herbal medicinal products

Background: 

Nitrosamines are genotoxic and carcinogenic substances that can be generated from secondary or tertiary amines and nitrosating agents (e.g. nitrous acid and its salts, nitrites, nitrogen oxides) under certain conditions. Apart from reactant concentration, other key factors that influence the probability and extent of nitrosamine formation include pH value, temperature and time. Traces of nitrosamines may potentially be found in active pharmaceutical ingredients (APIs), excipients and primary packaging materials.

Regulatory requirements

Since nitrosamine impurities were discovered in the sartan group of APIs, holders of marketing authorisations for chemically synthesised medicinal products have been required to review the risk of nitrosamines being present in their products and conduct targeted analyses if a risk is identified. Substance-specific nitrosamines have been found in many active substances, whereby specific limits apply to the substances for which sufficient toxicological data is available and general limits apply to all others.

In spite of the fact that marketing authorisation holders (MAHs)/applicants for all human medicinal products should ensure that the presence of nitrosamines is controlled and kept as low as possible, irrespective of marketing status or the type of product, the “call for review”, i.e. the systematic pro activ evaluation or analytical review of all medicinal products that have already been authorised, does not currently apply to herbal medicinal products (THMP and WEU). However, the BfArM (Federal Institute for Drugs and Medicinal Devices), like other European marketing authorisation agencies, requires submission of a risk evaluation based on the CMDh’s questions and answers paper (EMA/409815/2020 Rev.21 of 19.07.2024) for every new application, including applications for herbal medicinal products.

Although herbal drugs and extracts pose a low risk in general, this must be substantiated conclusively on a case-by-case basis in due consideration of the extraction and manufacturing processes.

Apart from the active substances, the risk evaluation must also include any excipients, packaging materials and other substances (e.g. extraction solvents) used during production and storage. If a risk has been identified, analyses must be carried out to verify or refute the presence of nitrosamines and risk minimisation measures must be defined, if necessary.

PhytoLab’s service for you

The service provided by PhytoLab includes library database research, performance of the risk evaluations of active substances, excipients and all other relevant components, template completion and electronic submission. We also perform risk assessments for heavy metals in accordance with ICH Q3D and environmental risk assessments (ERA) for your herbal medicinal products.

Your contacts at PhytoLab:

Medical Affairs:

DR. HARTWIG SIEVERS
Phone +49 9163 88-154
hartwig.sievers@phytolab.de

Sales:

ELKE LENZER
Phone +49 9163 88-597
sales@phytolab.de