August 31, 2022

Olu Aloba, Vice President, CMC Services
Marianthi Karakatsani, Director, Regulatory Affairs CMC

Nitrosamines in pharmaceuticals have been of special concern since their presence at unacceptable levels in popular medicines was highlighted in 2018.¹ Since then, improved understanding of their chemistry has enhanced the risk assessments, testing, and mitigation steps required to help minimize nitrosamine contamination in drug substances, excipients, and drug products. In addition, regulatory authorities have largely harmonized requirements and allowable limits in their respective regions. This article will briefly discuss the background to contamination of pharmaceuticals with nitrosamines and review current regulatory requirements for risk assessment, testing and mitigation, and monitoring of materials to control the presence of nitrosamine contaminants.

Introduction

N-nitrosamines, or nitrosamines, have been in the news and of concern ever since their presence at unacceptable levels in popular medicines was highlighted in 2018. Since then, developments in process chemistry, analytical technology, and regulatory guidances have shaped the current nitrosamine state of play. Specifically,

• Improved understanding of process and reaction chemistry has enhanced the risk assessments required to help prevent introduction of nitrosamines into the manufacturing process and to detect potential nitrosamine sources;
• Analytical methodologies for detecting and quantitating nitrosamines have been improved by use of simpler sample preparation techniques and methods with higher sensitivity and specificity and lower limits of quantitation; and
• Allowable nitrosamines limits and timelines for required action by marketing authorization holders and sponsors as well as pharmaceutical manufacturers have largely been harmonized among different regulatory authorities (see table in Regulatory Resources section).

Although various regulatory authorities have listed requirements and recommendations within their respective issued documents, these requirements are mostly similar and well aligned. Therefore, this article will focus primarily on the requirements and considerations in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines.

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Regulatory Focus, August 2022. © Regulatory Affairs Professionals Society