United for safety - Navigating innovation with nitrosamine risks

The pharmaceutical industry stands at the intersection of balancing science and innovation leading to therapeutic and commercial success with patient safety. Questions related to PFAS, microparticles/microplastics, synthetic colour and TiO₂ use, EG and DEC adulteration, supply chain security, and medicine shortages continue to have the attention of regulators globally. Among the issues affecting medicinal product manufacturers, nitrosamine impurities in medicinal products stand alone as having a unique focus for medicinal product manufacturers and regulatory authorities due to their inherent risk to patient health and safety. Since their discovery in several widely used medications in 2018, regulatory agencies worldwide have intensified scrutiny, leading to hundreds of product recalls and a re-evaluation of formulation practices.

Nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) have been detected in numerous drug products, prompting more than 1800 recalled batches of drug products in the United States only since 2018 (Figure 1). These recalls have not only disrupted supply chains but also triggered litigation and reputational damage for manufacturers. While the focus has largely been on oral tablets, other delivery formats—such as topical, transdermal, and parenteral—also pose risks.  

(Source: https://onlinelibrary.wiley.com/doi/10.1002/ardp.202200484)

Given the identified pathways and known nitrosamine compounds that can form, it should be no surprise that some 220 or more APIs are suspected of potential nitrosamine risk (Table 1) when exposed to a nitrosating agent such as those listed above. 

Generally, risky APIs are those comprising a secondary or tertiary amine or an amide containing APIs at risk if the amide hydrolyzes, forming a secondary amine. Peroxides can contribute to nitrosamine formation, directly and indirectly. Peroxides can promote API degradation with the release of secondary amines, which are at risk. Such is the case with some amide groups leading to a secondary amine through peroxide hydrolysis. 

Both the FDA and EMA have established acceptable intake (AI) limits for nitrosamines based on carcinogenic potency. The FDA’s 2024 guidance outlines structural classifications of nitrosamine impurities and mandates risk assessments, confirmatory testing, and reformulation strategies where necessary. Similarly, the EMA’s Article 5(3) opinion requires marketing authorization holders to conduct a three-step review: risk evaluation, confirmatory testing, and updates to marketing authorizations (more detail in part two of this series).

Root causes of nitrosamine formation

Nitrosamines can form at various stages of drug production due to: 

These complexities make nitrosamine mitigation a multifaceted challenge requiring robust formulation strategies. 

Excipients, often overlooked, play a pivotal role in nitrosamine formation. Nitrites present in excipients can act as precursors to nitrosamines. Therefore, selecting low-nitrosamine grades of excipients is essential. Manufacturers must ensure excipients are sourced from suppliers who maintain low nitrite levels and implement control strategies to ensure consistency. Reformulating products with low-nitrosamine excipients or using them in the first place in the case of potential API is becoming a regulatory must. Working with a reliable partner for robust quality control across the supply chain is pivotal. 

The widespread recalls due to nitrosamine contamination underscore the urgent need for proactive formulation strategies. Regulatory agencies have set clear expectations, and the pharmaceutical industry must respond. Incorporating low-nitrosamine grades of excipients is not merely a compliance measure—it is a strategic imperative to safeguard patient health, ensure regulatory approval, avoid rejects and maintain brand integrity.

IMCD collaborates with several leading manufacturers to offer excipients that are tested for low levels of nitrosamines and nitrites, helping pharmaceutical companies meet stringent regulatory requirements. Bring us your formulation challenge — we’ll craft the perfect excipient solution for you.