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Impurities in Active Pharmaceutical Ingredients: Limiting Potential Carcinogenic Risk

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Register for our webinar now to learn more about relevant analytical methodologies for characterization of mutagenic impurities in APIs

10 Jun 2019
Finn Price
Administrator / Office Personnel

Expert insights

Impurities in an API can significantly affect stability, efficacy, and patient safety. Recently, hundreds of lots of Angiotensin II Receptor drugs have been recalled due to the presence of high potency mutagenic impurities (nitrosamines) found in these products as a result of a manufacturing process change. Guidance for the control of mutagenic impurities in pharmaceuticals has been provided by ICH in M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.

Analysis of mutagenic impurities is challenging due to the very high toxicity of these compounds which then requires very low detection limits for quantitative methods (parts per billion). This also places a much higher burden on the analytical screening methods required to identify unexpected or unknown mutagenic impurities in pharmaceutical products as screening at low levels requires high instrument sensitivity and low background noise. In addition, limitations on the commercial availability of impurity standards can require alternative quantitation strategies including relative quantitation versus a surrogate standard. This has the potential to adversely affect quantitative accuracy.

In our upcoming webinar on June 25, Dr. Mark Jordi, President of Jordi Labs, will explore the regulations covering mutagenic impurities. He will also review relevant analytical methodologies for characterization of mutagenic impurities through the lens of a case study showing the synthesis of amino-drug intermediates prepared via the reduction of aromatic nitro groups to the corresponding amines.

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Reduction of nitro groups to amines has been reported to result in the formation of nitroso and hydroxyamine impurities. The resulting amino-drug intermediates were characterized using Quadrupole Time-of-Flight Liquid Chromatography-Mass Spectrometry (QTOF-LCMS) to identify potential mutagenic impurities. This process was facilitated using differential analysis software to identify low-level impurities. Preparative fraction collection was used for isolation of individual impurities allowing for further structure confirmation by NMR and FTIR and toxicological review of the resulting structures was used to asses potential safety concerns. A comparison of the response factors for structural analogs containing nitroso, hydroxyamine, amino and nitro groups was performed as a means to determine the accuracy of relative quantitation as this approach is commonly used due to the lack of commercially available standards of these impurities. Quantitative methods for the nitrosamine impurities were developed and validated using triple quadrupole liquid chromatography-mass spectrometry (QqQ-LCMS).

In particular, you will learn about:

  • Understanding regulatory expectations for impurities in drug substance and product with an emphasis on mutagenic impurities
  • Impurities specification requirements based on ICH Q3 and M7 guidelines
  • Approaches for identification, isolation and structure confirmation of low-level impurities

The live webinar will take place on Tuesday, June 25, 2019, at:

  • 16:00 BST
  • 11:00 EDT
  • 08:00 PDT
  • 17:00 CEST

Scheduling conflict? No matter, register to receive an on-demand link to watch later>>

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Infrared / IR SpectroscopyInfrared (IR) spectroscopy measures the interaction of infrared light with a sample, including transmission, reflectance & absorbance, facilitating the identification of analytes. Equipment used for quantitative analysis includes Fourier-transform infrared (FTIR) spectrometers, infrared cameras, FTIR gas analyzers, as well as attenuated total reflectance (ATR) accessories and pellet or film presses. Find the best IR spectroscopy products in our peer-reviewed product directory: compare products, check customer reviews and receive pricing direct from manufacturers.LC-MSLC-MS (liquid chromatography-mass spectrometry) systems and equipment are used for separation and quantitative analysis of complex mixtures, combining liquid chromatography and mass spectrometry. Quantify proteins, contaminants, pesticides or screen for drug metabolites with a high level of sensitivity. LC-MS systems and equipment include reverse phase, normal phase and specialized columns integrated with various MS detectors such as time-of-flight (TOF), quadrupole, orbitrap or ion trap mass analyzers. LC-MS/MS instruments equipped with a qTOF or triple quadrupole analyzer give greater sensitivity and resolving power to your analysis. Find the best LC-MS equipment in our peer-reviewed product directory: compare products, check customer reviews and receive pricing direct from manufacturers.NMR and EPR SpectroscopyNuclear magnetic resonance (NMR) spectroscopy is used to resolve the local chemical environment of atomic nuclei with spin, revealing information on molecular structure, dynamic processes and chemical reactions of organic molecules, from proteins to synthetics. Electron paramagnetic resonance (EPR) also known as electron spin resonance (ESR) spectroscopy is used to detect and quantify paramagnetic species in a sample, including free radicals as transition metal ions. By immersing the sample in a strong magnetic field, both NMR and EPR spectrometers probe the sample with either radio waves or microwaves respectively. A range of benchtop, solid-state and time domain NMR spectrometers & EPR spectrometers are available, as well as NMR tubes, NMR solvents, software, coils, and magnets. Find the best NMR & EPR equipment in our peer-reviewed product directory: compare products, check customer reviews and receive pricing direct from manufacturers.Process ChemistryProcess chemistry is an important stage of drug development for scaling-up drug production or chemical synthesis reactions. It is useful for optimizing economical and efficient drug production. Process chemistry uses reactors and pump systems as well as reagents, standards and buffers.RegulatoryPharmaceutical regulations impact on all areas of drug development, manufacture and control and supply. Services are provided from the early stages of drug development and clinical trials through to dossier submission, approval and marketing. Regulatory also includes submission of analytical studies from the pharmaceutical product and safety. Active PharmaceuticalsThe Active Pharmaceutical Ingredient (API) of a drug is the component that causes the direct effect of the product. The remaining inactive components are known as excipients.Triple Quadrupole MsMutagenesisPharmaceuticalsPharmaceuticals are medicinal drugs used in healthcare to diagnose, prevent, cure and treat illnesses. Pharmaceuticals that are excreted after use appear in wastewater and can have detrimental effects on the environment.CarcinogensInfraredManufacturingManufacturing is the production of merchandise for use or sale using labor and machines, tools, chemical and biological processing, or formulation.LC-MSLiquid Chromatography-Mass Spectrometry (LCMS) is a powerful analytical technique that combines the separation power of liquid chromatography with the detection capabilities of mass spectrometry. It is widely used for qualitative and quantitative analysis of complex mixtures in pharmaceuticals, proteomics, and environmental studies. Browse our peer-reviewed product directory to find the best LCMS systems, compare products, check reviews, and get pricing directly from manufacturers.

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