Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Nitrosamine Risk Management for Medicinal Products: WHO's Role and a Case Study of Camzyos® ***

Kevin Hohl (Abschlußjahr: 2024)

Summary
Language: English
Nitrosamine impurities have posed a significant challenge to the pharmaceutical industry and regulatory bodies for six years due to their carcinogenic potential. The discovery of nitrosamines in valsartan in 2018 heightened scrutiny of their presence in pharmaceuticals leading to recalls and investigations uncovering more contaminations in various medications, raising safety concerns.
Regulatory agencies worldwide responded by issuing guidelines for manufacturers to review, test, and mitigate nitrosamine impurities in their products. While the initial focus was on simple dialkyl-nitrosamines like NDMA and NDEA, attention shifted in 2020 to nitrosamine drug substance-related impurities (NDSRIs), which are linked to the chemical structure and synthesis of APIs.
A 2022 study predicted that about 40% of APIs could form NDSRIs, complicating regulatory efforts to determine acceptable intakes (AIs) and necessitating corrective actions. Updated guidelines in 2024 listed confirmed and potential NDSRIs and their AIs, though data on their mutagenicity and carcinogenicity remains limited. Despite improved guidelines reflecting the varying carcinogenic potency of NDSRIs and simple nitrosamines, regional differences in AI derivation methods persist, underscoring the need for a harmonized approach.
This thesis investigates the World Health Organization’s (WHO) role during the last six years during the nitrosamine crisis and critically scrutinizes the WHO’s activities in evaluating the associated risks, in offering guidance for the pharmaceutical industry, patients and regulatory bodies and in implementing mitigation measures, especially with regards to their essential medicines and prequalified finished pharmaceutical products (FPP). In this context it also demonstrated how a thorough nitrosamine risk assessment on the basis of a concrete example could be conducted taking into account global marketability and emphasizing the need for harmonization of regulatory frameworks to ensure pharmaceutical quality, safety, and therapeutic diversity.
By evaluating the WHO’s press releases, Model Lists of Essential Medicines (EML) and lists of prequalified FPPs and APIs it is demonstrated that the WHO in general has actively addressed nitrosamine issues, focusing on prequalified products, such as rifapentine and rifampicin. They monitored major regulators' announcements, provided recommendations, and implemented policies requiring comprehensive risk assessments for APIs and FPPs submitted for prequalification. The WHO revised interim limits for nitrosamines as needed, ensuring compliance with acceptable levels, and no product's prequalification status was withdrawn due to nitrosamine findings. However, the WHO’s delayed response to the nitrosamine contamination crisis in pharmaceuticals and the late publication of a draft guideline only reiterating existing EMA and FDA communications highlighted gaps in their proactive stance. Additionally, this thesis reveals that their focus has been primarily on prequalified products, lacking transparency regarding non-prequalified essential drugs and manufacturers of affected rifampicin medicines. Despite the significance of drugs like metformin and lisinopril, similar measures were not taken for non-prequalified drugs.
To improve pharmaceutical safety and quality globally, the WHO should adopt more pro-active measures, such as standardized NAP tests during manufacturing to confirm or exclude NDSRI risks. Incorporating these test results into registration dossiers would ensure comprehensive safety assessments. The WHO should also expand its scope to include non-prequalified essential drugs, ensuring consistent communication about potential nitrosamine contamination.
The case study on recently approved Camzyos® demonstrates the complexity of nitrosamine risk management, emphasizing early identification of vulnerable amines, sufficient time for toxicity assays, and sharing data between manufacturers to enhance industry knowledge. Proactive quality analysis, including global standards for in-process analysis and developing reaction matrices, can help predict and prevent harmful nitrosamine formation, ensuring consistent product quality and safety. It is expected that Nitrosamine risk assessments become fundamental in the product life cycle management.
The conclusion of the thesis underscores the critical importance of a harmonized global approach to managing nitrosamine risks in pharmaceuticals. It calls for consistent and coordinated efforts to protect patient safety and maintain the therapeutic diversity. The WHO's role is highlighted as essential in standardizing regulatory frameworks and facilitating international cooperation to effectively mitigate nitrosamine impurities. The ICH's initiative to issue a harmonized addendum to the ICH M7 guideline on nitrosamines represents a promising step forward, though it is still in its initial stage.
Pages: 77
Annexes: 6, Pages: 18