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

The new regulation (EU) 2017/745 introduces new requirements to enhance the safety of patients and users. One of the novelties of this new regulation is the creation of a European database dedicated to information on medical devices called EUDAMED.

This database will allow:

• Increased transparency of information on medical devices with public access.
• Better coordination between Member States in the post-market surveillance of medical devices.

EUDAMED is a secure platform used to collect and share data related to medical devices placed on the European Union market, as well as those undergoing clinical investigation.

The regulation introduces new requirements for the various actors involved in EUDAMED.

This database will consist of six interconnected modules:

Source : European commission

And the Distributors?

The MDR imposes no requirements on distributors regarding EUDAMED. They have no secure access to EUDAMED and only have public access. However, some countries may set additional requirements, such as France, which requires distributors to register via the ANSM form.

EUDAMED Deployment Schedule

In October 2019, the European Commission announced a two-year postponement of EUDAMED’s launch to May 2022.

Some modules are already available and can be used voluntarily. A roadmap project was released on July 10, 2024, indicating a full deployment of EUDAMED scheduled for the second quarter of 2027.

On 27 November 2025, the European Commission published Decision (EU) 2025/2371 on the functionality and compliance with specifications for EUDAMED modules:

• Registration of economic operators” module (ACT module)
• Medical device registration and UDI database module (UDI/DEV module)
• Certificates and notified bodies module (NB/CRF module)
  • Market surveillance module (MSU module)

These 4 modules are therefore operational and will be compulsory from 28 May 2026 (i.e. 6 months after publication in the OJEU) in accordance with Regulation (EU) 2024/1860. 

The remaining 2 modules are not currently available:

• Clinical investigations/performance studies module (CI/PS module)
• Post-trade surveillance and vigilance module (VGL module)

A roadmap has been updated:

Useful Documents and Guides:

Q&A “on practical aspects related to the implementation of the gradual roll-out of Eudamed pursuant to the MDR and IVDR, as amended by Regulation (EU) 2024/1860 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards a gradual roll-out of Eudamed, the obligation to inform in case of interruption or discontinuation of supply, and transitional provisions for certain in vitro diagnostic medical devices” (22/11/2024)

USER GUIDES to record the information in EUDAMED

MDCG “EUDAMED”

European Commission – The EUDAMED four first modules will be mandatory to use as from 28 May 2026

OJEU – Commission Decision (EU) 2025/2371 of 26 November 2025 concerning the opinion on the functionality and compliance with functional specifications of certain electronic systems included in the European database on medical devices referred to in Article 34(1) of Regulation (EU) 2017/745 of the European Parliament and of the Council

Article written by Camille Neermul

In Europe, changes to a marketing authorisation (MA) for a human medicine are covered by Regulation (EC) No. 1234/2008 of November 24, 2008. This regulation has been applicable since January 1, 2010 to MAs obtained in centralized, decentralized and mutual recognition procedures, and since August 4, 2013 to MAs obtained in national procedures. It presents multiple possibilities for classifying the modifications that can be made to a MA, including the Post-Approval Change Management Protocol (known by the acronym “PACMP”) which we will focus on in this article.

Origin and definition 

A PACMP is a regulatory tool providing predictability and transparency in terms of requirements and studies necessary for the implementation of a strictly CMC (for “Chemistry, Manufacturing & Controls”) change, because the approved protocol of the planned changes constitutes an agreement between the MA holder and the regulatory authority. This is a stepwise approach to evaluate modifications, initially allowing for an early evaluation of the modification strategy and, in a 2^nd step, a subsequent separate evaluation of the data produced after implementation of the planned changes on the basis of the agreed strategy.

The objective of this tool is to allow faster and more predictable implementation of modifications after approval, given that the MA holder will have previously obtained the agreement of the authorities on the proposed strategy and the tests allowing to check the effect of the modification on the quality of the product. Typically, the variation category designated for reporting changes under a PACMP is at least one category lower than it would normally be (e.g., Type IB instead of Type II). The implementation of the changes planned in an approved PACMP is therefore faster and less risky for the laboratories that request it, which ultimately benefits to the marketing of the drug and therefore to the patient.

In 2012, the EMA compiled a set of questions and answers regarding the PACMP in the document “Questions and answers on post approval change management protocols (EMA/CHMP/CVMP/QWP/586330/2010)”. This document was revised in December 2025 to reflect experience gained since its initial publication, the revision of the regulations on variations (2024), and the associated guidelines on variations (2025) applicable on January 15, 2026. The following topics are covered:

• Suggestions for PACMP content; 
• PACMP submission and evaluation mechanisms; 
• Implementation of the change(s) after finalisation of the studies described in the PACMP; 
• Types of changes that may be subject to a PACMP; 
• Multiple changes within the framework of a single PACMP; 
• Place of the PACMP in the Module 3 of the MA; 
• PACMP and development according to the traditional approach versus the improved approach (so called “QbD” for “Quality by Design”). 

In 2019, the ICH Q12 guideline “Technical and regulatory considerations for pharmaceutical product lifecycle management“, proposed in order to provide a framework to facilitate the management of changes to chemical properties, manufacturing and control measures after the authorisation, in a more predictable and efficient manner throughout the lifecycle of the product, has reinforced the place of the PACMP as an essential regulatory tool in the management of the lifecycle of medicines in Europe.

Scope of the PACMP use 

The PACMP concerns both CMC modifications relative to the drug substance (DS) and modifications relative to the drug product (DP). It applies to all medicinal products for human use, including biotechnological or biological products, whether a traditional or improved (“QbD”) approach was followed for the development of the product. However, its use is optional.

A PACMP can be applied to a single product, multiple products, or multiple products and multiple sites.

The presence of a PACMP in its MA file involves careful risk analysis and a full understanding of the different risk assessments to ensure that the quality, safety and efficacy of the medicine are never compromised.

It has to be noted that no modification described in a PACMP should result in additional risks to patient safety, product quality or efficacy. Also, a CMC modification that would require human efficacy, safety, or pharmacokinetic/pharmacodynamic data to evaluate the effect of the modification (e.g., certain formulation changes, clinical or nonclinical studies to evaluate new impurities, evaluation of immunogenicity or antigenicity) cannot be included in a PACMP.

Formalisation of the PACMP in the MA file 

The PACMP takes the form of one or more document(s) presented in section 3.2.R “Regional Information” of the MA file. It can be planned as soon as the MA application is made or during a MA variation application (Type II).

MA modifications linked to the PACMP 

The different variations linked to the introduction, deletion or modification of a PACMP in a MA file are presented in the table below.