3D-Printed Pharma: The Billion-Dollar Opportunity

Personalized medicines could turn the world of pharma upside down, unlocking the manufacture of rare disease treatments, improving patient compliance, and helping tackle inequalities, among other advances. The potential for truly customized tablets, capsules, and other delivery forms has remained just out of practical reach – until now. As 3D printing technology becomes more advanced and tightly regulated, the potential to produce safe, potent, and profitable personalized drugs could finally be here. With the global 3D printing market for all medical applications (including pharma and nutraceuticals) predicted to reach a value of $1.2 billion 2024, the billion-dollar question this article will aim to answer is: What 3D printing production strategies can help drug developers seize the available opportunities?

Read on as we seek to answer this question and more, exploring 3D printing’s development from a theoretical possibility to a viable pharmaceutical production method, the significance of this rise for producers and patients, and how excipients, the often-unsung heroes of the pharma world, hold the key to fully unlocking its potential.

The Beginnings of 3D-Printed Pharma

The concept of “print-to-order” pharmaceuticals feels quintessentially modern. However, it roots stretches back as far as the 18th-century development of “photo-sculptures” and early “stack-and-cut” topographical maps. The late 1960s saw the first experiments with laser beams being used to solidify photosensitive polymers, and later, partially melted powders. The first appearance of additive manufacturing (AM) technology, as would be recognized today, emerged in the 1980s with the invention of stereolithography. In brief, this method involves a tank of uncured, photosensitive resin attached to a nozzle, a moveable platform, a UV laser, and a mirror system. These apparatuses are fed the target shape via computer-aided design (CAD) files, before the syringe deposits layers of resin onto the platform, where they are subjected to precise and localized polymerization (curing) by the UV beam. Layer by layer, these sheets of resin build the 3D shape determined by the original CAD file.

Stereolithography is considered the first true 3D printing technique, but it would ultimately be eclipsed in popularity by another method developed just a few years later. Like stereolithography, fused deposition modeling (FDM) features the layered depositing of a material according to a pre-programmed design. In contrast to the earlier method though, in FDM, the deposited material is usually a form of thermoplastic polymer, heated to a semi-solid state within the nozzle, before being extruded onto the printing platform, where it fuses with the previous layer cures instantly. Even as new technologies continued to be introduced in the subsequent decades, the speed, convenience, and resultant cost-efficiency of FDM helped secure its position as the leading 3D printing technique and revolutionary development in the field of drug manufacturing.

Getting Personal: 3D Printing and the Healthcare System

Should the patient adapt to the drug, or the drug adapt to the patient? This is a question that clinicians and pharmaceutical manufacturers have been grappling with practically since the dawn of medicine. Certainly, the theory of personalized medications, tailored to the symptoms, needs, and preferences of individual patients is idyllic. The practical and economic realities of drug production though have made “one-size-fits-all” the most viable approach — that is until the introduction of 3D printing. With its capacity to produce fully customized medicines virtually on-demand, drug printing opened the door to a whole new pharmaceutical business model, where medicines are manufactured and sold according to need rather than the projected return on an industrial product run. Taking this into account alongside the equally exciting potential of 3D printing other fields, such as biomechanics and surgery, and the staggering $1.2 billion future market valuation for medical 3D printing begins to make sense.

One of the main barriers that could prevent printed medicines’ meteoric rise is regulation — or lack thereof. Like all technologies new to the notoriously strict pharmaceutical space, 3D printing existed  official limbo for years until the launch of the first U.S. Food and Drug Administration (FDA) approved 3D-printed pill, Spritam (levetiracetam), in 2015. Almost a decade later, Spritam remains the first, and only, FDA-approved drug produced in this way, despite promising results in the manufacture of 3D-printed orally dispersible films (ODFs), among other breakthroughs. This reticence on the part of regulators could stem from concerns surrounding safety, quality, and consistency. For instance, most of the 3D printing machines available to drug manufacturers were originally intended to produce plastics, rather than life-saving pharmaceuticals. There is also little standardization between printing machines and their parts, leaving organizations, like the FDA, unable to establish broadly applicable guidelines for 3D-printed tablet production.

Contrary to the popular belief that pharmaceutical standards move at a snail’s pace, regulatory structures are constantly evolving to accommodate fresh technologies or pressing public health concerns. Logically then, the key to finally securing clearer rules could lie in a two-pronged approach: demonstrate the benefits personalized, 3D-printed medications could bring to some of the world’s most vulnerable patients and devise new ways to make their production safer and more in line with the types of ingredients regulators are used to seeing in pharmaceuticals.

Reasons to Take Notice: The Patient Perspective

Put simply, 3D printing is opposed to the traditional one-size-fits-all approach – which ironically, does not fit many patient groups. Take children, for example — until relatively recently, there were few universal protocols for administering drugs to patients under twelve years of age, often forcing clinicians to adopt adult medicines, which were not tested or officially approved for use pediatrics. While doctors always seek to provide the best care for their young patients, this off-label practice could, in the worst-case scenario, heighten the risk of adverse side effects. At best, it was usually inconvenient or unpleasant for the children who were required to swallow standard-sized tablets and capsules. Older patients and those with swallowing issues face similar challenges in accessing medications that are both therapeutically effective and easy to take.  promise Being able to build them own medications via 3D printing could be transformative for these patient groups, allowing them to customize factors, such as format, flavor, texture, color, shape, and size.

That being said, 3D printing is not the only avenue to improve medication compliance, particularly as the development of alternative dosage forms like ODFs, mini pills, and even medicated gummies has advanced in recent years. In contrast, the shift in manufacturing practices offered 3D printing could be indispensable in expanding access to rare disease medications. One of the key advantages of technologies like FDM is that they significantly reduce the time to prototype for new medications, unlocking faster entry into first-in-human (FIH) clinical trials and with it, lower the cost of development. In addition, the same cost-benefit analyses that usually discourage large-scale manufacturers from producing treatments for an inherently small market do not apply to 3D-printed pharma. The potential for such a positive impact makes the need for optimizing 3D production methods even more imperative.

The Excipient Factor

As discussed, many of the regulatory headaches surrounding 3D printing distill down to safety and quality. Focusing on FDM specifically, the success of the printing exercise rests on selecting a filament polymer with the correct thermophysical properties to melt, pass through the extruder, fuse with the previous layers,a nd solidify quickly. As such, manufacturers typically use synthetic oil-based materials, such as polyvinylpyrrolidone and polyvinyl alcohol, to act as an excipient, which by their nature are less attractive to both regulators and end users.

In addition, typical drug product development considerations such as drug dissolution profile and drug-polymer chemical compatibility further limit the formulation options for 3D printing. Researchers at Roquette set out to change this picture by investigating whether the FDM process could be adapted to allow for the use of more widely accepted, plant-based materials like modified starches in the formulation of printed drug products.

The resultant study focused on two drug preparations: Formulation one (F1) used diprophylline, used in the treatment of respiratory disorders, as the model active pharmaceutical ingredient (API) alongside pregelatinized hydroxypropyl pea starch as the polymer matrix excipient. Formulation two (F2) featured a combination of pregelatinized potato starch and hydroxypropyl methylcellulose (HPMC K4M), in conjunction with diprophylline and a range of other APIs, namely theophylline anhydrous, caffeine anhydrous, and indomethacin. In both formulations, sorbitol, and spray-dried (SD) mannitol were included as plasticizers, while stearic acid was used as a lubricant. The ultimate goal  study was to evaluate the suitability of different modified starch excipients to produce immediate and controlled release tablets through a combination of hot melt extrusion (HME) and FDM, with the secondary aim of evaluating the best-performing plasticizers for 3D-printed formulations.

A mixture design approach was used to vary formulation components and make clear the effects of different plasticizer ratios, starch, and stearic acid concentrations on filament properties and tablet printability. As a first step, flat cylindrical tablets were printed from optimized iterations of F1 and F2 using a hot melt extruder and benchtop 3D printer with the parameters stated in Table 1.

To assess the drug release kinetics of the resulting tablets, immediate and controlled-release dissolution studies of 1- and 12-hour durations respectively were performed using USP apparatus 1 (baskets) for the formulation containing indomethacin, and USP apparatus 2 (paddles) for the other model APIs. Simulated gastric fluid (SGF pH 1.2) was used to evaluate the dissolution profile of the immediate-release tablets, while the controlled-release formulations were assessed via a two-stage dissolution process, beginning at pH 1.2 for the first two hours, followed by a transition to pH 6.8 — similar to that found in the intestine. The in vitro drug release assay was measured via UV spectrophotometry, and all tablets were also subjected to stability testing through month-long storage in heat-sealed aluminum pouches, kept at either 25°C with 60% relative humidity (RH) or 40°C at 75% RH. The effort put into these meticulous preparations was more than rewarded when the study’s authors took stock of the results.

A New Protocol for 3D-Printed Pharma?

Firstly, it was found that the use of sorbitol returned a stronger plasticizer effect than that of mannitol, and researchers were able to determine optimal ratios for both excipients to create the correct balance between filament brittleness and pliability during printing. Next, they observed that the level of starch content had a significant impact on the extrudability of the formulations, with a high starch to low HPMC concentration yielding brittle filaments, while formulations containing no starch could not be extruded at all. Using an optimized ratio of 1:1 starch to HPMC led to the formation of filaments capable of the continuous extrusion required for FDM 3D printing.

With similarly promising results from the API release and stability assessments for optimized formulations, researchers concluded that their hypothesis had been correct. Two distinct base formulations containing hydroxypropyl starch and pregelatinized starch/HPMC (in combination with sorbitol and mannitol) were able to yield extrudable filaments with good printability, capable of achieving immediate- and controlled API release for the respective model drugs. These findings point to a feasible, more natural alternate future for 3D-printed medications, where plant-based polymers replace conventional synthetic polymers, and regulatory skepticism gives way to mainstream acceptance.

Opportunity – Seized?

The beauty – and frustration – of any scientific undertaking is that it is never truly complete. Further research into the use of plant-based polymeric excipients, and 3D-printed drugs in general, is needed before the dream of print-your-own medications can be realized. The tide of change is, however, trending in the right direction. With digitalization now ubiquitous across industries and artificial intelligence (AI) dominating conversation, 3D printing represents an important bridge, where the digital can become physical. It is only logical that time, effort, and resources will be poured into developing such an important intersection, in the process bringing the possibility of personalized medicine a step closer. Market projections may point to a billion-dollar industry, but 3D printing’s potential to solve the toughest challenges in drug delivery? That is truly priceless.

Author Details

Bing Xun Tan, Pharmaceutical Application, Lab Manager- Roquette 

Publication Details