Since N-nitrosamine impurities were first detected in several high blood pressure medications, authorities have scrambled to remove the risk to patients. First, there was a recall of selected lots, then, in 2019, the European Medicines Agency announced that companies would be required to conduct a scientific evaluation on the presence of N-nitrosamine impurities in human medicines containing chemically synthesised active pharmaceutical ingredients (APIs).

Initially, the requirement was limited to chemical medicines, but the Committee for Medicinal Products for Human Use (CHMP) later widened the scope to include biologics. The procedure involves a three-step approach.

First, companies were required to carry out an evaluation to identify if APIs and/or finished products could be at risk of the presence of N-nitrosamines. The conclusions were to be reported to the authorities by no later than 31 March 2021 for chemically synthesised APIs, and by 1 July 2021 for products containing biological APIs.

If a risk is identified, step two requires companies to carry out confirmatory testing to confirm or refute the presence of N-nitrosamines. The agency has said MAHs should report the outcomes as soon as possible.

If the presence of N-nitrosamine(s) is confirmed, the third phase involves marketing authorisation holders (MAHs) informing authorities of their risk mitigation strategies and implementing effective risk mitigation controls through the submission of variations, or other regulatory pathways requested by the authority (for example, referrals). The third phase is to be completed no later than 26 September 2022 for products containing chemically synthesised APIs, and by 1 July 2023 for products containing biological APIs.

Keeping authorities informed

While the deadlines do allow companies time to conduct confirmatory testing and adopt risk measures, it is recommended that as companies work through each step they should share information with authorities as soon as they have results and not wait for the deadlines.

Based on the first assessment, companies are required to have appropriate control strategies to prevent or limit the presence of N-nitrosamine impurities and, where necessary, to improve their manufacturing processes. If there is a risk of N-nitrosamine impurities forming, companies will need to modify manufacturing processes to minimise the risk as much as possible. EMA has laid out some recommendations with regards to risk management approaches, and has offered different options for setting N-nitrosamine limits.

The authorities have also established specific limits for N-nitrosamine presence in finished products, calculated as the N-nitrosamine daily limit divided by the maximum daily dose of the preparation concerned. The limits established are:

  • 96 ng/day for NDMA
  • 5 ng/day for NDEA
  • 5 ng/day for EIPNA
  • 5 ng/day for DIPNA
  • 96 ng/day for NMBA
  • 5 ng/day for MeNP
  • 5 ng/day for NDBA
  • 3 ng/day for NMPA

The limits are only applicable if a finished product contains a single contaminating N-nitrosamine.

Limit values will no longer need to be assessed if it can be demonstrated that the N-nitrosamine content is permanently below 10% of the defined limit value and the root cause for the occurrence of the impurity is known and well understood. In addition, testing will no longer be required if the N-nitrosamine level is permanently below 30% of the defined limit value. Where several different N-nitrosamines are present, the theoretical excess cancer risk over a lifetime exposure must not exceed 1 in 100,000.

Challenges ahead for companies

While the vast majority of companies had completed the first step in time for the deadline, the second phase is more complicated because there are specific analytical methods that companies will need to use to test their products.

The Official Medicines Control Laboratories has established methods to determine various N-nitrosamines in sartans with a tetrazole ring, metformin and ranitidine, which can serve as a starting point for the development and validation of analytical methods for testing other APIs and finished products. Information on these methods is available on the European Directorate for the Quality of Medicines & HealthCare (EDQM) website.

With an experienced CMC team in place, ProductLife Group can manage every step for companies. Indeed, we have been helping several companies prepare their processes, including working with suppliers, API manufacturers, and finished product manufacturer to complete the initial risk assessment and submit it to the authorities.

For the complex second step, our quality assurance experts can handle full management of the process, helping to gather results and perform a risk assessment.

The challenges for companies managing their N-nitrosamine requirements are partly capacity, and partly specific knowledge of the processes required. To manage the risks, companies need to have a good understanding of their APIs and their manufacturing processes, as well as a strong relationship with their manufacturers. The priority, as with any regulatory, safety, or CMC issue, is to keep the product on the market and ensure the safety of patients.

More information on PLG website.

By Sandrine Doleans, CMC Platform Leader, ProductLife Group

Register to our news and events

Go to our Events to register
Go to our News to get insights

Nitrosamine Risk Assessment in the Spotlight as First Deadline Passes