Low Nitrite Excipients as Part of Your Nitrosamine Mitigation Strategy

Introduction

N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. It came to light in early July 2018 when the European Medicines Agency (EMA) reported the recall of several products containing Valsartan due to N-nitrosodimethylamine (NDMA) contamination. Regulatory organizations including Central Drugs Standard Control Organisation (CDSCO), the Food and Drug Administration (US-FDA), and the European Medicines Agency (EMA) have continuously worked to quantify the amine impurities an effort to address this global problem. Researching novel approaches and methodologies for the accurate estimate of nitrosamine impurities from diverse pharmaceutical APIs, however, is a difficult challenge for scientists, researchers and industrialists. Their high hydrophilicity and low molecular weight are the main issues.

The pharmaceutical industry faces the difficult task of controlling and minimising nitrosamine impurities to acceptable levels across the entire drug supply chain. This is a significant challenge given that nitrosamine impurities can be introduced into drug products through multiple routes, including during the manufacture of APIs, the production and storage of formulated drug products, or even via the packaging materials used.

The effects of N-nitroso compounds on human health are well known. Certain N-nitrosamines are described as highly probable human carcinogens. They are usually formed by the reaction of secondary or tertiary amines with a source of a nitrosating agent, typically derived from nitrite.

Approach for knowing nitrites in excipients

Pharmaceutical excipients make up a large portion of the end drug product, accounting for up to 90% of the total volume in some cases. In most cases, the nitrite contribution is dominated by the highest formula % excipients. For example, microcrystalline cellulose (MCC) is widely used in pharmaceutical development and is one of the most common fillers /diluents contributed to oral solid dosage form formulations, usually present in much higher concentration compared with other excipients. So, the high nitrite content in MCC can be a significant risk for nitrosamine formation and consequently patient health. These excipients are fundamental to the functionality of a drug product, providing different roles from manufacturability to stability, dose uniformity, and effective delivery of the active pharmaceutical ingredient (API). However, despite their many advantages for formulations, they may play a critical role in nitrosamine formation.

Concern for nitrosating compounds in excipients has focused attention on nitrites and nitrates, neither of which are powerful nitrosating compounds on their own, but, under certain conditions, can potentially react with other materials to form nitrosamines. Nitrite can form the reactive species nitrous anhydride (N2O3) under mildly acidic conditions. Nitrates can react to form nitrite through enzymatic reduction, which then can form the reactive nitrous anhydride under acidic conditions.

Strategies for nitrosamine risk mitigation

The risk of the presence of nitrosamine compounds within excipients itself is very low; however, many excipients contain traces of nitrites that can result in formation of nitrosamines under specific conditions within the drug product. Claims of nitrites and nitrates free excipients are unrealistic by excipient manufacturer because minimal traces in excipients are inherently present in the raw materials used to manufacture the excipients and it cannot be completely removed. Selecting low nitrite excipients can be an effective way to minimize the risk of nitrosamine contamination without compromising the therapeutic efficacy of the final drug product, as well as carrying minimal risks and regulatory requirements. Research has also demonstrated that choosing an excipient with low levels of nitrites can substantially reduce nitrosamine formation, compared to using excipients with high nitrite levels.

Selecting low nitrite excipients is only one tool that may reduce the risk of nitrosamine formation, risk assessment of every stage in process, especially when a vulnerable amine is present in the formulated drug product. Such an approach carries minimal risks and should form a part of holistic strategy to reduce the risk of nitrosamine formation and influence of API. Risk assessments by the drug product manufacturer should be designed to evaluate the potential sources of nitrosamine formation and contamination during manufacturing of drug products.

The IPEC questionnaire templates are good resources for excipient manufacturers to provide information on this topic, and their use is encouraged. Many excipient manufacturers have been using these templates or similar formats to inform drug product manufacturers. This questionnaire includes a matrix to consider the structure and the origin of the excipient as a first indication of risk. Factors considered were the presence of nitrosating agents in the production process, the type of water that is used, the use of recycled/recovered solvents, the presence of amines, amides, primary amines or ammonium salts and the multipurpose use of the equipment.

Conclusion

Nitrosamines are highly potent carcinogens whose exposure through food, beverages, and recently, medicines need to be monitored and reduced to the possible extent. In light with the discovery of nitrosamine contamination of pharmaceutical products, it is necessary to systematically identify the source of contamination to reduce the nitrosamine impurities in final finished products. Finished pharmaceutical products can get contaminated with nitrosamines through API synthesis and formulation.

Selecting of low nitrite excipients can be an effective tool for mitigating nitrosamine formation in drug products, particularly in high-risk formulations containing secondary amines. It is essential to consider factors such as how to accurately measure nitrite levels in excipients, supplier variations, and formulation conditions, before implementing this approach. The most important factor for successful implementation is effective communication between pharmaceutical developers and excipient providers.