FDA sets acceptable intake limits for Nitrosamines in pharmaceuticals

USA — In a pivotal move, the US Food and Drug Administration (FDA) has taken the reins of pharmaceutical safety to new heights.

A final guidance, hot off the press last Friday, has unfurled a comprehensive framework designed to predict the mutagenic and carcinogenic risks associated with nitrosamine drug substance-related impurities (NDSRIs).

Not stopping there, the FDA has also set forth recommended acceptable intake (AI) limits for these compounds when detected in drug products and active pharmaceutical ingredients (APIs).

This directive isn’t just a bureaucratic memo; it’s a call to action for manufacturers of approved products.

The FDA is urging them to embark on an intensive evaluation of NDSRI risks within a mere three months from the final guidance’s publication.

The clock is ticking, with a definitive deadline set for November 1, 2023, by which these assessments should be fully realized. But this is merely the first step on a carefully plotted roadmap.

By August 1, 2025, another benchmark looms. Manufacturers and applicants are tasked with ensuring that any lurking NDSRIs within their drug products align with the FDA-recommended AI limit, a threshold carefully calculated to curtail carcinogenic potency.

This is a substantial stride forward in an industry that is just emerging from the shadows of the Valsartan debacle and more recent cases of Nitroso STG-19 19 (NTTP) detection in diabetes medication Januvia.

A major turning point in the saga was the worldwide alarm triggered by the discovery of novel nitrosamine impurities in valsartan and other angiotensin II receptor blocker (ARB) drugs in 2018.

This sent regulators across the globe into a frenzy, initiating an industry-wide scramble to address these potentially hazardous impurities.

Interestingly, this new guidance goes beyond the FDA’s prior endeavor, the February 2020 directive on nitrosamine control and testing, which notably omitted coverage of NDSRIs. This deficiency has now been rectified through this comprehensive framework.

Limited data to inform safety assessments

The FDA’s pursuit of stakeholder input on nitrosamine testing earlier this year is a testament to its commitment to a collective approach in handling these challenges.

It acknowledges the dearth of compound-specific data essential for NDSRI safety assessments, underscoring the impetus for this robust guidance.

This uncertainty has had ripple effects, prompting manufacturers to conduct unnecessary studies or even withdraw products from the market – leading to supply disruptions and, in some grim scenarios, drug shortages.

Such crises impede patient access to crucial medications, especially those deemed medically indispensable.

With an unmistakable resolve, the guidance lays out a meticulous three-step strategy for manufacturers and applicants to gauge the presence of NDSRIs. In essence, it mirrors the framework set in the 2020 nitrosamine testing guidance.

The first stride necessitates a thorough risk assessment of nitrosamines within APIs and drug products. Following this, a confirmation test is required if potential risks come to light.

Guidance sets AI limits

Crucially, the FDA introduces a groundbreaking methodology for setting acceptable intake (AI) limits, predicated on a predicted carcinogenic potency categorization.

Built upon the principles of the International Council on Harmonisation’s M7(R2) guideline, this approach employs structure-activity relationship (SAR) concepts to classify the mutagenic and carcinogenic risk of impurities.

Central to this methodology is the AI limit – a value designed to reflect an incremental cancer risk of one additional case in 100,000 individuals, given a conservative estimate of daily exposure to the impurity over a lifetime of 70 years.

The guidance shows the gamut of predicted carcinogenic potency categories and their corresponding AI limits, spanning from 26.5 ng/day to 1500 ng/day.

Never one to shy away from details, the guidance also boasts a user-friendly flowchart, engineered to predict the carcinogenic potency category of an NDSRI and, subsequently, prescribe an AI limit. Yet, as robust as this guidance is, it doesn’t operate in isolation.

FDA’s watchful eye extends to the market. It mandates that any drug product or API exceeding these set thresholds should not find its way onto shelves.

However, a prudent approach is adopted, with the FDA reserving the right to exercise enforcement discretion when circumstances warrant, particularly to avert or mitigate drug shortages.

As a parting note, the agency introduces a new online resource – a webpage designed to host current recommended acceptable intake limits for select NDSRIs that may be at risk of formation in human drugs.

For all the latest healthcare industry news from Africa and the World, subscribe to our NEWSLETTER, and YouTube Channel, follow us on Twitter and LinkedIn, and like us on Facebook.