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The pharmaceutical industry’s journey with nitrosamines has been one of the most significant quality challenges in recent memory.
What started as isolated contamination findings has evolved into a full-blown, global regulatory focus, pushing companies to rethink how they assess and control risks in both legacy and new products.
As regulations continue to tighten, a recent real-world case provides valuable lessons on how to move from simply meeting deadlines to truly managing risk. Here's what we’ve learned from turning regulation into practice.
The Regulatory Landscape Keeps Moving
Since the first nitrosamine impurity was discovered in Valsartan in June 2018, regulatory agencies like the EMA, FDA, and PMDA have issued detailed guidance and expectations.
What began as targeted recalls soon evolved into a broad, global initiative, marked by EMA's September 2020 publication of a three-step risk assessment framework. Companies were required to complete initial risk evaluations by March 2021, with confirmatory testing and regulatory action deadlines following in October 2023.
Risk assessments were initially rushed to meet early deadlines, but regulators are now looking for deeper, more dynamic risk management.
Today, it’s clear: completing a one-time assessment isn’t enough. Regulators expect companies to update and refine their evaluations as new information, testing methods, and scientific understanding emerge.
Takeaway: Regulations are a moving target — static risk assessments are no longer enough.
Early Risk Assessments Were Just the Beginning
Many companies initially performed high-level evaluations based on limited data — often focusing only on the most commonly known nitrosamines such as NDMA, NDEA, EIPNA (NEIPA), DIPNA (NDIPA), NMBA, MeNP, NDBA, and NMPA — and many concluded "no risk" without a full understanding of manufacturing processes, degradation pathways, or supplier inputs.
Real cases show that surface-level assessments often miss hidden risks. In some instances, subsequent deep dives uncovered unexpected nitrosamines, especially complex species like NDSRIs (Nitrosamine Drug Substance-Related Impurities).
Thorough knowledge of manufacturing processes, reagents, and potential degradation is essential to identify hidden vulnerabilities.
Takeaway: A ‘no risk’ conclusion is meaningless without process deep-dives.
Collaboration Is Critical for Nitrosamine Control
In the early stages of regulatory scrutiny, one of the biggest roadblocks was the limited cooperation from raw material suppliers. Many were either unaware of nitrosamine-related risks or reluctant to share detailed manufacturing information and risk assessments. This lack of transparency significantly delayed evaluations and hindered effective risk mitigation.
Fortunately, this dynamic has improved. As awareness has grown and regulatory expectations have become clearer, suppliers and third-party manufacturers are increasingly proactive and collaborative — providing more comprehensive documentation and engaging in joint efforts to assess and control nitrosamine risk.
Managing nitrosamines is not a "quality team only" job. Real success stories consistently show strong cross-functional collaboration between:
Companies that treated nitrosamine risk as a shared ownership issue moved faster, communicated better with authorities, and avoided costly surprises.
Takeaway: Nitrosamine control is a team sport — success depends on cross-functional and supplier collaboration.
Testing Complexities: Expect the Unexpected
Developing ultra-sensitive analytical methods for nitrosamines has been a major challenge. Testing often reveals unexpected species, especially when considering long-term product storage or minor impurities reacting under specific conditions.
In the real-world case discussed, targeted testing under stressed conditions uncovered a low-level nitrosamine that had gone undetected in initial screening. This finding triggered a revision of the risk assessment and proactive regulatory updates, demonstrating the value of stress testing and broad analytical approaches early.
Additional challenges, such as matrix effects, interferences, and artefact formation — especially in the presence of nitrites—have highlighted the need for careful method development.
In some cases, nitrosamines can form during analysis itself, requiring preventive strategies and extremely low detection limits to meet regulatory expectations.
Takeaway: Broad, stress-based analytical testing uncovers risks that standard screening can miss.
Regulators Expect Dynamic Risk Management
One clear message from recent regulatory interactions: risk assessments must live and breathe. Changes in suppliers, manufacturing scale, formulation tweaks… all of these can potentially impact nitrosamine risk. Authorities now expect:
Regulators have also reminded marketing authorization holders and applicants of their obligation to ensure that medicinal products are manufactured and controlled using methods that reflect the current state of scientific and technical progress. Waiting for "perfect" data before communicating can backfire. Transparency and early engagement with regulators build trust and flexibility.
Takeaway: Treat risk assessments as living documents, not one-off reports.
Learning the Hard Way: Action Beats Perfection
In some instances, companies that waited too long to act, hoping to resolve uncertainties before engaging with regulators, ended up facing recalls, market disruptions, or regulatory enforcement.
The most effective strategy? Adopt a risk-based approach:
This mindset shift from perfection to proactive risk management aligns with current regulatory expectations and helps ensure continued patient safety and product availability.
Takeaway: When in doubt, act — waiting can cost markets, money, and trust.
Future-Proofing Nitrosamine Control in Development
Perhaps the biggest takeaway from recent cases is the need to design out risk early.
Leading companies are now:
By embedding nitrosamine control into the DNA of product development, companies can avoid costly surprises later.
Takeaway: The cheapest nitrosamine to control is the one you never create.
Conclusion
The nitrosamines crisis has reshaped pharmaceutical quality management — from emergency response to long-term strategy.
The real-world lessons are clear:
Turning regulation into practice isn’t just about compliance — it’s about protecting patients, protecting products, and protecting trust.
At QbD Group, we help companies move from compliance to confidence — embedding nitrosamine control into product lifecycles so you can protect patients, products, and trust.
If you’d like expert support with your nitrosamine strategy, contact our team today to discuss your needs.
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