Lise CHEVANCE

Innovation in the pharmaceutical sector is complex, costly, and highly regulated. To support innovative project leaders, startups, SMEs, manufacturers, and researchers, the European Medicines Agency (EMA) has established several scientific and regulatory support mechanisms.

Unlike other organizations, the EMA does not directly fund projects, but it plays a key role in securing and accelerating the development of drug innovations.

The EMA’s role in innovation

The EMA is responsible for the evaluation and supervision of medicines at the European level. Its objective is twofold:

• to guarantee the safety, quality, and efficacy of centrally authorized medicines,
• to promote rapid access to innovation, particularly when medical needs are not being met.

To this end, it offers tools that allow for early interaction with developers in order to anticipate regulatory challenges.

1. Innovation Task Force (ITF): The entry point for innovative projects

The Innovation Task Force (ITF) is a multidisciplinary group within the EMA that provides a platform for discussing the scientific, regulatory, and legal challenges of innovative medicines, such as advanced therapy medicinal products (ATMPs).

ITF guidance meetings allow developers, including academic researchers, European consortia, SMEs, or large companies, to engage in early and informal dialogue with the EMA. These free, online exchanges help clarify technical and scientific issues even before formal scientific advice is provided.

The ITF provides particular support to key areas of innovation, such as artificial intelligence, platform technologies, new methodological approaches, and the 3Rs principles for animal research. By facilitating these early exchanges, the ITF helps innovative projects reduce regulatory uncertainty and better plan their development.

2. The SME Office: Strategic Support for SMEs

The EMA’s SME Office supports small and medium-sized enterprises in the development and marketing of medicines within the European Union and the European Economic Area. To benefit from this support, companies must apply for SME status and meet the relevant European eligibility criteria.

Once SME status has been granted, companies can benefit from fee reductions or exemptions for regulatory procedures such as scientific advice, inspections and pharmacovigilance activities. SMEs also have access to additional practical services, including free-of-charge translation of product information into all EU languages for initial marketing authorisations, significantly easing administrative requirements.

In addition, SMEs are included in the EMA’s public SME register, which is designed to facilitate interactions, partnerships and collaborations with other stakeholders across the sector.

3. Scientific Advice and Protocol Assistance: securing the development strategy

EMA Scientific Advice helps developers ensure that their tests and studies are appropriate and well designed, thereby reducing the risk of major objections being raised during the evaluation of a marketing authorisation application. This approach also helps protect patients by avoiding participation in studies that would not generate meaningful or useful data.

Scientific advice is provided by the Committee for Medicinal Products for Human Use (CHMP), based on recommendations from the Scientific Advice Working Party (SAWP). For medicines intended to treat, prevent or diagnose diseases that pose a declared or potential public health risk, such as COVID-19 or avian influenza, the CHMP bases its advice on recommendations from the Emergency Task Force (ETF).

Protocol Assistance also covers aspects related to clinical trial applications, enabling developers to secure both regulatory and scientific elements before initiating clinical studies. In practice, this service reduces regulatory risk and facilitates development planning, particularly for innovative medicines or those addressing urgent public health needs.

4. Qualification of novel methodologies: recognising innovative approaches

The qualification of novel methodologies allows the EMA to assess and provide an official opinion on innovative methods or tools used in medicine development. This can include biomarkers, imaging methods, experimental models, or any scientific approach applied in non-clinical or clinical studies.

The process is overseen by the CHMP, which relies on recommendations from the Scientific Advice Working Party (SAWP). The evaluation is based on data submitted by the developer and often includes a public consultation with the scientific community, ensuring transparency and open discussion.

In some cases, before a methodology is fully qualified, the EMA may issue a letter of support. These letters summarise the methodology, its context of use, and the available data, and encourage data sharing and further studies to achieve formal qualification.

In summary, this process validates innovative methods before they are widely adopted, providing developers with regulatory recognition and greater scientific certainty for their projects.

5. Quality Innovation Group (QIG): supporting innovation from the manufacturing stage

The Quality Innovation Group (QIG) brings together experts in the quality of chemical and biological medicines, including advanced therapy medicinal products (ATMPs), as well as specialists in good manufacturing practice inspections. The group was established to assist developers from the earliest stages of a product’s lifecycle, facilitating discussions with various stakeholders: ad hoc experts, academics, European assessors and inspectors, international regulators, industry and academic associations, and through the EU Innovation Network.

The QIG supports the use of innovative methodologies in medicine development, such as new technologies, novel materials or devices, and the digitalisation of manufacturing processes. Its goal is to provide consistent guidance throughout the product development process, whether during formal regulatory procedures (scientific advice, protocol assistance, marketing authorisation applications, or post-authorisation procedures) or through informal meetings that help identify potential regulatory issues early on.

6. EU Innovation Network (EU‑IN): a collaborative platform for innovation

The EU Innovation Network (EU‑IN) is a working group aimed at strengthening collaboration between the EMA and national competent authorities on regulatory matters related to emerging therapies and technologies. The group also supports the development of innovative medicines and associated technologies. Its primary mission is to facilitate the development of these innovations by addressing gaps in early regulatory support, providing a platform for sharing best practices, and fostering direct engagement with innovators, thereby better supporting innovative projects across Europe.

7. PRIME: priority support for high-impact medicines

The benefits include:

• enhanced regulatory support,
• more frequent interactions with the EMA,
• the possibility of an accelerated assessment.

PRIME is particularly strategic for breakthrough innovations with high clinical impact.

The PRIME (PRIority MEdicines) programme is an EMA initiative designed to support the development of medicines that address unmet medical needs. It is a voluntary scheme based on early and enhanced dialogue with developers to optimise development plans and accelerate assessment, allowing patients to access promising treatments sooner.

Through PRIME, the EMA provides proactive support to ensure the generation of robust data on a medicine’s benefits and risks, and facilitates accelerated evaluation of marketing authorisation applications. The programme builds on the existing regulatory framework and tools, including scientific advice and accelerated assessment. Developers of medicines benefiting from PRIME can expect to be eligible for accelerated assessment at the time of their marketing authorisation application.

By engaging early with developers, the programme helps improve the quality of scientific evidence, ensuring that collected data are suitable for regulatory evaluation, while allowing patients to benefit sooner from therapies that may significantly improve their quality of life.

In summary

EMA’s innovation support is based on a key principle: better support for better innovation.

Even without direct funding, these mechanisms make it possible to :

• reduce regulatory risks,
• accelerate development,
• improve the chances of accessing the European market.

For any company or team developing an innovative medicine, engaging early with the EMA is a true strategic advantage. Atessia supports its clients throughout these processes, whether for ITF briefing meetings, the SME Office, Scientific Advice, or programmes such as PRIME, helping to secure and optimise the development of their innovative medicines.

Article written by Lamya SAOUSSEN, Junior Regulatory Affairs and External Communication Advisor  

Sources :

https://www.eurogct.org/research-pathways/research-and-innovation/early-interactions-regulators/support-innovative-0

ITF : https://www.ema.europa.eu/en/human-regulatory-overview/research-development/innovation-task-force-briefing-meetings

SME : https://www.ema.europa.eu/en/about-us/support-smes

Scientific advice : https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance

QIG : https://www.ema.europa.eu/en/committees/working-parties-other-groups/chmp-working-parties-other-groups/quality-innovation-group

EU-IN : https://www.ema.europa.eu/en/committees/working-parties-other-groups/eu-innovation-network-eu

PRIME : https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicines

Since 2018, the risk of contamination of medicines by nitrosamine-type impurities has emerged as one of the most sensitive topics in pharmaceutical quality. What initially appeared as an isolated signal has become a true global regulatory issue, mobilizing authorities, manufacturers, and control laboratories. Understanding this risk—its origins and its implications—has now become essential for all stakeholders in the medicinal product lifecycle.

1. Where Does the Nitrosamine Risk Come From?

Nitrosamines are compounds classified as potentially carcinogenic. They can form under certain chemical conditions, particularly in the presence of:

• a nitrosatable agent: precursor (e.g., secondary, tertiary, quaternary amines and ammonium salts)
• a nitrosating agent (e.g., nitrites)
• a favorable environment (acidic pH, high temperature, aqueous phase, impurities)

There are two main types of nitrosamines:

• Generic nitrosamines: small, non‑specific molecules (e.g., NDBA, NDEA, NDIPA, NDMA, NEIPA, NMBA¹)
• Nitrosamine Drug-Related Impurities (NDSRIs): nitrosamines specific to active substances or their impurities, including:
  • impurities resulting from nitrosation of an active substance (N‑nitroso impurity, i.e., NO‑API)
• impurities resulting from nitrosation of an impurity of an active substance

Due to their structure, approximately 40% of pharmaceutical active substances and 30% of their impurities are considered potential nitrosamine precursors².

Their detection in several “sartan” medicines (valsartan, candesartan, irbesartan, losartan, and olmesartan) highlighted a previously underestimated risk: the possibility of forming these impurities during synthesis, manufacturing, or even storage of the active substance or finished product.

2. A Strengthened Regulatory Framework

Given the scale of the issue, authorities such as the EMA, FDA, and Health Canada quickly issued expectations. In Europe, the EMA and CMDh published a series of guidelines and Q&A documents requiring Marketing Authorisation Holders (MAHs) to follow a structured three‑step approach (adopted by most EU national competent authorities):

Step 1 – Risk Assessment & Notification to Authorities

Each active substance and finished product must undergo a thorough analysis of potential nitrosamine sources as identified in the Q&A document (EMA/409815/2020).

Step 2 – Confirmatory Testing & Notification

If a risk is identified, validated analytical methods must be implemented to confirm or rule out the presence of nitrosamines.

Step 3 – Short-, Medium-, and Long-Term CAPA

If a nitrosamine is detected at levels exceeding 10% of the Acceptable Limit (AL)—derived from the Acceptable Intake (AI)—the manufacturer must propose corrective and preventive actions (CAPA), such as:

• modification of the manufacturing process
• change of raw material supplier
• change of primary packaging
• strengthened controls
• regulatory dossier updates

These requirements apply to chemical, biological, herbal, and radiopharmaceutical products.

The Q&A (EMA/409815/2020) describes when and how to submit Step 1 and Step 2 reports. Templates are available on the EMA, CMDh, and national authority websites.

Compliance is subject to regular authority oversight, including inspections.

3. Definition of Parameters and Toxicological Tests

The following toxicological parameters and tests are defined in ICH M7 “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” (Rev2):

AI – Acceptable Intake (ng/day)

• Maximum allowable daily amount (mass) for a given product, based on toxicity data (notably TD50).
• Associated with a negligible cancer risk.
• Based on the carcinogenic potency of a substance (TD50).
• Applicable to all routes of administration.

TD50 – Toxicological Dose 50 (mg/kg)

• Dose causing tumors in 50% of animals (equivalent to a cancer risk probability of 1:2).

AL – Acceptable Limit (ng/g or ppb)

• Maximum acceptable concentration of an impurity in a drug substance or product, derived from the AI and the Maximum Daily Dose (MDD).
  
  

4. European Reference Texts: A Constantly Evolving Regulatory Framework

Nitrosamine risk management now relies on a robust set of European documents, regularly updated to reflect scientific advances and regulatory experience. Key publications from the EMA and EDQM include:

• EMA “Questions & Answers on Nitrosamine Contamination”: the regulatory cornerstone detailing expectations for risk assessment, confirmatory testing, and risk reduction/minimization strategies
• CMDh guidelines: specifying MAH obligations, including deadlines for risk assessments and variations
• EDQM monographs:
  • Specific monographs for the five initially affected active substances (valsartan, candesartan, irbesartan, losartan, olmesartan)
  • Revised general monographs, with a dedicated “N‑Nitrosamine” paragraph added under “Production”:
  • General monograph 2034 “Substances for Pharmaceutical Use”
    • General monograph 2619 “Pharmaceutical Preparations”

Six analytical procedures for quantifying NDSRIs and impurities from manufacturing intermediates, developed by OMCLs, are available on the EDQM website (Nitrosamine testing activities of the OMCL Network).

These documents form an essential reference framework for industry, which must not only comply but also maintain active regulatory surveillance. Current trends clearly show that European authorities will continue refining their expectations, reinforcing the need for a proactive and well‑documented approach.

5. Long-Term Vigilance

• European regulatory authorities (EMA/CMDh/EDQM) have continuously adjusted their recommendations to control risks, based on real‑time scientific knowledge. This has significantly disrupted the entire pharmaceutical supply chain (API manufacturers, finished product manufacturers/MAHs).
• Reference regulatory texts evolve rapidly; MAHs must monitor updates in real time. Tools such as questionnaires are provided to support MAHs in conducting the required risk assessments.

Manufacturers must therefore maintain continuous surveillance, integrate this risk into their quality systems, and follow regulatory developments closely.

Conclusion

The nitrosamine issue has profoundly transformed how the pharmaceutical industry approaches impurity control. Beyond regulatory compliance, it is a matter of patient trust and safety. Companies adopting a proactive, scientific, and well‑documented strategy will be best positioned to meet regulatory expectations and ensure product quality.

Atessia supports manufacturers in their compliance strategies.

1. NDBA: N‑nitrosodibutylamine; NDEA: N‑nitrosodiethylamine; NDIPA: N‑nitroso‑diisopropylamine; NDMA: N‑nitrosodimethylamine; NEIPA: N‑nitroso‑ethyl‑isopropylamine; NMBA: N‑nitroso‑N‑methyl‑4‑aminobutyric acid.

2. Schlingemann et al. J. Pharm Sci. 112 (2023), 1287 1304

Sources :

CMDh/412/2019: CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines

EMA/409815/2020: « Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products.

EMA/144509/2025 : Nitrosamine impurities in human medicines

ICH M7(R2) Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk


Article written by Alison HEWAT

Prior control of advertising

The control exercised by the French Health Authorities over advertising for medicinal products is probably one of the most demanding. Any advertising for a medicine is therefore subject to control and authorization by the ANSM*. Since 2012, this authorization system has been entirely based on an a priori process, i.e. the distribution of an advertisement can only start once the precious visa has been granted. In the absence of a visa, the distribution of an advertisement may lead to criminal and financial penalties.

Regarding the content of promotional documents, in application of the French Public Health Code and taking into account the state of scientific and medical knowledge, the ANSM will ensure the security of the message which must not induce bad prescribing or a danger to the public. Vector of proper use, advertising must also present the medicine objectively, and ensure compliance with the standards in force such as the MA** and the therapeutic strategies recommended by the HAS***.

Regarding advertising aimed at health professionals, in order to enable them to form their own personal idea of ​​the therapeutic value of the medicine, the ANSM ensures that the target population and the benefit-risk ratio are clearly perceptible, particularly in the documents used by persons carrying out a promotional information activity. Numerous guidelines, which are mandatory in practice, have been drawn up by the authorities to assist pharmaceutical companies in this delicate task.

Concerning advertising to the general public is only permitted for certain medicines:

• Medicinal products not subject to compulsory medical prescription, non-reimbursable and not including in their marketing authorization a ban on advertising due to a risk to public health, in particular when the medicinal product is not suitable for use without medical supervision;
• Certain vaccines included on a list from the Ministry of Health;
• Smoking cessation products.

It should also be noted that control of advertising is also exercised a priori for certain categories of medical devices presenting a significant risk to human health, the list of which is defined by a ministerial order. As with medicinal products, advertising for these devices is therefore subject to prior authorization in accordance with the French Public Health Code.

An Immutable Authorization Schedule

But the real constraint lies in respecting the timetable governing this control, implying for pharmaceutical companies to anticipate and plan their needs well in advance. Advertising is indeed subject to strict filing periods (4 per year for documents for healthcare professionals, and 8 per year for advertisements targeting the general public), and files are processed by the authorities within a regulatory time limit of 2 months.

Outside of these periods called the “deposit slot”, it is forbidden to apply for a visa. Only medicinal products that have been subject to an advertising ban during a reassessment of the benefit/risk ratio can derogate from this principle, and be the subject of a visa application outside the determined periods.

At the end of the evaluation period, the request will result in the granting of a prior authorization called the GP visa for advertising aimed at the public and the PM visa for advertising aimed at healthcare professionals, for a duration of 2 years. However, in the event of breaches of the requirement criteria on the content or presentation of the communication tool, the ANSM may issue a refusal. The applicant will then have no choice but to make a new request during the next slot. Each year, more than 10,000 visa applications are generally submitted to the ANSM (including both GP and PM visas), and this number tends to increase over time. Among these applications, approximately 15% are rejected (according to the ANSM’s 2022 and 2023 activity reports), a percentage that also appears to be rising each year.

It should be noted that it is possible to submit visa applications before the final decision on an initial marketing authorization (MA) or a modification of an existing MA, in the following cases: for an initial European MA obtained through the centralized, decentralized, or mutual recognition procedures, after the end of the European phase and based on the draft translation of the MA; for an initial national MA, based on the draft MA; and for MA modifications resulting from the above-mentioned European procedures, once the European phase is completed, also based on the draft translation. Naturally, the visa will only be valid if the MA itself is granted. The MA holder must ensure that the advertising strictly complies with the annexes of the approved MA.

The dematerialization of applying

Accelerated by the COVID-19 health crisis, the ANSM has implemented the dematerialization of visa applications via the national platform demarches-simplifiées.fr. The ANSM is thus temporarily opening a specific form for each filing period, and requests sent in paper format must now be exceptional. The applicant must then complete by scrupulously following the notice made available to users of the platform, by attaching a receipt of €510 previously issued after payment to the tax authorities.

ATESSIA supports laboratories throughout the entire review process of both promotional and non-promotional external communication materials : from communication strategy to the validation and submission of dossiers.

Article written by Mathilde ISRAEL, Regulatory Affairs and External Communication Advisor.

* ANSM : Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM is the French Authority in charge of assessing and surveying pharmaceutical products) 

** MA : Marketing Authorization

*** HAS : Haute Autorité de Santé (HAS is taked for the French Government with the evaluating of health products from a medical and economic perspective and recommending best practices)