Modern advances in pharmacology have resulted in positive benefits for patients fighting disease, including increased life expectancy and reduced suffering from disease symptoms. Many of us, our family members, friends, and loved ones have come to rely on modern medicines. Therefore, it is paramount that prescribed drugs have the desired therapeutic efficacy, without fear of harmful side effects from impurities.
During pharmaceutical manufacturing, it is critical that containers for drug products not release any chemicals that can build up and create the risk of toxicity or impact the stability or efficacy of the drug.
In this blog post, we explore different types of impurities and the analytical solutions that can help detect them before they reach the final drug product, thus ensuring safety and stability.
Extractables and leachables
Extractables and leachables (E&L) are examples of impurities that can affect drug stability and toxicity. A drug container-closure system should not release chemicals that can accumulate in the drug in quantities sufficient to present a risk of toxicity or affect its stability or efficacy.
What are extractables?
To study the risk of materials, extraction studies are performed, generally using aggressive solvent conditions, including acidic, basic, organic and aqueous solvents, and Soxhlet or accelerated solvent extraction.
It is important that the extraction process does not deform the material of interest. Compounds present in the resulting extracts are called “extractables.” Extractables studies are typically performed to create a “worst-case scenario” and assist in materials selection and early risk assessment.
What are leachables?
Leachables are chemical species that make their way into the product under normal product, application, or storage conditions.
There is generally an overlap such that the leachables involved may be classified as a subset of the extractables. Forced or accelerated leachable studies can be performed to assess leachables that migrate under simulated environmental conditions by analyzing the drug formulation after exposure to elevated temperature.
However, if the leachable interacts with the drug product or packaging materials, new components can be present. These are termed secondary leachables. Drug formulations often contain buffers, surfactants, fillers, and other excipients. This complexity means there sometimes are secondary leachables that can be identified only after long stability studies over the typical drug shelf life.
Why is important to monitor for extractables and leachables?
Accurate identification of E&L compounds is vital to ensure that products we consume or use are safe. It also safeguards that there are no potentially harmful chemicals being absorbed into a finished drug product, medical device, or food contact material when it is manufactured, packaged, or stored.
Explore our learning center for more extractables and leachables information.
What are nitrosamines?
Nitrosamines, or more correctly N-nitrosamines, refer to any molecule containing the nitroso functional group. These molecules are concerning because nitrosamine impurities are probable human carcinogens.
The unexpected finding of nitrosamine impurities in drugs such as angiotensin II receptor blockers (ARBs), ranitidine, nizatidine and metformin, has clarified the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence. Stringent regulatory guidances not only helps make drugs safer but — through method requirements — are helping laboratories to identify the appropriate tools needed for accurate and confident analysis.
How are nitrosamines formed?
The presence of nitrite in the pharmaceutical manufacturing process can represent a risk for formation if a primary or secondary amine is present. Read more about the formation and analysis of nitrite and amines by ion chromatography in this application note. It is an essential part of a risk-based strategy to monitor and limit the nitrite and amine levels in pharmaceutical raw materials, API manufacturing steps, the final API and subsequent drug product.
How to detect nitrosamines?
Nitrosamine impurity analysis requires robust and sensitive analytical methods to ensure confidence in the obtained results. The wide Thermo Scientific portfolio is proven to be excellent for nitrosamine analysis, ensuring your exploratory and routine methods are performed as accurately and reliably as possible while maintaining requirements from regulatory bodies worldwide. Products for the analysis of nitrosamines include:
- Liquid, gas and ion chromatography for robust separation
- High-resolution, accurate-mass (HRAM) mass spectrometry for ultimate confidence in avoiding false positive results
- Tandem mass spectrometry, the best tool in routine analysis
- Single, GMP compliance-ready software solution for all our technology solutions
Looking for more information? Visit our dedicated nitrosamine impurity analysis page.
Summary
A range of analytical workflows and techniques are required for comprehensive impurity profiling, including sample preparation, gas or liquid chromatography and mass spectrometry. Thermo Fisher Scientific has an extensive portfolio for comprehensive impurity profiling of pharmaceuticals to support your compliance testing.
To discover workflow solutions for E&L, genotoxic impurities including N-Nitrosamines, download our interactive infographic, Workflow solutions for pharmaceutical impurity analysis, by clicking here.
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