Tolerability of Risk: A commentary on the nitrosamine contamination issue.

Abstract For decades, regulators have grappled with different approaches to address the issue of control of impurities. Safety-based limits, such as permissible daily exposure (PDE), acceptable intake (AI), threshold of toxicological concern (TTC) and less than lifetime limits (LTL) have all been used. For many years these safety-based limits have been recognized as virtually safe doses (VSDs). Recently, however, many regulatory agencies are seeking to impose limits for N-nitrosamine impurities, which are significantly below the VSD. This commentary will discuss the evolution of safety-based limits for impurities, provide an overview of the valsartan N-nitrosamine contamination issue and review the toxicology of N-nitrosamines. The outcome of a lessons-learned exercise on sartan medications undertaken by the European Medicines Agency (EMA) will also be discussed. The review will also highlight the many analytical challenges inherent with controlling impurities to ppb-based limits. The use of highly sensitive, low ppb limits, methods may lead to future issues of batch rejection, based on false positives. Regulators initially viewed the N-nitrosamine risk as being insufficient to prompt immediate product discontinuation and patients were specifically advised to continue using their affected medication. Patients were also informed that exposure to N-nitrosamines is extremely common via food and drinking water.