Some nitrosamines (e.g. NDMA, NDEA) are classed as ‘cohort of concern’ genotoxic impurities and require control to extremely low limits in drug products. There has been a recent regulatory focus on nitrosamines due to detection of certain nitrosamines above the acceptable daily intake in several marketed drug products, leading to market-wide product recalls. Regulators require that novel nitrosamines, for which there is no or limited safety data, are regarded as mutagenic, and therefore controlled to very low acceptable daily intakes, which can be down to the order of nanograms. This can be challenging in drug products where the drug substance contains an amine functional group vulnerable to nitrosation. Nitrites are ubiquitous in excipients at trace levels and can act as nitrosating agents towards vulnerable amines (usually secondary or activated tertiary amines).
There is a need for strategies to control the formation of nitrosamines in drug products such as the addition of a compound to act as a scavenging agent or oxidising agent towards nitrites (e.g. ascorbic acid/sodium ascorbate) or using an additive to control pH of the drug product, keeping the pH unfavourable for nitrosamine formation. However, there is very little industry experience with these approaches to inhibit nitrosamine formation in solid phase drug products. One of the most challenging aspects remains determining and ensuring sufficient distribution of the additive within each unit dose to prevent nitrosamine formation at levels above the permitted limit.
Proposed Interactions with GSK / Industry:
- Regular catch-up meetings (~quarterly or as required)
- Annual reports
- Yearly presentation at GSK or cross-pharma group
- Potential to come to manufacture at GSK Ware R&D
The principal supervisor for this project is Prof Catherine Tuleu (UCL School of Pharmacy, Faculty of Life Sciences), and Dr Kersti Karu will be the subsidiary supervisor (Dept of Chemistry, Faculty of Maths & Physical Sciences).
Main methods and techniques
Literature review of additives (include review of solid state reaction mechanisms relevant to nitrosation of amines); selection of additives, model secondary amines, pharmaceutical formulations and processes to be tested; lab scale blending, direct compression, wet granulation; HPLC MS/MS analysis, trace levels down to ng/g.
Person specification
We are looking for an enthusiastic candidate to join our dynamic group at UCL School of Pharmacy, Chemistry Mass Spectrometry Facility and GSK. The studentship offers an excellent opportunity to develop and control the formation of nitrosamines in drug products and monitor these side products using mass spectrometry analytical platforms.
Applicants are expected to hold a first degree in pharmacy, chemistry, chemical engineering, pharmaceutical science, or analytical science (minimum 2.1). The successful candidate will develop skills in mass spectrometry techniques. Mass spectrometry experience is desired but not essential.
Applicants will also need to meet UCL MPhil/PhD entry and English Language requirements. See here for further details.
How to apply
Applications must include CV, personal statement, and the contact details of two referees. Applications should be emailed to Ms Michelle Ward at [Email Address Removed]
The deadline for applications is Friday 16th June 2023.
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