Euro Roundup: EMA seeks feedback on revised guideline on the chemistry of active substances

The European Medicines Agency (EMA) has started a consultation into proposed changes to its guideline on the chemistry of active substances. EMA’s planned updates include revisions related to nitrosamines.

EMA’s Committee for Medicinal Products for Human Use adopted the current version of the guideline in 2016. That document describes the type of information required for the manufacture and control of existing or new chemical entities used in medicinal products. In 2022, EMA outlined the need to revise the guideline to reflect recommendations to reduce the risk of nitrosamines and to “help the European medicines regulatory network be better prepared to manage future cases of unexpected impurities.”

The 2022 concept paper consultation informed the draft guideline EMA published this week. Most of the guideline is unchanged from the currently adopted version. All the sections retain their previous titles, but EMA has added text to multiple sections, including to provide advice on how to reduce the risk of nitrosamine impurities.

“Risk of formation and carry-over of nitrosamines during the starting materials synthesis should be evaluated (e.g., use of nitrosating agents, secondary or tertiary amines, etc.),” EMA said. “If a risk is identified, adequate control strategies (in the specification of the starting material or further downstream in the active substance process) should be established, or other starting material sources using a different manufacturing process may be explored.”

Another new paragraph deals specifically with the risk nitrosating agents or amines will contaminate raw materials such as reagents, catalysts and solvents including water. Manufacturers need to consider the potential for the contamination of raw materials to carry over from the steps used to prepare them, EMA said, because it could cause nitrosamine formation in the active substance process. The agency wants manufacturers to define and justify “adequate acceptance criteria.”

EMA added a paragraph about semi-synthetic active substances, “where a starting material is obtained from fermentation or by extraction from biological material.” The agency is recommending companies “sufficiently” understand and “appropriately” discuss the impurity profile of the fermented or extracted starting material. For fermented starting materials, manufacturers should discuss the possible carryover of specific impurities, such as DNA from the fermentation process, as well as typical impurities.

Another new paragraph describes EMA’s preferred approach to starting materials of animal or human origin. In that section, the agency states manufacturers must provide information, including viral or transmissible spongiform encephalopathies safety data, on the source, processing, characterization and control of all materials of animal or human origin.

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

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

Draft Guideline

EMA working parties share regulatory guidance roadmaps in 3-year work plans

Three EMA working parties have released their plans for the coming years, providing roadmaps of the guidelines they plan to draft, revise and publish from 2025 to 2027.

The cardiovascular working party’s plan features four short-term goals and four related long-term goals. In the short term, the working party wants to release a draft guideline updating a note on the clinical investigation of medicinal products for the treatment of peripheral arterial occlusive disease. The draft will discuss endpoints to establish efficacy in different settings and other topics.

In parallel, the party will work on draft revisions to two pediatric addendums on pulmonary arterial hypertension and weight control. The desire to update the weight control addendum reflects “numerous developments in this field” since the publication of the current text.

The working party is also drafting a reflection paper on evaluating the cardiovascular safety of oncology medicinal products considering “growing interest and awareness regarding cardio-oncology field as well as increased number of patients surviving cancer.” The working party’s long-term goals are to publish final versions of the four draft documents created under the short-term plan.

The CNS working party is aiming to finalize three central nervous system guidelines on the clinical investigation of treatments for migraine, bipolar disorder and Parkinson’s disease from the second quarter of 2025 to the first quarter of 2026. Over the same period, the party plans to publish concept papers on the clinical investigation of treatments for amyotrophic lateral sclerosis, retinopathies and myasthenia gravis.

At the infectious diseases working party, the goal is to finalize three projects in 2025 and start work on four more papers by 2027. The documents nearing completion are an update of the guideline on the clinical evaluation of treatments of hepatitis B virus infection and a concept paper on updating the guideline on clinical evaluation of antifungal agents. The party also plans to contribute to an update of a guideline on investigating medicinal products in neonates.

New activities in the pipeline at the infectious disease group include the development of a guideline on the evaluation of influenza treatments and a concept paper, followed by a guideline, on evaluating hepatitis D drugs. The party also plans to update a guideline on evaluating antifungal agents and a reflection paper on developing products indicated for HIV pre-exposure prophylaxis.

Cardiovascular, Infectious Diseases, CNS

MHRA report reveals headcount growth and missed targets in financial year

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published its annual report and accounts for the 2023 to 2024 financial year, revealing that the organization grew its headcount but continued to miss multiple targets.

The latest report puts MHRA’s headcount at 1,416, up from 1,285 the previous year. However, MHRA continued to miss targets, and its performance deteriorated in some areas. The agency met its target for 25% of new active substances assessed via the national route, down from an 88% on-time rate in the previous year. MHRA aims to hit its target 97% of the time.

The percentage of medicines assessed via recognition within the published recognition pathway timeline fell too, sliding from 29% to 12% year on year, but there were improvements in other areas. MHRA assessed 40% of clinical trial applications within 30 days of submission. The figure is up on the 25.9% rate of on-time assessments in the previous year but down on the 98% targeted by the agency.

MHRA Report

EMA recommends steps to minimize risks of using weight-loss drug with opioids

EMA is advising patients to stop taking the weight-loss medicine Mysimba for at least three days before starting treatment with opioid medicines because of potential interactions between the drugs.

Mysimba, a formulation of naltrexone and bupropion sold by Orexigen Therapeutics, is used to manage weight in adults with obesity or overweight with weight-related complications. EMA reviewed evidence that patients treated with Mysimba experience insufficient effects of opioids as part of anesthesia and intra- or post-operative analgesia.

The agency also assessed reports of rare but serious and potentially life-threatening reactions such as seizures and serotonin syndrome when Mysimba and opioids are given together. The evidence informed a recommendation that Mysimba must not be used in people receiving treatment with opioid medicines.

EMA Notice

Euro Roundup: EMA seeks feedback on revised guideline on the chemistry of active substances

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