Latest Updates on Nitrosamine Impurities Testing

In an exclusive interview with Thiruamuthan, Assistant Editor at India Pharma Outlook, Amit Chopra, CEO – South Asia and Middle East, Cotecna Inspection, discusses how FDA and EMA have intensified nitrosamine scrutiny, and explains why it has become one of the most consequential pressure tests for modern pharma — reshaping how companies design, test, and govern medicines long before a tablet ever reaches a patient. Amit Chopra is a seasoned business leader with deep experience in strategy, M&A, and innovation across technology-led sectors. He has driven significant growth at Thermo Fisher Scientific, holds IICA accreditation as an Independent Director, and is known for his focus on inclusive leadership and strong operational excellence.

Regulators worldwide have heightened nitrosamine scrutiny in medicines. How is this shift impacting the current testing framework across Indian and global manufacturing facilities?

Regulatory authorities internationally, including the FDA, EMA, and USP, now require thorough and defined risk assessment, confirmation testing, and stringent ongoing control strategies, especially for evaluations of NDSRIs. These expectations have tightened method validation parameters and strengthened release testing requirements across all dosage forms. In turn, manufacturing and testing facilities serving regulated markets in India are upgrading their analytical, document control, and risk management processes in response to these regulatory authorities. This is necessary to achieve timely product approvals in order to maintain continued access to the global market and to meet the expectations of collaboration partners.

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Nitrosamines such as NTTP and NDBA are under stricter oversight. In what ways are LC-MS/MS and GC-MS improving detection sensitivity and reliability?

As highlighted in USP <1469>, advanced LC-MS/MS and GC-MS/MS analytical workflows will identify nitrosamines with extreme sensitivity, in most cases achieving sub-parts-per-billion (sub-ppb) values. These methods incorporate isotope labelled internal standards to help correct for matrix effects in order to determine quantitation, as well as orthogonal confirmation techniques, which additionally provide evidence of analyte identity. Hence, the combination of these approaches will provide very reliable and reproducible nitrosamine detection in drug products. Because of its reliability, precision and regulatory acceptance, LC-MS/MS and GC-MS/MS workflows have materialized as the global standard for nitrosamine testing, making it easier to adhere to ever-tougher safety regulations.

Low detection thresholds often clash with matrix interferences and limited reference standards. How are manufacturers practically overcoming these barriers in routine testing?

Manufacturers respond to these analytical and regulatory challenges by utilizing matrix-matched calibration, which recognizes interferences that may be unique to the sample type, and by employing stable-isotope internal standards to improve accuracy and precision. Selective sample cleanup methods are used to remove potential contaminants to minimize background noise, while the use of orthogonal confirmatory methodology is used to verify the identity of analytes. In instances where sufficient authentic reference standards are not available or scarce, validated surrogate standards, with scientifically justified response factors can be used for reliable quantitation. These approaches are well accepted and accepted by regulatory agencies worldwide and produce consistent, reproducible, and compliant testing of various pharmaceutical matrices.

Rising testing volumes are straining laboratory turnaround times and costs. How are Indian labs balancing operational efficiency with strict regulatory compliance requirements?

Accredited laboratories that are NABL or ISO-17025 certified are enhancing their capabilities by establishing dedicated laboratories to solely conduct nitrosamine testing. Testing procedures are conducted using standardized methods that comply with USP, providing consistent and validated procedures for all samples tested, along with risk-based triaging to determine high-risk batches and effectively test samples consecutively and efficiently from a testing perspective. In parallel, laboratories will document their methods and retain records that will facilitate an audit to be completed in anticipation of an audit. Together, this creates the capability for timely reporting of results, while being fully compliant with regulatory expectations and ready for an inspection by a global authority like the FDA or EMA.

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Pharma companies in India are modifying synthesis routes, expanding validations, and conducting risk assessments. How effective are these strategies in achieving global nitrosamine compliance?

Reformulated synthetic strategies removing nitrite and amine starting materials, in conjunction with enhanced cleaning procedures and broader method validation, have significantly reduced nitrosamine formation and nitrosamine risk in pharmaceuticals. Regulatory agencies accept these proactive control measures to be effective risk mitigation controls. Organizations that utilize a solid corrective action plan (CAPA), have ongoing monitoring, and conduct regular risk assessments have proven to manage nitrosamine risks effectively. These systematic methods give these organizations the ability to sustain ongoing international regulatory compliance and product safety and quality as they operate globally.

Predictive toxicology models and AI-enabled testing platforms are advancing rapidly. How might these innovations redefine nitrosamine detection and risk assessment over the next decade?

Regulatory authorities are increasingly incorporating computational approaches to manage nitrosamine risks. Under ICH M7 guidelines, QSAR and SAR models are already being applied to predict mutagenic potential and support risk assessments. At the same time, the FDA is testing tools based on artificial intelligence to predict nitrosamine potency for a more accurate assessment of chemical hazards. Over the next ten years, the use of predictive toxicology and AI-enabled platforms will create a significant paradigm shift - one that could lead to better, quicker, and more accurate regulatory assessments of chemical hazards. Some of the ways these advances could impact regulatory activities include the potential for refinement of acceptable dose limits, prioritization of testing, and acceleration of regulatory decisions without compromising product safety.