NDSRI Impurity Analysis in Pharmaceuticals: FDA & EMA Regulatory Requirements

Introduction: Why NDSRI Impurity Analysis Method for Pharmaceuticals Matters Today

The detection and control of Nitrosamine Drug Substance-Related Impurities (NDSRIs) has emerged as a critical requirement for pharmaceutical manufacturers globally. Regulatory agencies like the FDA and EMA have issued stringent guidelines for controlling these genotoxic impurities. The NDSRI Impurity Analysis method for Pharmaceuticals has thus become a regulatory expectation, driving innovation in analytical chemistry and lab services.

At ResolveMass Laboratories Inc., we support drug developers and manufacturers with cutting-edge NDSRI Impurity Analysis methods tailored to meet evolving global regulatory expectations. This blog explores the current FDA and EMA regulatory requirements, validated testing approaches, and real-world strategies for compliance and risk mitigation.

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What Are NDSRI Impurities and Why Are They a Concern?

Nitrosamine Drug Substance-Related Impurities (NDSRIs) are a class of probable human carcinogens that can form during the manufacturing of drug substances, especially those containing secondary or tertiary amines. Examples include NDMA, NDEA, NMBA, and others.

These impurities may arise from:

• Reaction of amines with nitrosating agents
• Use of contaminated raw materials
• Specific process conditions like pH and temperature

Due to their genotoxic potential, both the FDA and EMA have classified nitrosamines as Class 1 impurities requiring control below acceptable intake limits (typically ~26.5 ng/day for NDMA).

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NDSRI Impurity Analysis Method for Pharmaceuticals: Core Techniques

1. LC-MS/MS Based NDSRI Detection

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) is one of the most sensitive methods for NDSRI impurity analysis. It offers:

• Detection in the low ppb range
• High specificity for co-eluting peaks
• Easy validation under ICH Q2 (R2) guidelines

Explore our LC-MS/MS workflow at NMR Analysis for Peptides

2. GC-MS for Volatile NDSRIs

For volatile nitrosamines, Gas Chromatography coupled with Mass Spectrometry (GC-MS) is preferred. ResolveMass’s advanced GC-MS methods:

• Comply with USP <467> & ICH M7 guidelines
• Offer fast turnaround time
• Suitable for both drug substance and excipients

More GC-MS aligned impurity insights at NMR for Small Molecules

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FDA Regulatory Requirements on NDSRI Impurity Analysis Method for Pharmaceuticals

The U.S. FDA recommends a three-step mitigation approach:

1. Risk Assessment

Companies must evaluate the risk of nitrosamine formation or presence in all marketed products. This includes assessing:

• Starting materials
• Manufacturing process
• Storage conditions

2. Confirmatory Testing

Risk-positive products must undergo confirmatory testing using validated NDSRI impurity analysis methods. FDA guidance recommends using LC-MS/MS or GC-MS.

3. Mitigation Strategy

If NDSRIs are detected above limits, sponsors must:

• Submit control strategy in NDA/ANDA
• Implement process changes
• Conduct toxicological evaluations

Explore regulatory updates and validated testing at Nitrosamine Analysis

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EMA Regulatory Requirements for NDSRI Impurities

The European Medicines Agency requires MAHs to:

• Submit risk assessments by set deadlines
• Adopt strict daily exposure limits (e.g., 18 ng/day for NDEA)
• Use Structure Activity Relationship (SAR) tools for prediction
• Submit variations for risk-mitigated products

EU regulators also accept control strategies that include testing, process optimization, and specification changes.

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Case Study: NDSRI Detection in an API with Tertiary Amine Structure

Client: A generic drug company manufacturing antihypertensive tablets
Challenge: NDMA detected at 65 ng/day (exceeding ICH limits)
Approach:

• Performed LC-MS/MS testing using validated ResolveMass method
• Identified root cause: degradation of secondary amine excipient during drying
• Suggested alternate excipient and dry vacuum granulation process
• Re-tested: NDMA below 10 ng/day, within regulatory limit
  Outcome: Risk resolved. ANDA amendment approved within 3 months.

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NDSRI Impurity Analysis Method for Pharmaceuticals: How ResolveMass Excels

ResolveMass Laboratories Inc. leverages its deep analytical chemistry expertise to provide:

• ICH-validated methods (LC-MS/MS, GC-MS, HRMS)
• Dedicated nitrosamine analysis team with regulatory experience
• Structural elucidation using NMR Spectroscopy for Peptides and Small Molecule NMR
• Expert consultation on mitigation strategies

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Benefits of Partnering with ResolveMass Laboratories

• Custom analytical method development
• Rapid sample turnaround
• Regulatory support for USFDA/EMA submissions
• Cross-platform testing validation (LC-MS/MS, GC-MS, NMR)

📞 Connect with our scientific team: Contact ResolveMass

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Conclusion: Ensuring Compliance with NDSRI Impurity Analysis Method for Pharmaceuticals

In the current regulatory landscape, the NDSRI impurity analysis method for pharmaceuticals has become non-negotiable. As agencies intensify control on nitrosamines, it’s essential to adopt reliable, sensitive, and validated analytical methods.

ResolveMass Laboratories Inc. is committed to support pharmaceutical manufacturers with precise, rapid, and impurity testing—backed by deep scientific knowledge, regulatory alignment, and advanced infrastructure.

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📚 References:

1. EMA. (2023). Nitrosamine impurities in human medicines. Retrieved from
   https://www.ema.europa.eu/en/human-regulatory/research-development/nitrosamine-impurities
2. U.S. FDA. (2024). Control of Nitrosamine Impurities in Human Drugs.
   https://www.fda.gov/media/141720/download