Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The regulatory challenge of determining acceptable intakes for nitrosamine drug substance-related impurities while ensuring medicinal product supply ***

Marianna Costa (Abschlußjahr: 2023)

Summary
Language: English
Approximately two years after the discovery of the probable carcinogens N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) in Valsartan, which led to global recalls of affected medicinal products, manufacturers and marketing authorization holders (MAHs) were requested to undertake a three-step mitigation process in which they were expected to review their products for the presence of nitrosamine impurities and, if necessary, initiate measures to remove or reduce them.
In addition to the simple dialkyl-nitrosamines like NDMA and NDEA, which were detected in various active pharmaceuticals ingredients (APIs) and drug products between 2018 and 2020, others, and predominantly nitrosamine drug substance-related impurities (NDSRIs), were subsequently found which typically differ significantly from the simple nitrosamines in their overall chemical structure and thus in their carcinogenic potency. As NDSRIs are related to the API structure, the risk of their presence and formation in drug products is high and the reduction of NDSRI levels is usually difficult to achieve. These peculiarities lead to various regulatory challenges, first and foremost the determination of acceptable intakes (AIs) which form the basis for the control strategy and the necessity of corrective and preventive actions. Lastly, the high number of drug products or even whole therapeutical drug classes actually or potentially affected by NDSRIs poses a threat to the drug supply.
To support MAHs in implementing the three-step mitigation process, guidelines for the control of nitrosamine impurities have been published by various competent authorities and were revised more or less frequently over the past five years. This master thesis deals with the question of whether the currently existing regulatory framework can be considered sufficient to provide safe and continuously available drug products to patients. A thorough assessment and comparison of the guidelines provided by the European Medicines Agency (EMA), Health Canada (HC) and the United States (US) Food and Drug Administration (FDA), as well as an analysis of historical and recent regulatory events regarding nitrosamine impurities, show that the short-term supply of drug products affected by nitrosamine impurities could be ensured with the help of adjusted regulatory recommendations, whereby the application of temporary higher AIs based on less-than-lifetime adjustments is decisive. Assurance of long-term supply is now also likely for many approved drug products affected by NDSRIs with the recently introduced Carcinogenic Potency Categorization Approach (CPCA), which assigns significantly higher lifetime AIs up to the threshold of toxicological concern of 1.5 µg/day for mutagenic impurities to a large number of NDSRIs. However, a considerable proportion of NDSRIs will still need to be controlled in the medium-term with an AI of 18 ng/day or 100 ng/day and thus are assigned a carcinogenic potency about as high as NDEA and NDMA. Therefore, ongoing intensive cooperation between industry, authorities, research and other institutions to support MAHs with suitable analytical methods, innovative in vitro testing systems and regulatory advice and flexibility appears to be crucial to avoid drug recalls of approved drug products in the medium-term, given the challenges associated with the implementation of mitigation strategies for NDSRIs.
Despite many consistent recommendations, the detailed comparison of the EMA, FDA and HC guidelines also reveals some differences, discussed and evaluated in this master thesis in the light of ensuring long-term drug supply. Examples of the effects of drug recalls are used to illustrate that an ensured drug supply in the interest of public health is linked to an uninterrupted availability of drug products.
Deviations in the observed guidelines are found in the recommended lifetime AIs, control options and provisions for risk assessments which may lead to uncertainties for industry and regulators potentially resulting in prolonged pharmaceutical development and regulatory procedures. The focus in the existing guidelines lies on the mitigation of nitrosamine impurities in approved drug products, but given the various risk factors and root causes for the presence of nitrosamine impurities and their widespread occurrence in medicinal products, they need to be continuously considered and prevented during product development and also throughout the life cycle of medicines to ensure drug supply in the long-term. While the differing carcinogenic potency of NDSRIs and simple dialkyl-nitrosamines is now better reflected in the guidelines by the application of the CPCA, there are confounding regional differences in the application of AI derivation methods for NDSRIs and other nitrosamines, highlighting the challenge of adequately quantifying carcinogenic risk of nitrosamine impurities and the need for a harmonized approach to determine AIs.
Taking into account the continuously evolving science regarding nitrosamines, an international guideline should be envisaged with harmonized recommendations for the control of nitrosamine impurities in drug products to equally ensure a sustainable supply of safe medicines worldwide.
Pages: 94
Annexes: 14, Pages: 36