Analytical controls for oligonucleotide developers in an evolving technology and regulatory landscape

We recently spoke to Rachel Orr, Senior Scientist at GlaxoSmithKline R&D, about oligonucleotide analytical controls in an evolving technology and regulatory landscape.

What key analytical challenges do oligonucleotide developers need to overcome in order to achieve regulatory approval?

'Oligonucleotides are inherently difficult to analyze - they are neither traditional, small nor large molecules, and the techniques and well established methodologies for pharmaceutical analysis are all focused on these distinct classes. In addition, there is very limited regulatory guidance when it comes to oligonucleotides, so there are no set rules to follow. There are often discussions as to whether oligonucleotide analysis should follow small molecule rules and regulations or align with biopharmaceuticals; opinions are divided.

With limited experience across the industry in marketing applications it is difficult to assess what is needed in order to gain regulatory approval and this is one of the biggest challenges in CMC oligonucleotide development. There is no recent precedence of global oligonucleotide marketing applications and as such it is difficult to ascertain what may and may not be acceptable. Close engagement with the regulators is something which helps to form strategies and controls and hopefully this will increase the likelihood of success of regulatory approvals going forwards.'

How have advancements in technology improved the analytical process? Can you provide examples?

'Since the last successful oligonucleotide marketing application there have been considerable enhancements in technologies. UHPLC is now common throughout the industry and techniques such as high resolution NMR and mass spectrometry are much more affordable and quick. These advances in technology mean that the resolution and robustness of methodologies can be much improved, however has a downside that the regulators may well expect us to present them with these improvements by first intent.

Increased understanding of non "typical" molecules throughout the industry has enabled wider thinking and collaboration between different pharmaceutical companies, with more people working together on the problem progress will inevitably come quicker. As more people engage with the concept of oligos and as technology continues to evolve, I anticipate a large shift in the way we look to control oligonucleotides analytically in coming years.'

What are the most common mistakes that oligonucleotide drug developers encounter during CMC submissions?

'Again, due to there being so few oligonucleotides which have gone through the full CMC process I think it is difficult to make too many sweeping statements, however the key issues that I have come across all stem from attempting to fit oligonucleotides into a box. Whether it is the small molecule group or the biopharmaceutical groups who take on the challenge of oligonucleotides, it is generally only a few "experts" within that team who work on the molecules.

It is impossible to fit existing small or large molecule platforms onto oligonucleotides and a lot of time, resources and money can be wasted trying to do so! Due to the small pool of people working on the oligo projects it can also be challenging when it comes to elements such as wider reviews of submissions as the reviewers are not always as well informed about the challenges associated with oligonucleotide analysis. Education of these reviewers and key stakeholders is an activity that cannot be underestimated in time or importance! This emphasizes the benefits of cross-pharmaceutical company collaborations.'