Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals

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.

Section: Defining a Commonly Accepted Strategy For Read-acrossmentioning

confidence: 99%

“…Read-across to a suitable surrogate compound has been suggested by regulatory guidance ,,, as an alternative approach in cases where insufficient carcinogenicity data exist for the NA in question. However, the selection of this surrogate compound is a challenging process, particularly for NDSRIs.…”

Section: Defining a Commonly Accepted Strategy For Read-acrossmentioning

confidence: 99%

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

Nudelman

Kocks²,

Mouton

et al. 2023

“…30 In cases of excipients containing nitrosatable amines, the risk assessment is rather straightforward, benefiting from the lessons learned from the initial wave of drug substance contamination with N-nitrosamines (and the impurity can be accordingly controlled during the manufacture of the excipient, in solution phase). 9,15,24 4.2. Nitrosating Agents in Excipients.…”

Section: Vulnerable Amines In Excipientsmentioning

confidence: 99%

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

Self 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.

“…Since the consequence of overprediction may be more critical for these impurities, they may be subject to greater regulatory scrutiny. 22…”

Section: ■ Introductionmentioning

confidence: 99%

“…Similarly, while the control limit ensures the PR incorporates the dose levels and specific toxicity of an impurity (through the required purge), for more toxic entities, such as those within the cohort of concern, it is recommended to provide increased justification, incorporating some higher category evidence provision. Since the consequence of overprediction may be more critical for these impurities, they may be subject to greater regulatory scrutiny …”

Section: Introductionmentioning

confidence: 99%

Establishing Best Practice for the Application and Support of Solubility Purge Factors

Burns

Andrews

Baumann

et al. 2023

The increased usage of purge arguments for demonstrating control of mutagenic impurities in drug substances, in accordance with ICH M7, necessitates an increasingly standardized approach to their implementation across industry. The strength of the approach is highly reliant upon a conservative implementation of the principles to maintain regulatory confidence. Different parameters may influence a purge calculation, such as reactivity, solubility, and volatility. While reactivity data are commonly available in literature, there are comparatively fewer resources to draw upon when assigning purge values for solubility related purifications, despite these processes accounting for high degrees of purge and there being an abundance of different techniques which can be utilized. Herein, the authors seek to outline general principles to be adopted as an industry wide best practice for the application of solubility-based purge factors.