EMA Tag

03 Jul

Posted at 10:02h in Blog

EMA has published a Questions and Answers document (EMA/129980/2025) on how third party audit(s) should be reflected in part C of the QP Declaration with two new questions (Questions 3 and 9 under EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances).

  • Is an audit performed by a third party acceptable?
  • What are the expectations for the content of written final assessment of third-party audit reports?

The answers summarise quite clearly what is currently required and what a Qualified Person must be aware of, when accepting audit reports from external auditors, including the requirement of the written final assessment document and approval of third-party audit reports.

These Q&A’s were drafted and adopted by the GMDP Inspectors Working Group.

SOURCES:

https://www.ema.europa.eu/en/documents/other/questions-answers-how-should-third-party-audits-be-reflected-part-c-qp-declaration_en.pdf

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03 Jul

Posted at 09:55h in Blog

Revision 22 of the Q&A document “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” has been published on the EMA website.

The additions and changes made mainly concern the questions 10 and 22.

Updates to Q&A 10 to clarify the applicable acceptable intake (AI) limit to different administration routes and accepted in vivo study type.

Update of Q&A 22 to highlight expectations for the submission of changes in shelf-life and storage conditions required to comply with the interim limit during CAPA implementation.

 

SOURCES:

https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/referral-procedures-human-medicines/nitrosamine-impurities/nitrosamine-impurities-guidance-marketing-authorisation-holders

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08 Apr

Posted at 16:35h in Blog

The Directive I-SMI.RL.01, “Conduct of inspections of establishments manufacturing or distributing medicinal products or collecting blood.” Version 4.0 was approved on 21 October 2024 and has thus entered into force.

In February 2025, the “Questions and Answers (Q&A)” document related to centralized procedures was updated and published on the website of the European Medicines Agency (EMA).

The new edition of the Q&A document “European Medicines Agency post-authorization procedural advice for users of the centralised procedure” includes some additions and revisions and addresses relevant issues in the post-grant phase of marketing authorization.

Below are references to the chapters and questions that have been changed:

 

Chapter 1 Type IA Variations

Questions:

  • 4. How shall I present and submit my Type IA/ IAIN Variation(s)?
  • 12. When do I have to submit revised product information? In all languages?

 

Chapter 2 Type IB variations

Questions:

  • 4. How shall I present and submit my Type IB Variation?

In the related answer, the paragraph “Variations to implement changes for generic/hybrid/biosimilar products” was added.

  • 5. When shall I submit my Type IB Variation?
  • 10. How should I submit revised product information? In all languages?

 

Chapter 3 Type II variations

Questions:

  • 16. When do I have to submit revised product information? In all languages?

 

Chapter 6 Worksharing of variations

Questions:

  • 10. When do I have to submit revised product information? In all languages?

 

Chapter 19 Transfer of Marketing Authorisation

Questions:

  • 2. How shall I present my application for the Transfer of Marketing Authorisation?

 

Chapter 22 Article 61(3) Notifications

Questions:

  • 4. How shall I present my 61(3) Notification?

 

SOURCES:

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

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23 Dec

Posted at 09:44h in Blog

The European Medicines Agency (EMA) has updated the question and answer session good manufacturing practice (GMP) and distribution (GDP) on on its website “Guidance on good manufacturing practice and good distribution practice: Questions and answers”, regarding section “EU GMP guide annexes: Supplementary requirements: Annex 16”.

The question focuses on the method to be adopted to create and maintain a reliable documentation system to ensure the traceability of an active substance and a medicinal product useful to support the QP in fulfilling their legal obligations during batch certification and release.

Recommendations

  • Supply chain records should provide adequate traceability and be available in a timely manner, to facilitate quality defect investigations and product recalls, or requests of competent authorities.
  • Records should make it possible to identify, for active substances and medicinal products, all the entities, including suppliers and outsourced activities, involved in the manufacture of a specific batch of the drug product, in line with the registered supply chain.
  • Associated risks should be formally assessed and periodically reviewed with appropriate risk-mitigation measures determined to mitigate any risks identified.

 

SOURCES:

Guidance on good manufacturing practice and good distribution practice: Questions and answers | European Medicines Agency (EMA)

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01 Oct

Posted at 09:39h in Blog

The updated guideline will replace the “Note for guidance on chemistry of new active substances – (CPMP/QWP/130/96, Rev 1)” and the “Chemistry of active substances – (3AQ5a)”, it has been revised to cover new and existing active substances in one guideline.

As reported, the Concept paper on the revision of the guideline on the chemistry of active substances” of the Quality Working Party (QWP) was published for comments in June 2022. This document aimed to explain and clarify the need to revise and update the “Guideline on the chemistry of active substances (EMA/454576/2016)” and to outline the procedure for the revision.

The results obtained and insights gained were incorporated into the draft of revision 1 of the “Guideline on the chemistry of active substances,” which was published in July 2024. The draft is now open for public comments until the end of January 2025.

 

As already contemplated in the concept paper, the topic of N-nitrosamine was considered and integrated throughout the text of the guideline

 

SOURCES:

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-chemistry-active-substances-revision-1_en.pdf

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26 Jun

Posted at 10:47h in Blog

The Reflection Paper discusses methodological aspects of non-interventional studies (NIS) using real-world data (RWD) to generate real-world evidence (RWE) for regulatory purposes.

The draft document on the use of real-world data in NIS to generate RWE is open for comment until 31 August 2024.

While clinical trials are the main source of evidence for the assessment of benefits and risks of medicinal products in marketing authorization procedures (they generally use randomisation, blinding, and a controlled environment), NIS are so far more accepted in post-authorization safety assessments.

Their use to assess the efficacy of medicinal products is hampered by methodological restrictions, such as the absence of randomisation, uncontrolled conditions, non-standardised treatments and uncertainties about data quality and completeness.

The reflection paper provides some examples where NIS using RWD have supported regulatory decision-making processes.

  • To perform post marketing monitoring, investigate safety concerns and evaluate the effectiveness of risk minimisation measures.
  • To describe patterns of drug utilisation.
  • To characterise disease epidemiology.
  • To validate outcome measures.
  • To support the feasibility assessments and the planning of non-interventional post authorisation safety, efficacy and medicinal products utilisation studies.
  • To compare patient characteristics of the study population to those of the clinical practice population in the real-world.
  • To understand the clinical context, by describing standards of care, variability in clinical practices and unmet medical needs.

 

Conclusions

Non-interventional studies play an increasing role in the generation of evidence to define and complete the totality of the evidence required for novel vaccines and treatments as well as label extension for existing therapies.

The wide variety in research objectives, study designs, data and methods present a challenge for standardisation; on the other hand, the regulatory authorities evaluating the evidence generated from NIS and the different stakeholder groups have different expectations regarding their use and fitness for purpose.

It is important to continue the effort to achieve a shared approach.

 

SOURCES:

https://www.ema.europa.eu/en/reflection-paper-use-real-world-data-non-interventional-studies-generate-real-world-evidence-scientific-guideline

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26 Jun

Posted at 10:39h in Blog
  • The use of Real-World Data (RWD) is increasingly embedded in the scientific evaluation of human medicines.The newly published EMA document on the topic (Guidance on Real-world evidence provided by EMA), explains:
    • how RWE, derived from analysis of RWD, can be useful in the context of regulatory decision-making,
    • what types of studies can be conducted,
    • how the EMA can help identify the best resources to address a research question.

     

    An analysis of the RWD provided by the EMA could help

    • to fill knowledge gaps;
    • to provide independent and transparent RWE sources;
    • to carry out specific analyses tailored to the individual case, e.g. to support the work of EMA’s scientific committees;
    • generate evidence more quickly, shortening the process steps that an MAH would have to comply with to obtain the corresponding study approved;
    • avoid unnecessary duplication and inefficiency that might be typical of studies done by industry.

    An overview of the three main areas in which RWE can support regulatory decision-making is shown in the figure below (taken from the document).

  • SOURCES:

    EMA’s Big data website.

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04 Oct

Posted at 16:21h in Blog

The European Medicines Agency (EMA) has updated the Questions and Answers on the outsourced activities chapter to include “Chains of Contracts” in the pharmaceutical industry, a “setup” where one or more parties (sites/companies) are acting as signatory in a chain of contracts that links them together.

This new setup represents an innovative approach that allows greater flexibility in contractual relationships between different entities involved in the production of medicines, while maintaining high quality and safety standards.

Therefore, the setup introduces one or several separate legal entities between the contract giver such as MAH and MIA holder responsible for QP certification of the product and the contract manufacturer or any other entities included in the manufacturing/supply chain as a contract acceptor. In fact, the GMP activities concerned are sub-contracted over one or several levels”.

 

Principles

The Questions and Answers clarifies in which exceptional cases such a “chain of contract” setup would be acceptable instead of direct written contracts, the conditions to be met are as follows:

  • robust and timely communication – It should be ensured that robust and timely communication between the MAH, the MIA holder responsible for QP certification and the contract manufacturers is secured through the “chain of contracts”.
  • Access to contracts – The MIA holder and the QP should have access to all of the contracts in the “chain of contracts”. Contract manufacturers should have access to those contracts relevant to the activities they perform and the associated responsibilities. As per EU GMP Chapter 4 all these contracts are to be considered as part of the Pharmaceutical Quality System.
  • Written assessment – The MIA holder and the QP should perform a written assessment of the suitability and functionality of such a setup.
  • Notification of changes – Any changes in the “chain of contracts” must be notified to and approved by the MIA holder and the QP prior to the change of the respective contracts being implemented.
  • Audited and evaluated according to EU-GMP standards – All parties involved in the “chain of contracts” setup should be audited and evaluated in accordance with Chapter 7 and Annex 16 of the EU-GMP and should also be reflected in the supply chain diagram.
  • PQR – All contracts within the “chain of contracts” setup are reviewed as part of the product quality review (PQR) process.

Nonostante l’introduzione di questa nuova configurazione, l’EMA ha sottolineato che i “contratti scritti diretti” rimangono ancora la preferenza principale. I contratti scritti diretti sono quelli firmati tra le parti coinvolte direttamente nell’esecuzione delle attività specificate e offrono maggiore chiarezza e trasparenza nel processo.

Despite the introduction of this new setup, EMA underlined that “direct written contracts” are still prefererred. Direct written contracts are those “signed between the parties, that actually perform the activities stated in the contract”.

SOURCES:

Guidance on good manufacturing practice and good distribution practice: Questions and answers

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04 Oct

Posted at 16:14h in Blog

After the FDA had already published an initial discussion paper addressing Artificial Intelligence (AI) in the manufacturing of medicinal products, in early 2023, the EMA issued a draft reflection paper outlining the current thinking on the use of artificial intelligence (AI) to support the safe and effective development, regulation and use of human and veterinary medicines, on 19 July 2023.

This paper reflects on principles relevant to the application of AI and machine learning (ML) at any step of a medicines’ lifecycle, from drug discovery to the post-authorisation setting and reports the experience of the EMA in this context, in which scientific knowledge is rapidly evolving.

Recently the success of ChatGPT and related reporting have made the topic of Artificial Intelligence accessible to a wide audience.

 

General considerations

In general, it is mentioned that AI and ML, if used correctly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal products lifecycle.

A risk-based approach to the development, implementation and performance monitoring of AI and ML tools should enable developers to proactively define the risks to be managed during the life cycle of AI and ML tools.

AI and ML tools, when used properly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal product lifecycle. Section 5 of the document lists some guidelines and documents that may provide useful recommendations for implementing AI/ML applications.

It is essential to highlight that the marketing authorisation applicant or MAH is responsible for ensuring that the algorithms, models, datasets, etc. used are fit for purpose and meet ethical, technical, scientific and regulatory standards.

 

Content of the document

The document addresses the following topics:

  • AI in the lifecycle of medicinal products
    • Drug discovery
    • Non-clinical development
    • Clinical trials
    • Precision medicine
    • Product information
    • Manufacturing
    • Post-authorisation phase
  • Regulatory interactions
  • Technical aspects
    • Data acquisition and augmentation
    • Training, validation, and test data
    • Model development
    • Performance assessment
    • Interpretability and explainability
    • Model deployment
  • Governance
  • Data protection
  • Integrity aspects
  • Ethical aspects and trustworthy AI

 

Conclusion

The quickly developing field of AI and ML shows great promise for enhancing all phases of the medicinal product lifecycle.

Finally, the use of AI in the lifecycle of medicines should always comply with existing legal requirements, considering ethics and its underlying principles, and with due respect for fundamental rights. A human-centred approach should be adopted in the development and use of AI and ML.

SOURCES:

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19 Jun

Posted at 15:07h in Blog

The EMA has published an overview of the recommendations for the use of herbal substances and/or preparations in the paediatric population as set out in the European Union herbal monographs. The document summarises the indications and possible limitations of use in children, based on the assessment of the Committee on Herbal Medicinal Product (HMPC).

The age range and use of herbal medicinal products within this special patient population, are topics often addressed by healthcare professionals. The purpose of this overview is to provide a summary of the information included in the monographs for ease of reference.

The list is divided into two groups of herbal medicinal products:

  • well-established use -WEU: demonstrated sufficient safety and efficacy data (may only be placed on the market after obtaining a marketing authorisation);
  • traditional use -TU- accepted based on sufficient safety data and plausible efficacy (can be marketed after being registered through simplified registration).

The list is derived from the information contained in the EU herbal monographs, as adopted, and can be consulted either by alphabetical order or according to therapeutic areas, for example, constipation, cough and cold, wye discomfort, gastrointestinal disorders, sleep disorders and temporary insomnia, etc.

For each substance the indications in the therapeutic area, possible herbal preparations referred in the monograph, dosage form and method of administration, Target population and Justification for limited use, for example in children, are listed in a tabular list.

SOURCES:

More detailed information is available in the EMA document European Union herbal monographs: Overview of recommendations for the uses of herbal medicinal products in the paediatric population.

To view all EU herbal monographs go to Herbal: European Union herbal monographs.

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