EMA proposes GMP update to EudraLex to address nitrosamine impurities

The European Medicines Agency (EMA) has proposed expanding Annex 15 of the EU EudraLex to make it mandatory for all chemical and biological active substance (AS) manufacturers in a concept paper. The update is intended to address nitrosamine impurities found during the manufacturing of sartan medications.

In recent years, there's been concern about nitrosamine impurities found in sartans, or angiotensin II receptor blockers (ARB), often used to treat hypertension, heart disease, and kidney disease. Nitrosamines have been associated with an increased risk of cancer, and stakeholders in Europe, including regulators and researchers, have proposed more stringent good manufacturing practice (GMP) requirements to address the problem.

On 9 February, EMA, with the support of its GMP inspectors working group (IWG), proposed updating the EudraLex Annex 15 requirements for manufacturing qualification and validation based on what the agency had learned about nitrosamine impurities in a 2020 report. The findings of that report, which was co-published with the Heads of Medicines Agencies (HMA), found that active substance manufacturers lacked sufficient process and product knowledge during their product development stage to take steps to prevent the contaminations.

The proposed update would make it mandatory for active substance manufacturers to comply with the requirements in Annex 15, including those regarding validation master files, qualification and validation policies, and change control.

"These extensions are expected to improve AS manufacturers practice of defining and documenting the qualification and validation activities when drafting the validation protocol referred in paragraph 12.20 of EudraLex Volume 4, Part II," said EMA. "The control of a change will be also emphasised as an important part of knowledge management."

Furthermore, the update would extend the requirements to third-party contractors and require the active substance manufacturer to exercise greater control over outsourced activities. It would also require them to investigate instances where the manufacturing requirements don't meet predefined acceptance criteria and to extend the concept of User Requirements Specifications and Factory Acceptance Testing/Site Acceptance Testing to the manufacturer.

EMA said the update would further emphasize having a robust process development and clarify concurrent validation expectations.

"Provisions on supplier qualification will be also emphasised," said EMA. "The extension of process validation activities to process recovery of materials and solvents will be highlighted.

"It will focus the attention on the variables that impact critical quality attributes when drafting process validation protocol and provides guidance on continuous process verification and 57 hybrid approach," the agency added. "Emphasis on periodic review will be also provided.

Another key aspect of the proposal would provide more clarity of EMA's expectations when transporting the drugs and biological products, including quality risk management principles set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH guideline Q9 (R1).

EMA is proposing that the concept paper should be adopted by year's end and is taking public input on the proposal until 9 April on its website.

Concept paper

EMA proposes GMP update to EudraLex to address nitrosamine impurities

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