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