Potential cancer-causing agents turning up in drugs has been a major headache for the pharma industry. But some trade groups are balking at new rules for monitoring the chemicals, arguing that they could lead to shortages of crucial drugs.
The FDA needs to change its new approach to tracking nitrosamine, three trade groups recently told the agency. Nitrosamine was the culprit in Pfizer's Chantix recall this week, as well as numerous others around the world in recent years.
The FDA should work with other global regulators to set similar rules, adopt better testing strategies and limit testing to drugs at the highest risk of contamination, the industry groups said at a recent meeting with the agency, which was first reported by Endpoints News.
Current nitrosamine testing is expensive and can often lead to false positives, while the timelines for companies to assess risk and complete testing are "too short," the trade groups Pharmaceutical Research and Manufacturers of America (PhRMA), the Association for Accessible Medicines (AAM) and the Consumer Healthcare Products Association (CHPA) said, as summarized in a meeting memorandum.
Those challenges could ultimately delay the release of medicines and cause shortages, the groups warned.
Nitrosamines, which are everywhere in nature, can increase the risk of cancer if a person is exposed to high levels over time. Over the past few years, the nitrosamine N-Nitrosodimethylamine (NDMA) triggered high-profile, worldwide recalls of blood pressure drugs and the diabetes medication metformin. Regulators across the globe have responded by asking companies to monitor for impurities that can crop up in certain drugs.
As for the possibility of nitrosamine-fueled shortages, look no further than Pfizer's smoking-cessation drug Chantix. The drug was recently recalled after Pfizer's testing flagged unacceptable levels of the nitrosamine N-nitroso-varenicline. With Chantix now in shortage, the FDA is allowing Apotex to ship doses of its Chantix generic from Canada.
Many of the industry groups' complaints come down to consistency. The FDA's nitrosamine strategy isn't aligned with international standards set out in the industry guidance known as ICH M7, they said. Specifically, not all nitrosamine acceptable intake levels are set to the M7 standards.
The "FDA uses a more conservative approach," the groups said in the memorandum.
Meanwhile, the FDA's guidance allows different dose forms with the same active ingredient to have divergent AI levels, while many nitrosamines linked to complex drugs are missing AIs altogether.
Impurity testing itself is expensive and can yield false positives, the groups said. To cut back on testing, they suggested regulators set nitrosamine AIs for drugs with insufficient toxicity data.
Regulators should also limit their focus to drugs that present the highest risk and use the length of time a patient takes a given drug to calculate allowed levels of nitrosamine inputs, the groups argue.
During a question and answer portion of the meeting, the FDA said it "can work with manufacturers to mitigate the risk of nitrosamine impurities ... while avoiding interruptions by taking into account FDA’s determination of the need for the product and impact on drug supply."
The regulator says it has previously allowed companies hit with nitrosamine concerns to continue distributing batches "to alleviate a shortage," noting that it aims to weigh the benefits against risks for each potentially contaminated product on a "case-by-case basis."
"The biopharmaceutical industry supports broader global adoption of uniform standards through the International Council of Harmonisation to help ensure that the latest science about nitrosamines will guide decisions worldwide," Andrew Powaleny, senior director of public affairs at PhRMA, said in an emailed statement. The industry puts patient safety first when developing or making drugs, he said, which includes "taking immediate action" when potential impurities crop up.
In the case of Chantix, the FDA said it would allow certain manufacturers to temporarily distribute varenicline tablets with N-nitroso-varenicline above the FDA's acceptable intake limit of 37 ng per day but below an interim limit of 185 ng a day "until the impurity can be eliminated or reduced to acceptable levels." Verenicline is the generic name for Chantix.
Editor's note: This story has been updated with additional comments from PhRMA.