One Pill Fits All: The 3D Printing of Drugs

 

Image from: https://www.the-scientist.com/news-opinion/on-the-road-to-3-d-printed-organs-67187

 The other day I sat with my grandmother, watching her set up her pillbox. There were morning and night pills, once-daily pills, twice-daily pills, big pills and small pills. I sat there thinking, “I can hardly go a week without losing my wallet or keys; there is no way I could ever be so organized as to keep straight this medication regimen”. I thought there must be a better answer for this, and thankfully, scientists over the last 40 years have been working diligently on a solution: 3D printing of drugs. First patented in the 1986 by Charles Hull⁵, this technology is the precipice at which the future of personalized medicine lies; it could truly be the next major revolution in treating patients who are vulnerable to drug toxicity or failure to follow recommended therapies. With 3D drug printing, the possibility exists that instead of 16 pills per day, my grandmother could take one pill, with exactly the right concentration of each active pharmaceutical ingredient (API) personalized to her needs.

Additive manufacturing, or 3D printing, has been a rapidly expanding field in which innovation has driven this technology to applications in practically every industry which currently exists. The market for 3D printing is valued at $13.68 billion dollars for 2020, and is predicted to grow up to a worth in excess of $35B¹² as aggressive research and development takes place over the next several decades. There are several techniques with which an object can be created; each involves a layer-by-layer manufacturing process in which the object is first designed from a computer, and then the blueprint is transmitted to the printing equipment (for additional information into how 3D printing works, I suggest this video). This technique has been used already in the medical field for decades; there are people walking around with 3D printed limbs, rib cages, and jaws. Much like these devices are custom made for individuals, the pharmacotherapy of the 55% of American people who take a prescription medicine can be customized in the same way. Indeed, with Americans taking more prescription drugs than ever, it is no shock that 1.3 million people have ended up in the emergency room to be treated for adverse events related to their medications⁷. This serves as a crucial reminder that we must work to reduce inadvertent drug overdoses and toxic interactions, and increase patient compliance and overall prognosis through their polypharmacy regimens.  All of these  can potentially be accomplished by 3D printing medicines.

Figure 1: Dose flexibility scheme shown for different patient populations, where each pill has precisely the amount of API needed. 

3D drug printing has several key advantages over traditionally mass-produced pills^3,8,9:

1)     Provides dose flexibility, with tailored release profiles and pharmacokinetics

2)     Reduces waste in terms of mass-manufacturing and transport of conventional drugs

3)     Provides opportunity for mass production in remote locations (i.e. disaster zones, outer space, etc.)

The dose flexibility is the most commonly toted benefit, and for good reason.  Being able to change not only the identity of the API as well as their shape can alter the way drugs are released and transported around the body, enhancing both pharmacokinetics and pharmacodynamics of the medicine. 

Figure 2: Printlets showcasing the variety of shapes that can be created. Pills which are less dense will increase the speed of absorption. Also, compliance of pediatric patients may increased by utilizing more interesting shapes and incorporating various flavors. From:  https://www.ondrugdelivery.com/personalising-drug-products-using-3d-printing/

    It is well known that  drug therapy is complicated for certain populations. For example, older people generally have several comorbidities, which may have disease-related decreases in organ functioning. Pharmacogenomics studies have revealed that many of us have different levels of expression for metabolic enzymes which has implications for drugs toxicity.  As an example, we have discussed, warfarin in our 422G course, which is metabolized by a CYP2C9 enzyme. This particular enzyme has common genetic frequencies across patients with different ages and ethnicities⁶.  Thus,  for a patient with abnormal CYP2C9 expression, critically dangerous levels of warfarin can be avoided by taking a 3D printed drug. Children also have a documented need for customized medications.  According to the European Medicines Agency, many products are simply not produced in doses or formulations which meet the safety standards for pediatrics¹¹. Because drugs can be designed with precise spatial control and geometries, fewer excipients and APIs are needed as well¹. This could substantially bring down medication costs for drugs, especially those of rare diseases such as spinal muscular atrophy, where one annual course of treatment can run about $2 million². When one thinks about the logistical benefits of 3D printing, it is easy to see the carbon footprints of mass-scale drug production begin to slowly dissipate. Fuel and energy consumption, as well as the necessary resources to maintain those drugs which are temperature sensitive, would drop to more sustainable levels⁸, and bring cost savings in the billions according to FDA Commissioner Scott Gottlieb⁷. Lastly, 3D printing requires few resources in terms of space and operation of the equipment. This would provide critical medications at the point of care for patients in areas which aren’t reliably accessible can drastically improve outcomes of patients who otherwise may have gone untreated³.

       As we continue to navigate the technologies being developed at break-neck speeds, we must also keep in mind the ethical and regulatory considerations necessary to harness the power of these technologies and ensure they are applied in a safe manner to the global population. The first truly 3D printed drug was brought to market in 2016 by Aprecia⁴, a major milestone in the industry of pharmaceuticals. However,  there are still many hurdles we must cross before 3D drug printing reaches its full pharmacologic potential. Currently, the FDA has not been able to fully translate the regulatory pathways used for conventional drug manufacture to that of 3D printing of drugs, a process known as good manufacturing practices.  These practices state that all parts of the additive manufacturing printer must be able to be easily cleaned, and the printer must be validated to fabricate the pills between acceptable parameter ranges. Quality control of the products remains a big concern as the safe level of reproducibility of certain products has not been achieved. New challenges surrounding personal data security, counterfeit production, and as previously stated, translating the good manufacturing practice protocols from traditional drug production to 3D printed medications, will continue to slow the progress of bringing this technology to mass scale^9,12,13. Currently, none of the various techniques used to 3D print medications are fool-proof; some printers fabricate pills which are too friable, and others use heat or lasers which may degrade the API¹². Until these regulatory needs are met, unfortunately, we are stuck with our imperfect prescribing system. However, the good news is that the FDA and the federal government are continuing to allocate funds to develop the clarity and architecture needed to one day bring 3D drug printing to the masses awaiting its life-saving benefits.

 For more information on this topic, I suggest this Ted talk by Daniel Kraft, who describes the process of biomanufacturing pharmaceuticals, and its application to personalized medicine. https://www.youtube.com/watch?v=-RkhAP0_ms4

By Amy L. Rice, Post-Baccalaureate student at the University of Kentucky 

 References

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8.   8. Preidt, R. (2017, August 03). Americans Taking More Prescription Drugs Than Ever. Retrieved September 22, 2020, from https://www.webmd.com/drug-medication/news/20170803/americans-taking-more-prescription-drugs-than-ever-survey

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1212. Trenfield, S. J., Awad, A., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). 3D Printing Pharmaceuticals: Drug Development to Front-line Care. Trends in Pharmacological Sciences, 39(5), 440-451. doi:10.1016/j.tips.2018.02.006

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