FDA updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products

The FDA has recently updated its information on possible mitigation strategies to reduce the risk of nitrosamine drug-substance related impurities in drug products (NDSRIs).

Guidance for industry on nitrosamine was published in September 2020 and updated in February 2021. A summary is provided in the table below.

September 2020Guidance for industry published
This was to to help ensure the safety of the U.S. drug supply by recommending steps manufacturers of active pharmaceutical ingredients (API) and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products.
The guidance also described conditions that may introduce nitrosamine impurities and described a three-step mitigation strategy. 
February 2021The September 2020 Guidance for industry was updated.
It specifies timeframes for completion of nitrosamine mitigation activities by drug manufacturers. The strategy includes:
Step 1 – risk assessment
Step 2 – confirmatory testing if risks are identified
Step 3 – reporting changes implemented to prevent or reduce the presence of nitrosamine impurities in drug products in approved and pending new drug applications (NDAs) and abbreviated new drug applications (ANDAs)
31 March 2021Step 1 – risk assessment to have been completed by this date.
1 October 2023Steps 2 and 3 to be completed by this date.
Nitrosamine drug substance-related impurities (NDSRIs) – What they are, when they are generated and possible root cause of formation

FDA has recently received additional reports of certain types of nitrosamine impurities that formed in several drug products.

  • These nitrosamine drug substance-related impurities (NDSRIs) are a class of nitrosamines sharing structural similarity to the API.
  • NDSRIs can be generated during manufacturing or during the shelf-life storage period of the drug product.
  • In some cases, the root cause of NDSRI formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts.
  • Nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs in certain drug products. 
Does the FDA expect manufacturers to ascertain the presenence of NDSRIs?

Yes it does.

FDA expects manufacturers to ascertain the presence of nitrosamines, including NDSRIs, using the three-step mitigation strategy described in the agency’s guidance.

As manufacturers should now be engaged in the confirmatory testing and reporting changes stages of their mitigation activities (steps 2 and 3), if NDSRIs are detected in the drug product at objectionable levels, FDA encourages applicants to develop control strategies and/or design approaches to reduce NDSRIs to acceptable levels. 

Some mitigation strategies detailed in the FDA guidance for industry, to reduce NDSRIs to acceptable levels

Possible mitigation strategies provided in the guidance for industry include the following:

  • a supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and excipient lots to reduce the risk of nitrosamine formation in the drug product
  • derived from literature reports, this strategy concerns the use of commonly used antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) to inhibit the formation of nitrosamines in vivo based upon data from human gastric fluid in vitro studies. Recent work has employed this concept in formulation design and has preliminarily demonstrated that the addition of antioxidants to formulations may significantly inhibit the formation of NDSRIs in drug products.
  • Another possible approach is based upon the fact that the formation of nitrosamines typically occurs under acidic conditions, whereas, in a neutral or basic environment, the kinetics of these reactions are significantly reduced. Thus, formulation designs that incorporate excipients such as sodium carbonate that modify the micro-environment to neutral or basic pH, should in principle inhibit the formation of NDSRIs.  Manufacturers should determine the potential benefit from and demonstrate the suitability of any reformulation approach. 

FDA encourages manufacturers to consider the above as well as other innovative strategies to reduce the formation of NDSRIs to acceptable levels in drug products.

  • FDA will consider meeting requests, as appropriate, to discuss innovative mitigation strategies with prospective applicants or manufacturers
  • Applicants may also choose to submit formulation changes through supplements or amendments to their applications without scheduling a meeting with FDA
  • Any manufacturer, including non-application drug manufacturers, may implement any formulation changes in accordance with appropriate current good manufacturing practice regulations and related guidance.

FDA recommends that applicants or manufacturers interested in meeting with them, to prepare a comprehensive meeting package with the appropriate regulatory and scientific data using the above or other novel approaches to reduce the risk of nitrosamine impurities in drug products in accordance with existing guidance. Guidance on the meeting request/package to be submitted for an application is provided at the link below.

Source: FDA website