ABSTRACT
N-Nitrosamines (also referred to as nitrosamines) are a class of substances, many of which are highly potent mutagenic agents which have been classified as probable human carcinogens. Nitrosamine impurities have been a concern within the pharmaceutical industry and by regulatory authorities worldwide since June 2018, when regulators were informed of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin-II receptor blocker (ARB) medicine, valsartan. Since that time, regulatory authorities have collaborated to share information and knowledge on issues related to nitrosamines with a goal of promoting convergence on technical issues and reducing and mitigating patient exposure to harmful nitrosamine impurities in human drug products. This paper shares current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies.
Subject(s)
Nitrosamines , Humans , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Risk Factors , Pharmaceutical PreparationsABSTRACT
Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.
Subject(s)
Metformin , Nitrosamines , Dimethylnitrosamine/analysis , Humans , Metformin/analysis , Nitrosamines/analysisABSTRACT
The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence. Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens. Regulators first became aware of the presence of nitrosamines in EU medicines in 2018, with reports of detection of N-nitroso-dimethylamine (NDMA) in valsartan from one manufacturer. A subsequent EU review of all valsartan medicines was triggered by the European Medicines Agency (EMA) and was later extended to other angiotensin receptor blockers/sartans. A separate review was also started for ranitidine medicines. This was followed by an EU-wide examination of the risk of presence of nitrosamines in all human medicines. This article reflects on the investigation of the EU regulatory network into the presence of nitrosamines and the scientific knowledge informing recommendations for developers on how to limit nitrosamines in medicines.
ABSTRACT
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Subject(s)
Peptide Library , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Viral Proteins/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Amino Acids/chemistry , DNA/chemistry , Drug Evaluation, Preclinical/methods , Molecular Targeted Therapy , Peptides, Cyclic/genetics , Polymerase Chain Reaction , Respiratory Syncytial Viruses , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Von Hippel-Lindau Tumor Suppressor Protein/chemistryABSTRACT
Reductive desulfurisation of dithiocarbamates is conveniently achieved using H(3)PO(2)-Et(3)N-ACCN in refluxing dioxane. Fused and spirocyclic ß-lactams, prepared through 4-exo trig carbamoyl radical cyclisation-dithiocarbamate group transfer reactions, are reduced without fragmentation of the strained 4-membered ring. Diethyl tetraacetyl-d-glucopyranosyl dithiocarbamate is selectively reduced with or without acyloxy group migration depending on reaction conditions and choice of reductant. Deuterium incorporation from D(3)PO(2)-Et(3)N is observed for a system involving a nucleophilic radical intermediate, but not in the case of the electrophilic radical obtained through acyloxy group migration on a glucose derivative.
Subject(s)
Thiocarbamates/chemistry , Cyclization , Free Radicals/chemistry , Molecular Structure , Oxidation-Reduction , Spiro Compounds/chemical synthesis , Tin/chemistry , beta-Lactams/chemical synthesisABSTRACT
[formula: see text] The enantioselective synthesis of (R)-salmeterol has been achieved by using a sequence of supported reagents and sequestering agents. The saligenin core was installed by a regiospecific alkylation and a chiral auxilliary approach was employed to introduce the desired stereochemistry via a diastereoselective reduction.