A Few Good Questions From Last Week's 'Genotoxic Impurities' Webinar

By Harley Everett Wilcox, MBA
www.abclabs.com

I recently conducted a webinar on Genotoxic Impurities and during the course of the webinar, there were a number of good questions that I had the opportunity to answer. Here are a few of them…

“Describe the earliest – in terms of development phase – that you have seen potential Genotoxic issues. What were the options explored for solving those issues?”

The earliest I recall – referring back to an introduced Genotoxin  - was in the second step of five step synthesis. In terms of how it was handled - certainly, you could do the fate Analysis to see “what happens” to this particular entity. Within this process, we have purification steps and we’re going to monitor this throughout the entire synthesis so that it would hopefully be virtually non-existent in the last stages of the API. From an earliest-step scenario, we’re able to tell if we have a know structure of concern.

“What is the best way to determine initial indications that Genotoxicity might be an issue that needs to be explored?”

The best way to discover issues is to anticipate them by establishing a solid plan early on. You get your team together and say “let’s do a risk assessment”. It may be that you have a solvent that may be a problem, or a reagent that may cause issues. It’s during these early planning sessions that you would determine different levels of risk assessment as you proceed forward through the development of the drug. This level of early-stage planning becomes increasingly more important, because risk mitigation gets more resource dependent as you go along.

“Are there any differences in how regulations are applied to semi-synthetic (i.e., complex profile APIs) vs typical APIs?”

Once you move beyond the actual natural product (for instance, an extraction from the bark of a yew tree – where it has not been modified from the original natural product) to the place where you have modified a product with a synthetic step, I believe the agencies would look at that particular modified product as a new chemical entity, meaning that their standard set of assessments would be applicable. But if your compound is an oncology compound that is known to interact with DNA, then the whole Genotoxic argument becomes less relevant.

For more questions and answers from last week’s ABC webinar, please visit ABC’s website to view the entire presentation which can be streamed from their Resources page here:

http://www.abclabs.com/resources_webinars_2015-01_GenotoxinsInPharma-HowLowShouldYouGo.html