67 TWENTYFOURSEVENBIOPHARMA Issue 1 / March 2026 DIPHARMA nitrosamine risk assessment and control. The FDA, for example, issued its first formal guidance in 2020, following the 2018 valsartan incident. “What began as an urgent response to isolated findings has developed into a comprehensive, globally coordinated framework,” said Dr. Fanelli. “EMA, FDA, Health Canada, PMDA, EDQM, and other authorities have progressively refined expectations on risk evaluation, confirmatory testing, and acceptable intake limits. The introduction of structured guidance for both traditional nitrosamines and NDSRIs has provided much-needed clarity, but the landscape continues to evolve as new scientific evidence emerges.” In addition to these early guidances, Dr. Fanelli noted that regulators have continued to refine their expectations over time. For instance, he highlighted the widespread adoption of the Carcinogenic Potency Categorisation Approach (CPCA), a methodology used to assign acceptable intake limits to NDSRIs lacking direct toxicological data. However, while Fanelli noted that although regulatory framework is robust and continually evolving, issues are nonetheless present. “Despite these advances, several challenges remain,” said Dr. Fanelli. “Global harmonisation is still incomplete: thresholds, expectations, and timelines differ between regions, and companies operating internationally must navigate a mosaic of requirements. Another complexity concerns degradation-driven nitrosamines, which may form not during synthesis but during storage, often due to excipient interactions or packaging components. These mechanisms are still being investigated, and they require a degree of scientific insight that goes beyond standard analytical practice.” Risk evaluation and mitigation Dipharma has worked to develop advanced methodologies and approaches to preventing, detecting, and addressing nitrosamine impurities. This approach is predicated on a proactive approach that incorporates nitrosamine risk evaluation during route design and feasibility studies, before any sort of detection. “At Dipharma, we understood early that this was not an episodic event but a structural change in regulatory expectations,” said Dr. Fanelli. “We chose to invest proactively in scientific, analytical, and process capabilities because nitrosamine control aligns closely with our core strengths: chemical process understanding, rigorous analytical development, and a commitment to patient safety.” The company’s risk assessment protocol incorporates a risk matrix that divides APIs into three levels: high, moderate, and negligible risk. Placement in the model is based on an evaluation of all APIs and manufacturing processes, including the starting materials and their impurities, reagents and catalysts used in the process, solvents employed, and equipment used. A high-risk detection triggers a multidisciplinary scientific investigation: analytical confirmation, chemical interpretation, and process-level mitigation. APIs deemed a moderate risk require a controlled assessment and potential process refinements, while APIs with negligible risk require no further mitigation outside of GMP compliance. “When mitigation is needed, solutions are tailored to the specific chemistry of the process,” added Dr. Fanelli. “This may involve substituting vulnerable reagents, optimizing reaction conditions, or applying targeted denitrosation treatments. The goal is not just to meet regulatory limits but to build a robust process that minimizes risk over the long term.” Dipharma is capable of determining nitrosamines at levels as low as 0.8 ppb, which is significantly lower than some of the strictest regulatory thresholds. (A company whitepaper notes that in an “extreme case” of a product with a daily dose of 3.2 g/day, the NDEA limit is 8.3 ppb.) Additionally, when commercial reference standards are unavailable, the company can synthesize them internally, ensuring identification via retention time, fragmentation pattern, and isotopic profile comparison. “Companies choose Dipharma because we offer a combination of scientific depth and operational reliability that is essential in navigating nitrosamine challenges,” said Dr. Fanelli. “Our value lies not only in identifying or excluding impurities, but in helping partners understand the underlying mechanisms and define solutions that are both scientifically robust and industrially feasible.” The 15N-NMR approach for nitrosamine risk assessment In addition to other risk assessment methods, Dipharma recently published a paper in the Organic Process Research & Development publication concerning the company’s 15N-NMR Approach (15NMR), which combines the nitrosation assay procedure (NAP) test with 15N-NMR spectroscopy. This technique is designed to address limitations researchers found with traditional
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