USP Nitrosamine Impurities Chapter Reflects Coordination With EU As Well US Agencies
Executive Summary
The USP’s general chapter on nitrosamine impurities provides guidance on assessing risks and testing levels of the carcinogens in pharmaceuticals.
US Pharmacopeia final guidance on checking pharmaceuticals for impurities from potentially carcinogenic nitrosamines reflects careful coordination with the Food and Drug Administration and the European Pharmacopoeia to help ensure regulatory convergence.
Nitrosamines can form very easily and in a variety of ways, because they are everywhere in our environment, said Ed Gump, vice president of the Small Molecules Department at USP, which made the guidance, identified as "General Chapter <1469>," on nitrosamine impurities official on 1 December.
The USP proposed the general chapter in September 2020. Concern about nitrosamine impurities emerged in 2018 after the discovery that some sartan medications were contaminated with nitrosamine compounds, which led to the discovery of nitrosamines in other types of medicines including a common OTC heartburn ingredient, ranitidine. (Also see "Perrigo Among Firms Requesting Delay In Conducting US Nitrosamine Risk Assessments" - HBW Insight, 15 Dec, 2020.)
Nitrosamines are considered carcinogens, some of which have been found to cause cancer in various species at low doses and short treatment durations.
The chapter lists potential sources of nitrosamines, such as solvents, water and excipients, as well as the observed risk from each source. It recommends that a risk assessment be performed to determine the materials that could contribute to the presence of nitrosamines in the drug product and provides guidance on developing a control strategy.
It also includes guidance for testing for the presence of the impurities, as well as reference standards for eight nitrosamines, including:
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Deutero N-Nitrosodimethylamine RS (NDMA-d6)
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N-Nitrosomethylphenylamine (NMPA)
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N-Nitrosodibutylamine (NDBA)
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N-Nitrosodimethylamine (NDMA)
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N-Nitrosodiethylamine (NDEA)
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N-Nitrosoethylisopropylamine (NEIPA)
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N-Nitrosodiisopropylamine (NDIPA)
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N-Nitrosomethylaminobutyric Acid (NMBA)
The chapter will help the pharmaceutical world perform appropriate risk assessments to make sure their products will be safe for patients, Gump said in an interview with the Pink Sheet.
The FDA published its guidance in September 2020 and updated it in February. (Also see "US FDA’s 30-Day Extension For Nitrosamine Assessments Short Of Industry Recommendation" - HBW Insight, 25 Feb, 2021.)
More recently, the FDA suggested drug formulation options intended to inhibit the development of nitrosamines. The options, called “mitigation strategies” in an update the agency published on 22 November, include adding antioxidants such as vitamin C or vitamin E, which are dietary ingredients, to the existing formulations for OTC and Rx drugs. (Also see "US FDA Suggests Adding Antioxidants To Drug Formulations To Mitigate Nitrosamine Risks" - HBW Insight, 22 Nov, 2021.)
How USP Chapter Compares With FDA Guidance
The USP didn't establish specific intake levels for nitrosamines because it wanted to make sure potential divergence between its chapter and guidance the FDA was developing didn't create “confusion and unnecessary conflicts,” Gump said.
Rather, USP provided guidance for how users could apply and interpret the FDA acceptable intake levels.
Section 8 in the USP chapter provides analytical procedures that have been validated by USP laboratories and the substance for which they have been validated, added Edmond Biba, a principal scientist at USP.
USP also wanted to allow for the possibility that manufacturers could have their own methodology that might be more appropriate for their products than USP’s methods.
The chapter adds that the procedures included are example procedures, and that users can use their own procedures or USP’s, as long as they prove that the testing method can assess nitrosamines at the level required, Biba said.
When USP published its initial draft for public comment on 1 September 2020 and FDA published guidance that same day, USP officials realized that FDA’s document contained one nitrosamine that theirs did not, N-nitrosomethylphenylamine (NMPA). (Also see "US FDA Expectations For Removing Nitrosamines From All APIs, Drug Products" - Pink Sheet, 1 Sep, 2020.)
“We did adjust for that, and include that in our final iteration of the chapter,” said Gump.
The list of nitrosamines is not exhaustive and will be updated as needed, added Biba.
The chapter also references the International Council on Harmonisation’s M7 guideline on assessment and control of mutagenic impurities, as well as the procedures that FDA and the European Medicines Agency use for establishing acceptable intake levels.
Standards Aim For Regulatory Convergence
In an unusual step, the USP reached out to the European Directorate for the Quality of Medicines as it developed the chapter. A government liaison from EDQM, in addition to the usual representation from the FDA, participated in the project The EDQM’s European Pharmacopoeia Department sets quality standards for medicines that are legally binding on EU member states.
“We wanted to make sure that we weren’t going to have anything in our chapter that would create disconnects or challenges for manufacturers or regulators who might use this around the world,” Gump said.
He said that from recent conversations with USP’s pharmacopeial partners, he's aware they've struggled around how much effort it takes to invest in regulatory convergence.
“It turns out that’s really difficult because each region has its own unique requirements,” but “one of the things we are trying to do is looking at trying to partner more with EDQM and other pharmacopeias to make our standards convergent,” he said.
Gump emphasized that while the USP has not done a lot of this type of coordination, “it’s something I personally think is important, and I’m trying to find ways to do more of that, at least as it’s practical, recognizing that the world is a challenging place and there aren’t unlimited resources.”
This article was reported and originally published by Informa Pharma Intelligence's Pink Sheet newsletter.