Evaluating Nitrosamines from Elastomers in Pharmaceutical Primary Packaging

Abstract

Abstract: Nitrosamines have gained unexpected attention again, triggered by their discovery at significant concentrations in some active pharmaceutical ingredients (APIs) excipients. Regulatory agencies not only expect the marketing authorization holders to include a nitrosamine risk assessment in their drug development process but to also apply it retrospectively on the marketed drug product. As part of this risk assessment, all possible sources of nitrosamines need to be evaluated. This review provides the chemical background of nitrosamines and elastomeric formulations, the current regulatory status in the pharmaceutical and other industries and discusses analytical challenges of nitrosamine measurement. This evaluation of elastomeric components as a potential nitrosamine source proposes how this information can be used in a drug product risk assessment. Lay abstract: Nitrosamines are a group of chemical substances that in many cases have been shown to be carcinogenic. They can form in many ways, from acidic conditions in the human stomach to high temperatures during food preparation. They are also known to be generated during beer brewing and smoking of cigarettes, and naturally exist in the air, soil and our water supply. In the past years, they have also been discovered as impurities in drug products. Extensive investigations have been initiated to find the root causes, whereby all possible sources are included. One of these sources are elastomers, since they are used as primary packaging components in syringe, cartridge and vial systems. This review provides the chemical background of nitrosamines and elastomeric formulations, the current regulatory status in the pharmaceutical and other industries and discusses analytical challenges of nitrosamine measurement. This evaluation of elastomeric components as a potential nitrosamine source proposes how this information can be used in a drug product risk assessment.