risk assessment nitrosamine impurities

The execution of Risk Assessment for Nitrosamine Impurities is still a hot topic, and it’s not going to cool down any time soon.

Back in June 2018, a Chinese API manufacturer notified EU authorities that N-nitrosamines were identified in a batch of valsartan.

Nitrosamines are a genotoxic and carcinogenic agent in animals and is classified as a Class 2A carcinogen to humans.

And since then, testing has identified different Nitrosamines (NDMA, NDEA and others) in almost every high-volume drug product containing a sartan derivative or ranitidine and metformin products. And this at levels well above the acceptable daily intake limits.

Failed risk assessment

At this stage, research and analysis companies have identified the Continuous Process Improvement changes (such as Patent # WO/2011/124655) as the root cause for the amounts of NDMA. That and, of course, a failure at Risk Assessment level.

The consequences weren’t simple:

  • The unintentional product contamination administrated to patients throughout several years;
  • One of the largest product recalls in recent history;
  • An impact in brand and generic products alike;
  • A reminder to us all that lean manufacturing efficiency changes without the implementation of a proper quality system can adversely affect the patient;
  • The realization that there was a lack of proper risk assessment of nitrosamine impurities.

Meeting Regulator Expectations

Regulators, such as the FDA and EMA, expect that manufacturers of APIs and drug products take steps to prevent higher levels or eliminate N-nitrosamines.

EMA recommends the following steps:

  1. Perform Risk Assessment in APIs, marketed products, and products under application processes within the following deadlines:
    1. For chemical medicines, the FDA and EMA deadline has been extended to 31 March 2021.
    2. For biological medicines, the EMA requires the risk evaluation must be completed by 01 July 2021.
  2. Confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross-)contamination and report confirmed presence as soon as possible.
  3. Update FDA or EMA marketing authorizations:
    1. For chemical medicines, this stage should be completed by 26 September 2022.
    2. For biological medicines, the EMA marketing authorization should be completed by 01 July 2023.

We took a deeper look at the topic of how to cope with regulatory guidelines in a White Paper we published last month. You can obtain it from here:

Assessing the risks

When it comes to perform nitrosamine risk assessment, you should start by looking at the possible root sources such as:

  • Drug substance;
  • Excipients;
  • Packaging components;
  • Solvents;
  • Processing aids and their route of synthesis;
  • Manufacturing processes;
  • Interactions;
  • Process;
  • Degradation and its derivatives;
  • Cleaning process.

It’s important to identify the controls in place that can eliminate the risk of introducing nitrosamine impurities.

And from there you should move on to evaluate the different risk factors like the following examples:

  • Are nitrites (NO2-), nitrous acid, nitrates (NO3-), nitric acid, or azides (N3-) or their sources present in any excipients or processing aids?
  • Are secondary or tertiary amine contaminants present in any primary amines used in your manufacturing process?
  • Is there a potential for nitrosamine impurity formation during the finished product manufacturing, through degradation and by-products?

Keep in mind that these are just examples, the list of risk factors is quite extensive and should also include GMP quality system controls, engineering controls and manufacturing controls.

What should you do?

The systematic risk assessment described in ICH Q9 must include now the Risk Assessment of Nitrosamine Impurities. Regulators will include the newly developed nitrosamine risk assessment as part of the documents impacted by upcoming changes.

This is also a living topic. As new knowledge is being built along the way by the different stakeholders, companies may expect more information and/or requirements to be announced.

If you need to tackle nitrosamines in your process, we recommend the following steps:

iRISK™ QRM platform
  1. Start acting as soon as possible to cope with FDA and EMA’s deadlines;
  2. Seek a well-structured and solid QRM platform and proven QRM expertise;
  3. Adopt a structured risk management approach based on state-of-the-art tools. This approach should allow lifecycle management oversight;
  4. Document the adopted risk evaluation approach and the risk evaluation outcome, as well as data generated during confirmatory testing (if applicable).

What if you don’t know where to start?

There’s still time until the Biologic medicine deadline. 4TE has solid expertise with Quality Risk Management Optimisation and we deliver it through one of the best QRM platforms.

We recommend that you check our QRM Process Optimisation Services. If you think we may be able to help you out, don’t hesitate to book a call, we’ll do our absolute best to help.

Related topics

If QRM is a topic of interest to you, we recommend you checkout this article of ours: QRM over Lifecycle Management.