Today, the FDA issued a new immediately effective guidance entitled “Control of Nitrosamine Impurities in Human Drugs” that replaces the initial guidance by the same name that was issued on February 24, 2021. The new guidance can be found here.

The industry has been awaiting the issuance of this revised guidance and the “FDA made the determination to issue the guidance [as immediately effective] because of the importance of providing timely information to manufacturers and applicants regarding nitrosamine impurities, and the resulting recommendations to conduct risk assessments, testing, and other appropriate actions to prevent or reduce the presence of nitrosamine impurities, including NDSRIs, in APIs and drug products.” Of course, the FDA will accept comments to the guidance even though the Agency has made the guidance immediately effective.

There is a companion Federal Register Notice (here) that announces the availability of the guidance. It includes a description of the changes from the 2021 guidance and provides additional information about the document.

“The guidance describes two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API), and nitrosamine drug substance-related impurities (NDSRIs), which share structural similarity to the API and are generally unique to each API.” The guidance provides sufficient advice on how to approach the nitrosamine impurity issue in NDAs and ANDAs.

The guidance is broken down into the following major sections:

  • Nitrosamine impurities and Root Causes of Formation – which addresses both small molecule nitrosamines, as well as nitrosamine drug substance-related impurities (NDSRIs).
  • Recommendations for Control and Mitigation of Nitrosamines in APIs and Drug Products – which includes acceptable intake limits, and various mitigations strategies.
  • Implementation of Acceptable Intake Limits – which includes assessment of test results, recommended timetable for implementing risk assessment, confirmatory testing, and submission of required changes for nitrosamines, as well as requires submission classification types based on the changes required.

In addition, the guidance provides advice for maintaining the drug supply and how the FDA will “work with manufacturers and applicants to mitigate the risk of nitrosamine impurities in APIs and drug products to avoid interruptions in the drug supply.”

If you need further assistance with nitrosamine impurity issues, please contact Lachman Consultants at www.Lachmanconsultants.com/contact.