Nitrosamine Impurities in Medicines – Ph. Eur. Requirements and the Role of the CEP

Since 2018, nitrosamine impurities have become a critical concern for the pharmaceutical industry and regulatory authorities. Nitrosamines are considered potentially carcinogenic, and their presence in medicines must be controlled to the lowest acceptable levels. High-profile recalls, stricter regulations, and new international guidelines have significantly reshaped pharmaceutical quality control strategies.

European Pharmacopoeia (Ph. Eur.) Guidance on Nitrosamines
The European Pharmacopoeia (Ph. Eur.) has implemented dedicated chapters to support manufacturers in detecting and controlling nitrosamine impurities:

• Ph. Eur. 2.5.42 “Nitrosamines in active substances”: Provides validated analytical methods for detecting nitrosamines in active pharmaceutical ingredients (APIs) at trace levels.
• Ph. Eur. 2.2.46 “Gas Chromatography” and 2.2.29 “Liquid Chromatography”: Fundamental chapters describing chromatographic techniques commonly used in nitrosamine testing.
• General monographs: Define the requirement that APIs and finished pharmaceutical products must be free of unacceptable impurities, including nitrosamines.

These chapters form the foundation for compliance and reliable nitrosamine analysis within pharma QC laboratories.

The Role of the CEP (Certificate of Suitability)
The Certificate of Suitability (CEP), issued by the EDQM, is a cornerstone in regulatory submissions. In relation to nitrosamine contamination, the CEP has taken on increased importance:

CEP holders must conduct a risk assessment to evaluate possible nitrosamine formation or contamination across the API manufacturing process (solvents, reagents, catalysts, or raw materials).
Where risks exist, control strategies and validated methods must be integrated into the CEP dossier.
The EDQM has revised or conditioned many CEPs to ensure that nitrosamine risk assessments are robust and transparent.
This makes the CEP not only a regulatory document but also a tool for harmonized quality and safety across Europe’s pharmaceutical supply chain.

Global authorities, including EMA, ICH, and FDA, continue to strengthen requirements for nitrosamine risk assessments and testing. Manufacturers should prepare by:

Performing early-stage nitrosamine risk assessments throughout development and production.
Implementing robust nitrosamine testing methods based on Ph. Eur. guidelines.
Maintaining transparent communication with regulators on process changes or unexpected impurity findings.

The challenge of nitrosamines remains at the forefront of drug safety and regulatory compliance. Meeting these expectations requires a strong combination of analytical expertise, regulatory knowledge, and proactive quality control strategies.