FDA Considers Changing Its Nitrosamine Targets as Global Focus Continues

We need to talk about nitrosamines.  Recent industry comments submitted to FDA and new, international efforts against these nefarious, potentially carcinogenic organic compounds have the shifting state of regulation here back in the news.

What are nitrosamines?

Nitrosamines are chemicals that can form during drug manufacturing, known by their scientific names as N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).  N-nitrosamine drug substance-related impurities (NDSRIs) are a pernicious form of nitrosamines that possess structural similarity to active pharmaceutical ingredients (API).

In addition to human drugs, processed foods that contain nitrates and nitrites such as cured meats and alcoholic beverages may contain nitrosamines.  OTC products are also susceptible; testing has revealed nitrosamines in heartburn remedies containing ranitidine.

The evolving upswing in NDSRI regulation is due to their link to cancer.  According to several studies, nitrosamines are a potentially potent carcinogen, depending on the length and depth of exposure.

What is FDA doing about NDRSIs?

The canary in the coal mine for nitrosamines was their 2018 appearance in blood pressure medications called sartans.  That discovery set off a global response, that included a series of recalls, a number of FDA-issued guidances, public advisements, mitigation strategies, and warnings, and generally created the current regulatory focus that CDER Director Patricia Cavazzoni has recently called a priority for CDER.

Aside from its publications, FDA is continuing to investigate the presence of NDSRIs in drug products, which may lead to more inspections or, at least, heightened expectations for industry.  The Agency is trying to meet manufacturers a point where testing standards on how to identify and control NDSRIs become more standardized.  Yet, currently, how the Agency plans to handle nitrosamines is unclear, which has led to the delay in approval of many drugs with no path forward for many of these companies.

As FDA and industry continue to grow their respective understandings about NDSRIs, more of them are turning up.  In May, FDA published a Federal Register request for “collaborative efforts to develop NDSRI data,” and said that as companies are implementing risk assessments recommended in FDA’s 2020 Nitrosamine Guidance, the Agency has unsurprisingly “received an increasing number of reports of NDSRIs that had formed in drug products across multiple drug classes.”  And FDA has had numerous with meetings with individual stakeholders seeking a better understanding of their approach to nitrosamines.  Seek, and ye shall find, so FDA hopes.

Upcoming Deadlines and New International Guidances

Responses to the May 2023 request for comments were due to FDA in early July, as FDA originally hoped that industry would collectively detail its best practices by October 1, 2023.  However, discovering NDSRI-producing gaps in manufacture is so tricky, FDA is considering giving industry an extension on its homework project.  When asked in the Federal Register Notice if a one-year extension would be useful, the response was a resounding “yes!”  Respondents also asked FDA to align its standards to the emerging new guidances and ongoing global efforts to root out NDSRIs.  In addition to the FDA’s efforts, agencies in the E.U., Canada, Australia, and Malaysia have also recently updated their policies and recommendations.

The global search for nitrosamines is rapidly becoming a complex game of Three-Dimensional Chess, as international regulators try to work together to find solutions, walking hand-in-hand with the industry they must all oversee.  Meanwhile, manufacturers are on the hunt to find their quarry before their customers do it for them.  We’ll report back as this complex regulatory structure continues to take shape.