How N-nitrosodimethylamine (NDMA) or Nitrosamine impurity is impacting the Pharma industry

NDMA stands for N-nitrosodimethylamine, which is a chemical compound and belongs to a class of chemicals known as nitrosamines. NDMA is an organic compound with the chemical formula C₂H₆N₂O. It is a highly potent and toxic substance, classified as a probable human carcinogen by the International Agency for Research on Cancer (IARC).

Nitrosamine impurities are a class of potentially harmful substances that have received significant attention in the pharmaceutical industry in recent years. Nitrosamines are chemical compounds that can be found naturally in certain foods, water, and air, but they can also be formed during certain industrial processes or as byproducts of chemical reactions.

The concern with nitrosamine impurities arises from the fact that some nitrosamines have been classified as probable human carcinogens, meaning they have the potential to cause cancer. These impurities were found to be present in certain medications, primarily angiotensin receptor blockers (ARBs) used to treat high blood pressure and other conditions.

The presence of nitrosamine impurities in pharmaceutical products can be traced back to manufacturing processes or raw materials used in the production of drugs. Contamination can occur when specific conditions, such as the presence of certain precursors and reactions with nitrite, are present during drug synthesis or storage.

Once the presence of nitrosamine impurities was discovered in certain medications, regulatory agencies, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), issued guidelines and regulations to address the issue. Pharmaceutical companies were required to test their products for nitrosamine impurities and take appropriate measures to mitigate the risk to patients.

The identification and control of nitrosamine impurities have become a significant focus in the pharmaceutical industry to ensure the safety of medications. Efforts are being made to establish strict limits for these impurities and to improve manufacturing processes to prevent their formation or detect them at very low levels to ensure patient safety.

Some of the products that have been recalled include:

Valsartan-based medications: Valsartan is an angiotensin II receptor blocker (ARB) used to treat hypertension and heart failure. Numerous valsartan products from various manufacturers were recalled due to NDMA contamination.
Losartan-based medications: Losartan is another ARB used for hypertension and other cardiovascular conditions. Several losartan products were recalled due to NDMA impurity.
Irbesartan-based medications: Irbesartan, also an ARB, is prescribed for hypertension and diabetic nephropathy. Some irbesartan products were also recalled due to NDMA contamination.
Ranitidine-based medications: Ranitidine is commonly used to treat heartburn and acid reflux. Various ranitidine products, including over-the-counter formulations, were recalled due to NDMA contamination.

The FDA has been investigating the presence of nitrosamine impurities in medications since 2018. As a result of this investigation, the FDA has recalled a number of medications that contain nitrosamines. The FDA is also working with drug manufacturers to develop new methods to reduce the levels of nitrosamines in medications.

The FDA’s efforts aimed to ensure the safety of patients and the quality of pharmaceutical products. Some of the key guidance documents and white papers issued by the FDA related to nitrosamine impurities include:

“Control of Nitrosamine Impurities in Human Drugs”: This guidance provides recommendations to the pharmaceutical industry on detecting and controlling nitrosamine impurities in human drugs. It outlines risk assessments, testing methods, and acceptable limits for nitrosamines in various drug products.
“Risk Assessment for Nitrosamine Impurities”: The FDA published this white paper to provide information on the agency’s approach to risk assessment for nitrosamine impurities in drugs. It discusses factors considered in evaluating the potential risks associated with the presence of nitrosamines in medications.
“Testing of Nitrosamine Impurities in Drug Substances and Drug Products”: This white paper outlines analytical testing methods for detecting and quantifying nitrosamine impurities in drug substances and finished drug products. It provides guidance on appropriate testing strategies and methodologies.

These documents are part of the FDA’s efforts to address the nitrosamine impurity issue and set clear expectations for pharmaceutical companies in controlling and mitigating the risk associated with these impurities.

The European Medicines Agency’s (EMA) guidance aimed to address and manage the presence of nitrosamine impurities in pharmaceutical products to ensure patient safety and product quality. Some of the key guidance documents and updates issued by the EMA related to the nitrosamine impurity issue include:

“Guideline on the Limits of Genotoxic Impurities”: This guideline provides recommendations for setting limits on genotoxic impurities, including nitrosamines, in pharmaceutical products. It outlines the assessment of genotoxicity and risk management strategies.
“Questions and Answers on Nitrosamines”: The EMA published a series of questions and answers related to nitrosamine impurities in medicinal products. This document provides additional clarification and guidance on various aspects of nitrosamines, including testing requirements and regulatory expectations.
“Recommendations to Marketing Authorisation Holders”: The EMA issued specific recommendations to marketing authorization holders on measures to prevent and control nitrosamine contamination in medicines.

Analytical methods for the investigation of carcinogenic nitrosamines in active pharmaceutical ingredients (APIs) and drug products were actively being developed and refined by various regulatory agencies, research organizations, and pharmaceutical companies. These methods aimed to detect and quantify the presence of nitrosamine impurities, such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), and others, in pharmaceutical products to ensure patient safety.

The primary analytical techniques used for the investigation of nitrosamines in APIs and drug products include:

Liquid Chromatography (LC): High-performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography (UHPLC) are commonly used techniques for the separation, identification, and quantification of nitrosamines in pharmaceutical samples.
Mass Spectrometry (MS): Mass spectrometry is often coupled with LC (LC-MS) to increase the sensitivity and specificity of nitrosamine detection. Techniques like liquid chromatography-tandem mass spectrometry (LC-MS/MS) are widely used.
Gas Chromatography (GC): Gas chromatography is also utilized for the analysis of volatile nitrosamines in certain pharmaceutical products.
Nuclear Magnetic Resonance (NMR) Spectroscopy: NMR spectroscopy can be used to identify and characterize the structure of nitrosamine impurities in APIs and drug products.
Fourier Transform Infrared (FTIR) Spectroscopy: FTIR spectroscopy is useful for identifying functional groups, including nitrosamines, in pharmaceutical samples.
High-Resolution Mass Spectrometry (HRMS): HRMS is employed for the accurate determination of molecular weights and can be valuable for the identification of nitrosamine impurities.

Analytical laboratories, regulatory agencies, and pharmaceutical companies may use a combination of these techniques to investigate and monitor nitrosamine impurities in APIs and drug products. The limits for acceptable levels of nitrosamines vary depending on the specific product and regulatory guidelines.

Nitrosamines are formed when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions.

The potential root causes of the presence of nitrosamines in pharmaceutical products include:

The use of sodium nitrite (NaNO2) or other nitrosating agents in the manufacturing process. Sodium nitrite is a common food preservative, but it can also be used in the manufacturing of some pharmaceutical products. If sodium nitrite is not used properly, it can lead to the formation of nitrosamines.
The use of contaminated starting materials or intermediates. If starting materials or intermediates are contaminated with nitrosamines, these impurities can be carried over into the final product.
The use of certain excipients. Some excipients, such as starch and lactose, can contain trace amounts of nitrites. If these excipients are not properly cleaned, they can lead to the formation of nitrosamines in the final product.
The degradation of active substances or excipients. Under certain conditions, active substances or excipients can degrade and form nitrosamines. This can happen during the manufacturing process, storage, or use of the product.
The use of certain packaging materials. Some packaging materials, such as rubber stoppers and plastic tubing, can contain trace amounts of nitrites. If these packaging materials are not properly cleaned, they can lead to the formation of nitrosamines in the final product.

It is important to note that not all pharmaceutical products contain nitrosamines. However, the potential for nitrosamine formation is always present, and it is important for manufacturers to take steps to minimize the risk. These steps include:

Using good manufacturing practices (GMP) to ensure that the manufacturing process is properly controlled.
Using starting materials and intermediates that are free of nitrosamines.
Cleaning excipients and packaging materials thoroughly to remove any trace amounts of nitrites.
Monitoring the levels of nitrosamines in finished products to ensure that they are below acceptable limits.

By taking these steps, manufacturers can help to ensure that their products are safe and do not contain harmful levels of nitrosamines.

Federal Register notice Docket No. FDA-2023-N-1585 is a request for public comment on a proposed information collection for the Food and Drug Administration (FDA). The information collection is a request for data on the levels of nitrosamines in pharmaceutical products.

The FDA is proposing to collect data on the levels of nitrosamines in pharmaceutical products in order to better understand the potential risk to consumers. The information collection would require manufacturers of pharmaceutical products to submit data on the levels of nitrosamines in their products. The data would be submitted to the FDA on a voluntary basis. The FDA is seeking public comment on the proposed information collection. The public comment period ended on July 12, 2023. The FDA will consider all public comments before making a decision on whether to finalize the information collection.

The presence of N-nitrosodimethylamine (NDMA) and other nitrosamine impurities in pharmaceutical products is a serious concern for the industry and poses potential health risks to patients. As a community, we must take proactive steps to address this issue and ensure the safety and quality of medications.

Together, by taking proactive measures and working collaboratively, we can address the issue of nitrosamine impurities in pharmaceutical products and ensure the safety and well-being of patients worldwide. This is not only a responsibility but also an opportunity to build greater trust in the pharmaceutical industry and its commitment to patient health. Let us take action now to secure a safer and healthier future for everyone. Contact WiTii Consulting below to learn more about how your organization can tackle the problem of nitrosamine impurities.

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