Nitrosamine Impurities: The Need to Verify

Waters Staff

Reading Time: 3 minutes

The recent nitrosamine impurity crisis has brought into question the quality of many APIs (Active Pharmaceutical Ingredients) produced and sourced for a number of popular drugs, resulting in product recalls, lost profits, and regulatory actions. Within a drug manufacturing process that is increasingly outsourced and globalized, companies manufacturing the API or in-sourcing the API or other raw materials, must be concerned about identifying and monitoring known genotoxic impurities (GTIs) or potentially mutagenic impurities (PMIs). It is now even more critical to do more than just trust the quality of materials, but proactively verify them as well.

This is the approach currently required by regulatory authorities for nitrosamines, not just for the growing number of products and impurities immediately implicated, but for all possibly contaminated drugs and processes in a drug manufacturer’s portfolio. The EMA (European Medicines Agency), like the US FDA, has issued interim guidance on temporary detection levels for NDMA and NDEA in ARBs (Angiotensin II Receptor Blockers) based on daily dosage, but will require lower detection levels of 0.03 ppm by early 2021. Reliable methods with suitable sensitivity and specificity have been challenging to develop, due to differences in volatility and polarity of these impurities. To meet proposed global regulatory requirements for nitrosamines, the most sensitive LC-MS/MS instrumentation available is needed to ensure there are no detectable levels in the final product.

Which analytical solutions can reach sensitivity requirements for nitrosamine impurities? Can these platforms be easily implemented in environments where data compliance is required?

For nitrosamine analyses that require the highest sensitivity to meet FDA and EMA regulatory requirements:

  • ACQUITY UPLC I-Class PLUS / Xevo TQ-XS Tandem Quadrupole Mass Spectrometer with MassLynx Security Software
    • The ACQUITY UPLC HSS T3 Column is a highly reproducible reversed-phase C18 column chemistry capable of separating polar and non-polar analytes in a single run. An ideal choice for the separation of polar nitrosamine compounds.
    • The ACQUITY UPLC I-Class PLUS System affords high resolution and sensitivity using industry-leading ultra-low dispersion and delay volume.
    • The Xevo TQ-XS Tandem Quadrupole Mass Spectrometer, with the StepWave XS ion guide, is ideal for robust, high sensitivity quantification.
    • The IonSABRE APCI Probe ionization technique is appropriate for a range of nitrosamines, and Waters MS instruments are outfitted with a universal source design, making it easy to switch from one ionization source to another.
    • MassLynx Security with TargetLynx is the compliant-ready quantification mass spectrometry software that enables these high-sensitivity capabilities in a regulated environment.

For routine testing when the highest sensitivity is not required:

  • ACQUITY Arc UHPLC / PDA / QDa with Empower Software
    • The ACQUITY UPLC HSS T3 Column is a highly reproducible reversed-phase C18 column chemistry capable of separating polar and non-polar analytes in a single run. An ideal choice for the separation of polar nitrosamine compounds.
    • The ACQUITY Arc System is a quaternary-based LC system with the ability to easily switch between HPLC and UHPLC; it is fully compatible with optical detectors and the ACQUITY QDa Mass Detector to support routine analysis.
    • The 2998 Photodiode Array (PDA) Detector offers advanced optical detection, wide linear dynamic range, and unique lamp optimization for trace impurity detection and quantification in conjunction with Peak Purity spectral analysis capabilities to identify coeluting impurities.
    • The ACQUITY QDa Mass Detector for mass identification and confirmation.
    • Empower is the leading compliant-ready chromatography data software, with built in automated impurity quantification and reporting based on ICH guidelines, and is easily deployable in routine analysis testing environments.

Waters supports the analytical chemist at all phases of impurity analysis, through application expertise and fit-for-purpose technologies. Learn more at waters.com.

Learn more about the efforts to regulate and control for nitrosamines:

Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.
FDA Updates on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)
What has Zantac recall cost drugmakers?
FDA Updates and Press Announcements on NDMA in Zantac (ranitidine)
HSA Recalls Three out of 46 Metformin Medicines
EMA advises companies on steps to take to avoid nitrosamines in human medicines
Ad-hoc projects of the OMCL Network

The Current Concerns About Genotoxic Impurities Found in Commonly Used Prescription and Over The Counter Pharmaceutical Drugs