How Technology Can Provide a Safe Journey from Bench to Bedside

Franck A. Vendeix, PhD, Associate Director, Analytical Services, Scientific Expert Consultant for the Analytical Services Group at AMRI

As medical science advances at a dizzying rate, so does the technology we rely on to assure new treatments are as safe as they are innovative. From gene editing to RNA vaccines, the era of personalized medicine is upon us and it is fiercely competitive. It suggests that the pharmaceutical industry is turning to specialist contract research organizations (CROs) to provide advanced analytical services, using state-of-the-art techniques such as high field nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography – coupled with mass spectrometry (LC-MS) which can smooth and accelerate the drug development journey and eradicate costly delays due to unexpected drug development issues.

Personalized medicine

The days of the blockbuster drug are waning. Instead, personalized medicine, driven by advances in technology, offers the right drug for the right person at the right time. Gene editing was once the preserve of those with the resources to access zinc-finger nucleases but the emergence of CRISPR-Cas9 democratized the field. Gene editing accelerated research, but also raised safety concerns. As a 2018 paper in Nature Biotechnology found, the technique could cause significantly more off-target damage to the DNA than previously thought. Leader of the Wellcome Trust Sanger Institute study, Allan Bradley, said: “We found that changes in the DNA have been seriously underestimated. It is important that anyone thinking of using this technology for gene therapy proceeds with caution and looks very carefully to check for possible harmful effects.

We found that changes in the DNA have been seriously underestimated.

The paper, which found the issue had led to cancer in some early trial participants, highlighted the need to understand proteome changes during CRISPR applications, and the importance of robust high throughput mass spectrometry (MS). Technology developers and CROs have risen to the challenge. AMRI’s stateof-the-art LC-MS/MS systems provide precise, sensitive limits of quantification to enable the detection and quantification of the widest scope of chemical compounds in even the most challenging matrices.

Improved polarity switching allows for rapid chromatography and more efficient throughput, and the quadrupole linear ion trap mass spectrometer (QTRAP) functionality enables quantitative multiple reaction monitoring and QTRAP scans in the same injection. In short, it can provide sensitivity for the ultra-low level quantification of both small and large molecules.

Safe vaccine development

This industry leading analytical technology, in the hands of industry-leading chemists, is also proving invaluable in the current search for a SARS-CoV-2 vaccine. With more than 120 therapeutics currently being studied around the world, the race is on to be the team to stop COVID-19 in its tracks. However, a product will only be approved if developers can prove it is safe as well as effective ole in vaccine development as the landscape has shifted towards recombinant products, and this is only accelerating as its DNA, RNA and RNAi analyses capabilities expand.

Contamination mitigation

Over the past few years, a worrying trend of pharmaceutical contamination has developed, leading to multiple product recalls and interrupting supply for millions of patients. A number of drugs, including ranitidine, an H2 blocker, and the diabetes medication metformin, were found to contain the known carcinogenic N-nitrosodimethylamine (NDMA). NDMA is an N-nitrosamine, a group of compounds with a generic chemical structure that are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. The first discovery was made in 2018, in a drug containing the active pharmaceutical ingredient (API) valsartan, an angiotensin II receptor blocker (ARB) used to treat high blood pressure. Since then, private, industry and regulatory labs have found NDMA in at least six drugs, and the FDA has recommended the recall of five of them. While the levels of NDMA found were not thought to be high enough to endanger human health, the disruption of a recall is extremely costly and may leave patients without the medicines they rely on. This must be avoided, where possible.

NMR spectroscopy is an indispensable tool in the detection and quantification of impurities. The analytical technique enables the direct observation of chemical structures, providing detailed information about molecular structure and dynamic processes, including the determination of high resolution molecular structures. At AMRI, the 600 MHz NMR spectrometer is employed, which is equipped with a cryogenic probe. It is highly sensitive and enables the analyses of small and large molecules, with the capability of detecting impurities as low as 0.01 percent.

Bench to bedside

The pharmaceutical and biotechnology industries are routinely breaking new ground as cutting-edge techniques and leaps in medical understanding influence innovation. Products need to be as safe as they are effective. Any delay in proving these credentials to regulators can prove extremely costly.

That’s why drug developers are increasingly turning to expert organizations like AMRI, to pool collaborative problem-solving teams with leading technology and focused expertise, to expedite the journey from candidate selection to market approval.