N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations

Moser, Justin; Ashworth, Ian W.; Harris, Laurence R.; Hillier, Michael C.; Nanda, Kausik K.; Scrivens, Garry

doi:10.1016/j.xphs.2023.01.027

Cited by 23 publications

(46 citation statements)

References 15 publications

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“…It is to be noted that relevant levels of nitrosation are more likely to be obtained from secondary amines than from tertiary amines, unless the latter contain high levels of the respective secondary amines. − …”

Section: Why Pharmaceuticals Cannot Be Made “Nitrosamine-free”mentioning

confidence: 99%

The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny

Nudelman

Kocks²,

Mouton

et al. 2023

Org. Process Res. Dev.

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The onset of the N-nitrosamine (NA) saga in 2018 was chiefly related to certain small dialkyl N-nitrosamines originating from the synthesis of the active pharmaceutical ingredient (API). However, the subsequent comprehensive assessments performed on APIs, formulated drug products, and packaging put a different type of NAs in the limelight: a diverse range of complex so-called nitrosamine drug-substance-related impurities (NDSRIs). They may form due to the presence of potentially nitrosatable secondary or tertiary amine moieties in APIs or API impurities and nitrosating agents formed from low levels of nitrite present as impurities. The unique properties of the amine functional group make it irreplaceable in the synthesis of APIs. While nitrite levels may be reduced, the formation of NAs in drug products cannot be completely prevented, and the class default acceptable intake (AI) of 18 ng/day currently poses significant challenges in terms of both viable control and analysis at such low levels. Even so, NA exposure through pharmaceuticals is expected to be orders of magnitude lower than the exposure via food or endogenous formation. While robust carcinogenicity data are available for many of the small, simple NAs, there is a distinct absence of such data for most NDSRIs. Many working groups have therefore been established to share data and rapidly improve knowledge (whether in terms of toxicity data, structure–activity relationships, or analytical techniques), to define best practices to assess the genotoxic potential of NDSRIs, and to advance methods to calculate AIs based on solid scientific rationales. Ultimately, to protect patients from true cancer risk and secure access to important medicines, it is crucial for manufacturers and health authorities to pursue efforts to implement NA control strategies that are equally effective and realistic. As patient safety is paramount, the pharmaceutical industry is committed to ensuring that the medicines it supplies are safe and effective. Where legitimate safety concerns exist, it is undisputed that appropriate actions must be taken, which could include withdrawal of products from the market.

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Section: Why Pharmaceuticals Cannot Be Made “Nitrosamine-free”mentioning

confidence: 99%

The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny

Nudelman

Kocks²,

Mouton

et al. 2023

Org. Process Res. Dev.

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“…Water seems to play a role in NDSRI formation, not just during the manufacturing process, but also during storage, as NDSRI levels generally and consistently increased in correlation with increased humidity as used in accelerated stability studies. 25 The influence of water is likely multifold. During manufacturing, water can enhance the homogeneous distribution of the drug substance and impurities (especially nitrite) by the solubilization of these components, ultimately translating into an increased accessibility of nitrite for reaction with a proximal secondary amine.…”

Section: Solid Dosage Forms: Risks Associated With Unit Operations Du...mentioning

confidence: 99%

“…The drug substance structural features that pose a high risk for the generation of N -nitrosamines during drug substance production are well-known and have been amply discussed before. ,,, In contrast, considerably less is reported for NDSRI generation during drug product manufacture. A recent study by Moser et al addressed these scientific gaps to a large extent, albeit the investigation focused on model compounds (Scheme ) and formulations rather than actual drug products . The main conclusions were that the trends observed in solution hold for solid-phase chemistry: Aromatic (i.e., less basic) secondary amines (ArAlkNH) undergo faster nitrosation than aliphatic derivatives (Alk 1 Alk 2 NH). Tertiary amines pose a significantly lower risk (generally 2 orders or magnitude less reactive) than secondary amines (with the exception of structures containing two small, aliphatic substituents on the aminelike R-NMe 2 which can still be problematic, particularly when R bears structural features that promote fragmentation of the R–N bond, e.g., an adjacent electron-rich heteroaromatic substituent). ,, Protonated amines (R 1 R 2 NH 2 + ) are significantly more reactive than amine free bases. …”

Section: Vulnerable Amines In the Drug Substance: Relevance To Ndsrismentioning

confidence: 99%

“…Comparison of unit operations during tableting of drug substance model compounds. Reprinted with permission from ref (Moser, J.; Ashworth, I. W.; Harris, L.; Hillier, M. C.; Nanda, K. K.; Scrivens, G. N -Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations. J. Pharm.…”

Section: Solid Dosage Forms: Risks Associated With Unit Operations Du...mentioning

confidence: 99%

“…Partial solubilization of the drug substance may also alter its physicochemical properties such as increasing amorphous content, altering morphology and particle size as well as increasing surface area. All these factors can increase the rate of nitrosation reactions in the solid phase . Finally, the water content in the solid dosage form increases the mobility of reactants, according to the so-called “saturated solution layer” model .…”

Section: Solid Dosage Forms: Risks Associated With Unit Operations Du...mentioning

confidence: 99%

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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.

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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.

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