granulated with polymeric excipients using traditional pharmaceutical granulation process, then fed into the freeformer for printing. Thus, they experience only one “heat history,” reducing the risk of pharmaceutical degradation.
The UEA team has had success combining two or more drugs into one pill and can even create structures where one ingredient is formed in the centre of the pill, surrounded by another, or different compounds can be layered one on top of the other in a continuous process. In these situations, drugs can be released into the patient’s system simultaneously or sequentially, depending on which approach is most efficacious.
Using the freeformer, a wide range of filling level variants were able to be tested and created at UEA. The porosity of the tablet allowed the active ingredient’s release rate to be regulated. “The freeformer offered our team the flexibility to optimise various densities and adjust them precisely. The reproducibility of results was steady and robust,“ Dr Qi said.
LOOKING FORWARD
Dr Qi and her team are continuing her research to further promote the topic of personalised pharmaceuticals for patients. While using additive manufacturing technology to produce personalised medicine is proven to work, it is not yet available for clinical use. Obstacles to market entry include lacking clarity of suitable regulatory framework for point of care manufacturing, the need of new supply chain model and the cost-effective operational model for such point of care manufacturing hubs. Despite this, the scientist is optimistic that these hurdles can be overcome: “Science, industry, and healthcare providers, as well as regulatory authorities need to work together more closely. This is the only way in which we will be able to create a new regulatory framework for the decentralised manufacture of personalised medicines.” She goes on to add that this would require the redistribution of employees and a reorientation of patient care.
Dr Sheng Qi is filled with enthusiasm regarding the possibilities for this new medical technology. Her vision is as follows: “If we can personalise tablets, then we’ll be able to personalise almost anything. Take, for example, bioresorbable implants for cancer patients – the material could contain specifically tailored drugs that reduce the risk of developing cancer again and speed up the recovery process!“ Scientists and researchers like Dr Qi are actively working on the next generation of healthcare and wellness solutions. With machines like ARBURG’s freeformer, their aim for the future is to make the impossible possible.