Trends and Challenges in Nitrosamine Testing: Part Four – The Regulatory Landscape

Can you give me an overview of the regulatory environment for nitrosamines?
 

Kevin Parker: Regulators around the world such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have issued guidelines and limits around the control of n-nitrosamines in drug products. These often include guidelines and regulations concerning testing and detection of n-nitrosamines, determination of acceptable limits, reporting and recalling pharmaceutical products and issuing guidance documents on how to control for n-nitrosamines. 

Jingyue Yang: International regulatory agencies have actively collaborated to address nitrosamine impurities in pharmaceutical products since the issue first emerged. Various workshops and training sessions have been held by regulatory authorities to explain policies, as well as to gather insights and feedback from stakeholders. In a relatively short period, multiple agencies have released guidance documents. Over the past four years, the FDA has issued and revised guidance documents for industries reflecting the latest developments. Overall, regulatory agencies worldwide view nitrosamine impurities as a significant quality and safety concern and have dedicated substantial resources to developing proactive regulatory strategies as a result.

Alan Thompson: Agreed, Jingyue. Procedure EMA/369136/2020 (Procedure under Article 5(3) of Regulation EC (No) 726/2004 Nitrosamine impurities in human medicinal products, issued on June 2020) by the EMA gives an in-depth overview on all aspects of nitrosamines; from root cause of nitrosamine formation through to considerations for the development of quantitative methods, and calculation risk for exposed patients in case of detection of N-Nitrosamines in medicinal products. Further to this, EMA/409815/2020 Rev.16 (issued in July 2023) details questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. This includes an update to the limits which apply for nitrosamines in medicinal products.

Recommended Acceptable Intake (AI) Limits for NDSRIs, issued by the FDA in August 2023 contains a useful flowchart which can be used to predict the carcinogenic potency of an NDSRI, and subsequently identify an associated recommended AI limit and potency category. The calculation of AI assumes a daily administration of the maximum daily dose of the medicinal product, and is based on the approach outlined in the ICH M7(R1) guideline in addition to the principles related to the toxicological evaluation in the assessment report of the CHMP’s Article 5(3) opinion on nitrosamine impurities in human medicinal products.

Jessica Hoskins: At this point in time, I’d sum up the regulatory environment as continually evolving. As the analytical experts in the lab, we must be familiar with the regulatory environment and work closely with other areas of the organization to make sure we are developing methods to appropriately assess the risk of nitrosamine formation. As a large company focused on product quality and safety for patients, we have internal resources to help us keep up to date with the changing regulatory environment. USP’s Nitrosamines Exchange forum is also a good resource as a scientist to keep up with the latest developments. 

Naiffer Romero: Agreed, and as the regulatory landscape and guidelines continue to evolve, several key changes have emerged to address nitrosamine impurities. In accordance with regulatory guidelines, pharmaceutical companies now perform risk assessments for chemically synthesized drug products to identify potential nitrosamine impurities. This necessitates the prioritizing of investigations into nitrosamine risks through comprehensive risk assessments for all the components and processes involved in the manufacturing of a drug product. If a risk is identified, companies should develop and validate sensitive and specific methods for nitrosamine analysis in accordance with regulatory guidelines to confirm their presence and potentially report levels exceeding the limit of quantitation (LOQ). Supplier qualification has become critical, helping to ensure that raw material and excipient suppliers have appropriate controls to minimize nitrosamine risks. Robust change control procedures must be implemented to evaluate the impact of any changes on nitrosamine risk. Regulatory agencies have also established acceptable intake (AI) limits for common nitrosamines or provided interim limits when necessary, as others have mentioned. 

Any advice for ensuring compliance with nitrosamine regulations?
 

Jingyue Yang:  The FDA's publication of the RAIL Guidance (Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)) in August  2023 and the Nitrosamine Guidance (Control of Nitrosamine Impurities in Human Drugs) (updated in September 2024) have provided significant clarity regarding the recommended acceptable intake limits for various nitrosamines (see here). These guidelines enable the evaluation of recommended acceptable intake limits for a wide range of nitrosamines, offering clear benchmarks for method sensitivity requirements.  

Where provided, manufacturers are encouraged to adopt FDA recommended AI limits. For products marketed in the US, however, alternative approaches can be used if they satisfy the requirements of the applicable statutes and regulations. 

In part five, our gurus return to discuss future directions for nitrosamine analysis and regulation within the pharmaceutical industry

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