Following the discovery of N-nitrosodimethylamine (NDMA), a probable human carcinogen, in Valsartan blood pressure medicines last year, the same nitrosamine has now been found to be present in the heartburn and stomach ulcer medicine Ranitidine. The European Medicines Agency (EMA) have therefore asked Market Authorisation Holders (MAHs) to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicines containing chemically synthesised active substances.
The EMA now requires that MAHs review all their medicines for the possible presence of nitrosamines and assess the need to potentially provide test data for all drug products considered to be at risk.
Currently, the FDA have not published such a guidance but have confirmed that NDMA has also been identified in Nizatidine, another common H2 blocker, used in the treatment of peptic ulcer and gastroesophageal reflux disease.
Drug Development Solutions' Impurity & Contamination Centre of Excellence specialises in the analysis of low level organic and inorganic species using a variety of highly specialised techniques including LC-MS/MS, GC-MS and ICP-MS.
The team have extensive experience concerning the analysis of a full range of different nitrosamines in APIs, tablets, creams, and solutions using LC-MS/MS methods validated in accordance with the latest ICH Q2 guidelines.
LC-MS/MS is especially suited to the analysis of nitrosamines as most are not readily analyzable using alternative detection techniques. Nitrosamines vary greatly in volatility and most importantly need to be determined at very low levels. LC-MS/MS using a triple quadrupole mass analyser operating in multiple reaction monitoring (MRM) mode, provides the best combination of sensitivity and selectivity.
At LGC we work with you to determine the best course of action for your product. For most formulation types a limit test at an agreed Target Analytical Level (ideally set lower than the limits suggested by FDA and EMA) is generally considered to be the best approach, however where required fully validated quantitative methods can be developed.
As all APIs and formulations are different, each with their own challenges, we recommend that a short method development exercise is included as part of the analysis package. This ensures the LOD, specificity, accuracy and precision are acceptable and confirms that our methods are suitable for your specific product formulation.