N-Nitrosation in the absence of nitrosating agents in pharmaceuticals?

Jireš, Jakub; Douša, Michal; Gibala, Petr; Kubelka, Tomáš

doi:10.1016/j.jpba.2022.114872

Cited by 10 publications

(7 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides nitrosation side reactions encountered with vulnerable amine reagents used in API synthesis, N -nitrosamines can also be generated , from the reaction of vulnerable amine-containing (a) parent APIs (e.g., varenicline → N -nitrosovarenicline in Scheme C), (b) impurities present in the API and degradation product(s) of the API, (c) counterions (e.g., dimethylamine, diethanolamine salts of the parent API) and/or (d) excipient(s) with nitrite sources in synthetic reactions, nitrocellulose in blister packs as well as in excipients (e.g., cellulose, lactose, sodium starch glycolate, hydroxypropyl cellulose, etc.) present in formulations; − even trace nitrite in water has come under scrutiny …”

Section: Origins Of N-nitrosamines In Dss and Dpsmentioning

confidence: 99%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

View full text Add to dashboard Cite

The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence in all medicinal products. In the absence of rodent carcinogenicity data for novel N-nitrosamines derived from aminecontaining APIs, a conservative class limit of 18 ng/day (based on the most carcinogenic N-nitrosamines) or the derivation of acceptable intakes (AIs) using structurally related surrogates with robust rodent carcinogenicity data is recommended. The guidance has implications for the pharmaceutical industry given the vast number of marketed amine-containing drugs. In this perspective, the rate-limiting step in N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation to yield DNA-reactive diazonium or carbonium ion intermediates, is discussed with reference to the selection of read-across analogs to derive AIs. Risk-mitigation strategies for managing putative N-nitrosamines in the preclinical discovery setting are also presented.

show abstract

Section: Origins Of N-nitrosamines In Dss and Dpsmentioning

confidence: 99%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Peroxide was recently shown to lead to the formation of NDMA in metformin film coated tablets in the absence of an explicit nitrosating agent, in a model study by Dousa et al 43 The mechanism consists of a multistep oxidation of dimethyl amine to hydroxyl amine, which condenses with another molecule of DMA to form 1,1-dimethyl hydrazine and ultimately NDMA by oxidation. However, this pathway seems to be minor, not producing more than a tenth of the total NDMA levels observed.…”

Section: Vulnerable Amines In Excipientsmentioning

confidence: 99%

“…Finally, an alternative option to mitigate NDSRI formation in drug products is to reduce the acidity of the formulation by using basic excipients (e.g., Na 2 CO 3 ). , This approach is generally effective, as the nitrosation rate decreases strongly at higher pH. ,, However, there are cases where conditions favor N -nitrosamine formation at neutral and alkaline pH, typically under the action of a catalyst (e.g., a carbonyl compound such as formaldehyde, as detailed in Section ). The main limitation of this approach is that relevant pharmacological properties of the active substance such as stability, dissolution, bioavailability or palatability may be altered by changing the formulation pH.…”

Section: Use Of Nitrite Scavengers and Other Additives To Prevent Nds...mentioning

confidence: 99%

“…67 Finally, an alternative option to mitigate NDSRI formation in drug products is to reduce the acidity of the formulation by using basic excipients (e.g., Na 2 CO 3 ). 36,43 This approach is generally effective, as the nitrosation rate decreases strongly at higher pH. 13,14,23 However, there are cases where conditions favor Nnitrosamine formation at neutral and alkaline pH, typically under the action of a catalyst (e.g., a carbonyl compound such as formaldehyde, as detailed in Section 4.3).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

Cioc

Joyce

Mayr

et al. 2023

Org. Process Res. Dev.

View full text Add to dashboard Cite

The detection of N-nitrosamine impurities in medicines and the recent emergence of nitrosamine drug substance related impurities (NDSRIs) has posed a great challenge to manufacturers of drug products and regulators alike. NDSRIs are primarily associated with reactions occurring in the drug product which brings particular complexity. This paper will explore the current technical knowledge surrounding the formation of these impurities, including the risk factors, reaction conditions, and potential mitigation strategies. Scientific understanding of these areas is still evolving, and we will highlight both the scientific progress made and discuss the significant gaps in mechanistic knowledge still remaining. These gaps render accurate predictions of NDSRI formation extremely challenging. The pharmaceutical industry should continue to work on potential mitigation strategies and generation of additional scientific data to address the mechanistic gaps. Regulatory guidance and policy will continue to advance and adapt in response to further changes in scientific understanding.

show abstract

“…Nitrosamines are recognized to be probable or possible human cancerogenic substances and have been found in many pharmaceutical products [1,2]. Regulatory agencies worldwide have recently prompted marketing authorization holders (MAHs) to take action in relation to this health concern [3].…”

Section: Introductionmentioning

confidence: 99%

Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation

Berardi¹,

Jaspers²,

Dickhoff³

2023

Pharmaceutics

View full text Add to dashboard Cite

Risk control for nitrosamine impurities in drug products is currently a major challenge in the industry. Nitrosamines can form during drug product manufacturing and storage through the reaction of nitrites with amine-containing APIs or impurities. The level of nitrites in excipients and the rate of reaction often control the build-up of nitrosamine. Although the variability in nitrite levels across excipient types and suppliers is well recognized, the impact of excipient selection on the level of nitrosamine formed has not been systematically studied. This gap of knowledge is addressed in the current work. We present theoretical case studies of formulations where microcrystalline cellulose (MCC), or lactose supplier, or superdisintegrant type are changed in pursuit of lower levels of nitrite. The impact of the average, maximum, and minimum levels of nitrites in each excipient on nitrosamine formation in the dosage form is calculated. The input data for this calculation are the formulation composition, nitrosamine molecular weight (MW), percentage of conversion, and nitrite levels per excipient. The percentage of conversion (based on the formulation and manufacturing variables) and nitrite levels were taken from the recent literature. We show that changing the supplier of a single excipient, or of the three most critical excipients, can reduce nitrosamine formation by up to −59% and −89%, respectively. We also show that high-risk formulations, e.g., high MW nitrosamines, high dosage weights, and high percentages of conversion (e.g., wet granulation), can often be de-risked below regulatory acceptable daily intake via careful excipient selection. Finally, we provide an open-access tool that enables users to calculate the theoretical formation of nitrosamines in their specific formulations. This calculation template can be used for (i) the preliminary screening of the risk of nitrosamine formation in drug products and (ii) the preliminary assessment of the impact of excipient selection for risk mitigation.

show abstract

N-Nitrosation in the absence of nitrosating agents in pharmaceuticals?

Cited by 10 publications

References 24 publications

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation

Contact Info

Product

Resources

About