In this blog, Camille Pierres, Senior Expert at the Altran World Class Center dedicated to Compliance and Performance in Life Sciences, answers critical questions to help life sciences companies understand and fulfill on time the nitrosamines regulatory requirements.
1. What are nitrosamines?
Nitrosamine compounds are potent genotoxic agents in several animal species and some are classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC).
2. Nitrosamine impurities have been in the regulatory spotlight, but what is the background?
In September 2019, following the detection of unexpected nitrosamine impurities in sartans—a class of medicines known as angiotensin II receptor blockers used to treat high blood pressure and heart failure—and other drugs, the European Medicines Agency (EMA) and other regulatory authorities requested all marketing authorization holders (MAHs) to perform a risk analysis for the potential presence of nitrosamines. EMA has requested pharmaceutical companies to complete their reports by March 31, 2021, for chemical drug products and July 1, 2021, for biological drug products.
3. What is the impact on the pharmaceutical industry?
Due to the tight deadlines and broad scope—basically, all marketed drug products—many pharmaceutical companies are finding it challenging to produce the nitrosamine risk assessments by the EMA’s deadline. In addition to the risk analysis complexity, many stakeholders need to be involved in the process, including makers of active pharmaceutical ingredients (APIs), excipients, primary packaging manufacturers and drug product manufacturers. On-time compliance with the EMA requires companies to quickly hire skilled staff to cope with the volume of work needed to perform the risk assessments.
4. What do manufacturers need to do?
Drug product manufacturers or MAHs, in collaboration with their contract manufacturers, are required to conduct risk assessments of all their marketed drug products, chemicals and biologicals. Initially not considered a risk, EMA has included biological products in the scope.
The mandatory nitrosamines assessment is a worldwide regulatory initiative impacting both the European and North American markets. The US Food and Drug Administration (FDA) recently published a guidance recommending drug product manufacturers conduct a risk assessment of approved or marketed products within six months of the September 1, 2020 publication data of the guidance.
5. How to perform the risk evaluation?
Drug product manufacturers and MAHs should evaluate the risk of contamination or formation of nitrosamines at each step in the manufacturing process based on the information provided by APIs, excipients and primary packaging manufacturers.
Risk assessment is just the first step in the process. Once the assessments are concluded, confirmatory testing should be conducted for the drug products that have been identified as at-risk. If the presence of nitrosamines impurities is confirmed, manufacturers must take appropriate actions to reduce and mitigate nitrosamine impurities in drugs. Confirmation of impurities will lead to changes in the marketing authorization dossier, which should be submitted to the authorities for approbation before September 26, 2022, for chemicals and July 1, 2023, for biologicals to the EMA and September 2, 2023, to the FDA.
6. Due to the short deadlines and the broad scope of impacted products, conducting a robust nitrosamine risk assessment required by the authorities is becoming a nightmare for many manufacturers. How can they succeed?
The clock is ticking. But if manufacturers define the right approach and adopt a robust methodology, they can succeed in their nitrosamine risk assessment. Recently, Altran worked with the largest European pharmaceutical group to perform and review risk assessments for a portfolio of 750 drug products. Thanks to a dedicated team of experts and consultants that included 11 full-time employees, Altran provided technical support on the nitrosamine topic and full-time project management to ensure the project’s completion within nine months.
 H. Robles, in Encyclopedia of Toxicology (Third Edition), 2014