Chemistry of Active Substances Guideline: EMA Request Feedback

The European Medicines Agency (EMA) has initiated a consultation on the proposed revisions to the guidance on the chemistry of active substances including mainly updates related to nitrosamines.

New Guidance Amendments

The guideline, originally adopted by EMA’s Committee for Medicinal Products for Human Use in 2016, outlines the necessary information for the manufacture and control of chemical active substance used in medicinal products. In 2022, EMA highlighted the need to update the guideline to incorporate recommendations for reducing the risk of nitrosamines and to manage the other potential impurities.

EMA emphasised the need to assess the risk of nitrosamine formation and carry-over during the synthesis of starting materials, particularly when nitrosating agents or secondary and tertiary amines are involved. If a risk is identified, manufacturers should establish appropriate control strategies in the starting material specification or further downstream in the active substance process. Alternatively, they may consider sourcing starting materials from a different manufacturing process.

Risk of Contamination from Nitrosating Agents and Amines

A new section addresses the risk of contamination from nitrosating agents or amines in raw materials, such as reagents, catalysts, and solvents, including water. Manufacturers must evaluate the potential for these contaminants to carry over during preparation, which could lead to nitrosamine formation in the active substance manufacturing process. The EMA expects the API manufacturers to define and justify “adequate acceptance criteria.”

Starting Materials Derived from Fermentation or Extraction

Additionally, a new section on semi-synthetic active substances derived from fermentation or extraction from biological materials has been added. The EMA recommends that companies thoroughly understand and appropriately discuss the impurity profile of such starting materials. For fermented starting materials, manufacturers should consider potential carryover of specific impurities, such as DNA from the fermentation process, in addition to typical impurities.

Starting Materials of Animal or Human Origin

The guideline also introduces a paragraph which outlines the EMA’s preferred approach to starting materials of animal or human origin, requiring manufacturers to provide detailed information on the source, processing, characterisation, and control of all such materials, including safety data for viral or transmissible spongiform encephalopathies.

Specification of the Starting Material of Animal Origin

“The specification of the starting material of animal origin should adhere to the principles set out in the European Pharmacopoeia monographs,” EMA stated, emphasising the need to address the potential presence of foreign matter, microbiological contamination, total ash, heavy metals, environmental pollutants, radioactive contamination, residual solvents, and other relevant impurities.

The EMA is accepting feedback on the draft guideline until 31 January 2025.

[table id=9 /]

Summary

Although the new draft guideline was published in July, this article is aimed to remind that the public consultation is still open until 31 Jan 2025. This blog details the updates to the guidance which will assist our regulatory colleagues to understand the sections being updated. While most sections of the guideline remain unchanged and retain their original titles, EMA has added new text in multiple sections to provide guidance on minimizing nitrosamine impurities and other potential mutagenic impurities.

Public consultation to provide comments has started on 25 July 2024 until 31 January 2025. Comments are required to be provided using the EUSurvey form.

DLRC’s team of regulatory experts can advise on current guidance on the active substance and author and/or review the documents for regulatory submissions. Contact DLRC via hello@dlrcgroup.com to maximise the potential of your products and company.