The past few years have illustrated the startling speed with which medicine can evolve. Since 2018, the US Food & Drug Administration (FDA) has approved first-of-their-kind drugs based on RNA, gene therapy, and cancer-killing chimeric antigen receptor (CAR) T-cells and signed off on human trials to explore the clinical use of CRISPR-mediated genome editing. And throughout this process, the US Pharmacopeia (USP) has been working in the background to ensure that quality standards are in place for new medical products reaching the market. “200 years ago, our first monographs were basically recipes: ‘take bark from this tree and boil it for this long and you should get a brown liquid’,” says Michael Levy, Head of Research & Innovation (R&I) at USP. “Obviously we've evolved tremendously since then, but it’s just a continuation of what we’ve always done—we’re just doubling down on it.”

Regular revisions to quality standards to accommodate advances in knowledge and changes in medical practice were built into the USP process by its founders. Today, to ensure its standards stay current, USP also works to stay ahead of the rapidly changing technology curve. Well before a cutting-edge medicine reaches the market, the underlying tools and techniques are already percolating up into the scientific literature and presentations at international conferences. USP combs through this early-stage work and projects which prospects seem most likely to impact the quality of therapeutics within the next decade or so. “We ask what’s on the horizon, what are the quality issues potentially associated with that trend or technology, and how does USP need to respond,” says Levy.  USP then explores some of these technologies, working through a typical research approach with preliminary proof-of-concept work potentially followed by longer-term “incubation projects” conducted by subject-matter experts.

One example of a technology that USP R&I is exploring is the use of 3D printers in medicine production. The first 3D-printed pill has been approved by FDA and is already on the market – an anticonvulsant drug for people with epilepsy. Each pill is 3D printed with a carefully designed, highly porous structure that allows it to rapidly dissolve in liquid for easy administration. USP R&I is also exploring applications of this technology in other contexts, perhaps including multiple components or redesigning pill shapes to facilitate ease of swallowing. Safeguarding quality in this context will require a deep understanding of the printer technology to ensure consistency in production and minimize risk of cross-contamination, as well as careful profiling of the various ‘resins’ used to incorporate active ingredients into the printed pill. “This is still very early research,” says Levy.

Artificial intelligence (AI) is a bonafide buzzword in medicine today, but there are not yet standards for use in clinical settings. USP is working to change that. Credit: mmustafabozdemir/iStock/Getty Images

Quality in the virtual world

Most of USP’s history has revolved around chemical and biological entities that directly interact with a patient’s body, but the last few years have seen the advent of ‘digital therapeutics’. These are software tools designed to help patients and their physicians or caregivers to manage medical conditions. “These are software with no associated medicine, but which has been shown to have a positive therapeutic effect,” says Levy. For example, FDA has cleared mobile medical applications designed to help track and manage recovery from substance abuse issues. In 2018, USP established a collaboration with the Digital Therapeutics Alliance (DTA) aimed at helping to guide companies entering this space achieve the highest standards for their products. “We’re looking at how to ensure that these products work well and offer reproducible performance over time in a reliable way,” says Megan Coder, executive director of the DTA. She adds, “there’s scientific rigor and methodology that goes into each digital therapeutic.”

At first glance, it seems difficult to assess a digital therapeutic in the same manner as one would assess quality for an antibiotic or cancer drug. But the general principles used by USP to set standards for conventional drugs—identity, strength, purity, and performance—may be broad enough to be translated to the digital world. “For identity, for example, you can ask ‘how do I know that a piece of software is what I think it is?’” says Levy. “If there’s a trivial bug in the software and you patch it, is it still the same as the unpatched version?” Coder notes that the notion of active and inactive ingredients also holds true for digital therapeutics, just like with their chemical counterparts, and that one of DTA’s priorities in collaboration with USP is to explore formalizing quality standards for some of the commonly used ‘digital excipients’ in these products. “These are components that many digital products will have, like libraries and data stacks,” says Coder. “Then we can move on to explore the ‘active ingredients’, like algorithms that are unique to each product.”

This is only the beginning of a deeper push into the digital realm. Big data has become a fact of life in biomedical research and drug discovery, and many groups are turning to tools such as artificial intelligence (AI) and machine learning to efficiently extract meaning from many terabytes of information. USP recently launched an internal program to investigate some of the quality challenges surrounding AI technologies, and how to shore up confidence in these tools as they become more ubiquitous. For example, Levy notes that many algorithms currently used in research are essentially ‘black boxes’ in terms of how they process data, making it a challenge to assess quality. There may also be opportunities for standardization in terms of the datasets used to train these programs, just as validated reference materials are an essential tool for biochemical assays. “USP could help set standards to ensure that bias isn’t built into algorithms through their training datasets,” says Levy.

Levy foresees a future in which the now-disparate threads of pharmaceutical technology, medical devices, and digital systems are routinely integrated—and potentially even networked together. Accordingly, his goal is to expand on USP’s expertise in chemical and biological medicines by building a team of digital experts who can help prepare the organization for the challenges to come. “As that ecosystem becomes increasingly complicated, we will need to have the right capabilities to be able to look at quality standards in that area,” he says.

To learn more about the need for quality standards in medicines, visit The Science of Quality.