Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes.

The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a de minimis risk management framework.

Artificial Intelligence-Powered Surgical Consent: Patient Insights.

Introduction The integration of artificial intelligence (AI) in healthcare has revolutionized patient interactions and service delivery. AI's role extends from supporting clinical diagnostics and enhancing operational efficiencies to potentially improving informed consent processes in surgical settings. This study investigates the application of AI, particularly large language models like OpenAI's ChatGPT, in facilitating surgical consent, focusing on patient understanding, satisfaction, and trust.

'H-type' duplex gallbladder resected laparoscopically with transcystic choledochoscopy and stone retrieval.

A duplex gallbladder is an extremely rare congenital anomaly that while may remain asymptomatic, may also develop into biliary colic, cholecystitis, cholangitis or pancreatitis. In these circumstances, it is advisable to surgically remove both gallbladders. Typically, a cholecystectomy is performed laparoscopically as this aids patient recovery and complication risk; however, when congenital abnormalities are present, some may choose to revert to an open operation.

Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide.

In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde.

Revisiting the Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals.

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively.