Genotoxic Impurity

All drug substance and drug product synthesis incorporate the use of chemicals, reagents, catalysts and solvents. In addition, drug substances and drug products may undergo degradation and produce impurities. Impurities that are present in drug substances follow ICH guideline Q3A (R2) and impurities that are present in drug products follow ICH Q3B (R2). These guidelines are helpful, however, they have limited guidance in regard to DNA reactive impurities.

DNA reactive impurities are genotoxic and will impact the purity, safety, and quality of drug substances and drug products. These genotoxic impurities have “alerting structures” such aflatoxin-like, N-nitroso, and alkyl-azoxy groups and can cause DNA mutations and cancer at very low concentrations. ICH guideline M7 (R2) “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” is a useful guideline that emphasizes safety and quality risk management and also establishes levels for mutagenic impurities that create low carcinogen risk and thus are acceptable.

ICH M7(R2) utilizes the Threshold of Toxicological Concern (TTC) to define the acceptable intake of any uncharacterized chemical that can possibly cause a risk of carcinogenicity or other toxicity. Acceptable TTC based intake of an impurity is 1.5 µg per person per day and generally this concentration can be used for most pharmaceutical products to derive an acceptable limit of control. In addition, an acceptable intake will depend upon different clinical scenarios to include treatment duration.

Understanding your impurities early in the drug development process will facilitate implementation of controls and monitoring. Primera Analytical Solutions works closely with our clients to understand their impurity risk assessment, conduct degradation studies and develop an analytical program that is both phase appropriate and cost effective. We have the ability to work from early phase development to commercialization of the product.

Primera’s approach to genotoxic impurity testing is comprehensive. We have positioned ourselves to be able to handle all genotoxic impurities to include highly potent and highly carcinogenic materials, such as Nitrosamines. Our high containment suite contains all necessary equipment to handle these materials. We maintain a highly trained staff and provide all necessary personal protective equipment to successfully complete a study.

Genotoxic impurity testing requires the use of state of the art instrumentation because low detection levels, ranging from single digit ppb to a few hundred ppm level based on a specific API and/or finished product. Primera utilizes a variety of instrumentation to conduct genotoxic impurity method development and perform phase appropriate validation:

High Pressure Liquid Chromatography with a variety of detectors to include UV/Vis, ELSD, RI, CAD, Fluorescence, and MALS.
Liquid Chromatography-Mass Spectroscopy (LC-MS, LC-MS/MS)
Liquid Chromatography- High Resolution Mass Spectroscopy (HRMS)
Gas Chromatography- Flame Ionization Detector (GC-FID)
Gas Chromatography – Mass Spectroscopy (GC-MS)
Inductively Coupled Plasma Mass Spectroscopy (ICP-MS)

Genotoxic Impurity

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