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Qu'est-ce qu'un RMP EU ?

What is an EU RMP ?

A Risk Management Plan (RMP) is an essential element of pharmacovigilance activities. Its primary objective is to identify, characterize, and minimize the risks associated with a medicinal product, thereby ensuring continuous monitoring of the product’s benefit-risk balance. 

Responsibilities of the Marketing Authorization Holder (MAH) 

The MAH, together with the Exploitant in France, are responsible for: 

  • Establishing a risk management system 
  • Implementing, maintaining, and updating the RMP 
  • Continuously monitoring the safety profile of the medicinal product by analyzing pharmacovigilance data  to detect new risks that may alter the product’s benefit-risk balance 
  • Implementing risk minimization measures when necessary, and evaluating their effectiveness 
  • Updating the risk management system and RMP accordingly when new safety information becomes available 

The RMP is a dynamic document that must be regularly updated throughout the product’s lifecycle — for example, in  case of a variation or extension of indication, upon request from competent authorities (EMA or ANSM), or when a new risk is identified or an existing one is reclassified. 

Submission of the RMP to the European Medicines Agency (EMA) 

An RMP must be submitted to the competent authority (EMA for centralized procedure) in the following cases: 

  • As part of any initial Marketing Authorization Application (MAA) 
  • When an updated RMP is required during the post-authorization phase, either at the request of regulatory authorities or due to a change to the MA (e.g., new indication, new dosage, new route of administration) that affects the risk profile of the medicinal product 

RMP Structure 

The structure and content of an RMP vary depending on the regulatory status of the product (e.g., generic, biosimilar, well-established medicinal use product, combination product, etc.). 

Key components include: 

  • Summary of Safety Concerns : risks are categorized into three main types: 
  • Important Identified Risk: a risk for which there is sufficient scientific evidence to establish a causal relationship with the medicinal product. It may require specific monitoring or risk minimization measures. 
  • Important Potential Risk: a risk for which available data suggest a possible causal relationship, but the evidence is not conclusive. 
  • Missing Information: gaps in knowledge regarding the safety profile, such as lack of data in specific populations (e.g., pregnant women, children) or long-term use. 
  • Pharmacovigilance Plan : this section outlines how the MAH intends to monitor and manage the risks identified in the RMP. It includes: 
  • Routine activities, which are mandatory for all medicinal products (e.g., adverse event reporting, periodic safety reports, signal detection) 
  • Additional activities, conducted to further characterize or quantify known or potential risks (e.g., post-authorization safety studies) 
  • Risk Minimization Measures : where applicable, measures are proposed to minimize identified risks. These may include: 
  • Routine risk minimization measures, mandatory for all products (e.g., SmPC, patient leaflet, labeling) 
  • Additional risk minimization measures, such as patient alert cards, educational materials, or healthcare professional training 

The effectiveness of these risk minimization activities must be evaluated. This is often done through specific studies, which are included in the pharmacovigilance plan. 

Relationship Between RMP and PSUR 

The RMP and the Periodic Safety Update Report (PSUR) are complementary documents and are both part of the core post-marketing pharmacovigilance strategy. 

The RMP should reflect the conclusions of the PSURs. If a new safety signal discussed in the PSUR is reclassified as an important identified or potential risk, it must be incorporated into the RMP. Consequently, updates to the pharmacovigilance and risk minimization plans should be made to outline the MAH’s proposed approach to managing this new risk. 

Confidentiality 

The EMA publishes RMPs for centrally authorized products, both at the time of initial authorization and for subsequent updates during the post-marketing phase. 

It is the MAH’s responsibility to anonymize any personal data and redact commercially confidential information before submitting the RMP to the EMA for assessment. 

Article written by Marion PETOT, Consultant in Pharmacovigilance 

To learn more about our pharmacovigilance services, visit Atessia Vigilance: our dedicated subsidiary specializing in risk management and drug safety.

L'ICH et son influence sur la réglementation mondiale

ICH and its influence on global regulation 

Presentation of ICH (roles, history, missions, etc.) 

ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) is an organisation that brings together regulatory authorities and the pharmaceutical industry to discuss scientific and technical aspects of drug registration. 

In particular, this instance develop harmonised guidelines for global pharmaceutical development: the “ICH guidelines“. 

Since its founding in 1990, the ICH’s mission is to promote and support harmonisation worldwide to ensure that safe, effective and high-quality medicines are developed and registered efficiently.  

Like other organisations, ICH has had to adapt to an increasingly globalised drug development industry. 

ICH was incepted in 1990 and was formerly named the International Conference on Harmonisation (ICH). At the first ICH Steering Committee meeting of ICH, it was decided that the topics selected for harmonisation would be divided into three distinct domains in order to reflect the criteria which are the basis for approving and authorising new medicinal products: Safety (S), Quality (Q) and Efficacy (E)

Cross-cutting topics that do not fit uniquely into one of these three categories fall into the Multidisciplinary (M) domain. These include the “MedDRA” medical terminology, the “CTD” common technical format and the development of “ESTRI” electronic standards for the transfer of regulatory information. 

The ICH Assembly brings together all members and observers of the ICH Association as the overarching governing body of the organisation. 

Since October 2015, ICH has grown as an organisation and now includes 23 Members and 38 Observers. 

As an observer, the EDQM contributes to the development of ICH guidelines in a number of relevant areas (e.g.: control of impurities, development and validation of analytical procedures and continuous manufacturing). 

The evolutions of ICH 

Since its creation, the ICH has gradually evolved to meet the increasingly global challenges of the pharmaceutical industry. 

The key dates are listed below: 

>1980s: Lauch of harmonisation of regulatory requirements by the EC as Europe moved towards the development of a single market for pharmaceuticals. At the same time, discussions occur between Europe, Japan and the US on possibilities for harmonisation. 

>1989:  Specific plans for action for harmonisation begin to materialise at the WHO Conference of Drug Regulatory Authorities (ICDRA) in Paris. Soon afterwards, the authorities approached International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint regulatory-industry initiative on international harmonisation, and ICH was conceived. 

>April 1990: Birth of ICH  at a meeting hosted by EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the US met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. 

Now in its fourth decade of activity, ICH’s attention is directed towards extending the benefits of harmonisation beyond its founding regions (Europe, USA and Japan). In 2015, to facilitate this, a series of organisational changes took place. These changes constituted a number of reforms including: increasing international outreach; changing ICH’s governance structure; disseminating more information on ICH processes to a wider number of stakeholders; and establishing ICH as a legal entity to provide for a more stable operating structure. 

The resulting ICH association establishes an Assembly as the over-arching governing body with the aim of focusing global pharmaceutical regulatory harmonisation work in one venue that allows pharmaceutical regulatory authorities and notably concerned industry organisations to be more actively involved in ICH’s harmonisation work. 

The ICH’s work products 

The work carried out by the ICH falls into four areas: harmonisation activities, the development of guidelines, the development of standards (MedDRA dictionary, CTD format or ESTRI electronic standards) and other work (e.g.: the development of discussion papers). 

The ICH guidelines development process 

ICH harmonisation activities fall into 4 categories: Formal ICH Procedure, Q&A Procedure, Revision Procedure and Maintenance Procedure, depending on the activity to be undertaken. 

Each harmonisation activity is initiated by a Concept Paper which is a short summary of the proposal. Depending on the category of harmonisation activity a Business Plan may also be required. The Business Plan outlines the costs and benefits of harmonising the topic proposed by the Concept Paper. 

The Formal ICH Procedure (a step-wise procedure consisting of 5 steps) is followed for the harmonisation of all new ICH topics. 

The procedure is initiated with the endorsement by the ICH Assembly of a Concept Paper and Business Plan. An Expert Working Group (EWG) is subsequently established. 

The EWG works to develop a draft Guideline and bring it through the various steps of the procedure which culminate in Step 5 and the implementation in the ICH regions of a Harmonised Guideline. 

The five steps are as follows: 

  • Step 1: Consensus building 
  • Step 2a: Confirmation of consensus on the Technical Document 
  • Step 2b: Adoption of draft Guideline by Regulatory Members 
  • Step 3: Regulatory consultation and Discussion 
  • Step 4: Adoption of an ICH Harmonised Guideline 
  • Step 5: Implementation 

The ICH guidelines implementation process 

At Step 5 of the ICH process, harmonised ICH Guidelines are implemented by ICH Regulatory Members and Observers within their respective country/region. This is in line with the ICH Articles of Association and the aim and intention that all ICH Regulatory Members should implement all ICH Guidelines. 

For ICH Regulatory Observers, implementation of (certain) ICH Guidelines is a pre-requisite to become an ICH Regulatory Member. 

ICH Guidelines are implemented in accordance with the applicable national/local/regional rules, with the stage of implementation of all ICH Guidelines also being dependent on when a Member or Observer has joined ICH. 

In April 2025, a total of 163 guidelines (all domains combined) were published on the ICH website, broken down as shown in the graph below: 

Future ICH work impacting global regulation 

ICH continues to propose guidelines on pharmaceutical development topics requiring regulatory harmonization, or where a lack of recommendations has been identified. This is the case, for example, of the (long-awaited) draft ICH Q3E guideline on extractables and leachables. 

In addition, the updating of current guidelines is also supported, in order to take account of scientific progress. Examples include the recent update of the ICH Q2 guideline on analytical validation, and the forthcoming revision of the ICH Q1A-Q1F series of stability guidelines. 

Sources: 

EDQM – Pharmacopoeial Harmonisation 

ICH Official web site : ICH 

Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Senior Consultant 

Paediatric Investigation Plan

Paediatric Investigation Plans & paediatric requirements in the EU 

The need for a paediatric regulation for medicines

The need for a paediatric regulation in the EU is born almost 30 years ago with the report that:

  • Medicines were used in children based on empirical knowledge and off-label, with not approved adaptations of doses,
  • Pharmaceutical forms were not adapted to the paediatric population,
  • Clinical trials were not conducted in children to preserve this population from exposure to medicines under development,
  • Very few medicines were developed in this limited specific population partly.

In 2000, the International Conference on Harmonisation published a dedicated guideline (ICH E11 – « Clinical Investigation of Medicinal Products in the Pediatric Population ») with the objective to promote clinical research in the paediatric population.

In parallel, from 1997, the European Commission launched initiatives with different stakeholders that led to the publication of the so-called paediatric regulation (Regulation No. 1901/2006/EC) on 12 Dec 2006 that came into force in Jan 2007.

European Requirements for the paediatric development of medicines

That regulation, which has been amended twice, created the paediatric committee (PDCO) within EMA but also set up a comprehensive regulatory framework with obligations and incentives for Applicants and Marketing authorisation holders.

From 2007, any new Marketing authorisation application must be accompanied with the proof of compliance to an approved Paediatric Investigation Plan (PIP) that describes the studies that will be conducted in the paediatric population and associated timelines.

This requirement is also applicable to medicinal products with a valid patent or protection for which new indication (paediatric or not) new pharmaceutical form or new route of administration will be submitted.

This requirement is applicable whatever the chosen procedure (National, Decentralised, Mutual Recognition and Centralised).

The PIP details the following:

  • A calendar and specific measures to assess quality, efficacy and safety of the medicines in all subsets* of the paediatric population;
  • Any measure that will be put in place to adapt the formulation to the paediatric  population to enable a safer, more adapted easier use of the medicines in the paediatric population.

Template of the EU PIP is available on EMA Website and should be used by Applicant to support effective assessment of the PIP.

*ICHE11 defines the paediatric subsets as:

  • preterm newborn infants
  • term newborn infants (0 to 27 days)
  • infants and toddlers (28 days to 23 months)
  • children (2 to 11 years)
  • adolescents (12 to 16-18 years (dependent on region))

In parallel, the paediatric regulation set up rewards and incentives for some situations to support the development of medicines in children :

  • Scientific advice and protocol assistance linked to paediatric development are free of charge at EMA level;
  • Extension* of the protection (Patent or Supplementary Protection Certificate) by 6 months for a product authorised across the EU and for which results of the paediatric studies planed in the PIP have been included in the MA dossier (and included in the product information).
  • 2 additional years of market protection in case the results of the studies planed in the PIP are submitted in an application for an orphan medicinal products;
  • Finally, it created the notion of PUMA: Paediatric Use Medicines Authorisation which has a 10-year market exclusivity period.

*in this case, the MAH must market the product in the paediatric indication within 2 years upon approval. These deadlines are made available with a list published on EMA Website.

This incentives and rewards can be completed by other national incentives that are not detailed here.

Finally, this regulation provides that Marketing-authorisation holders must submit the results of studies on authorised medicines conducted in children to the European Medicines Agency (EMA) or to national competent authorities in the European Union (EU) included or not in a PIP. From 2007, MAH are requested to submit clinical study results in the paediatric population within 6 month from the termination of the study. Modification of SmPC can be requested by the HAs based on those data.

Specific cases

There are cases where the inclusion of a PIP is not a prerequisite for the submission of a MA or above-mentioned post MA submissions or where some adaptations are possible.

Exemptions :

First of all, some MA are exempted from the requirement to perform a PIP. These legal basis are:

  • Applications according to article 10*: Generic, Hybrid and Biosimilar
  • Application according to Article 10a*: Well-Established Use
  • Applications according to Articles 13 and 16*: Homeopathic and traditional herbal medicinal products

*of Directive 2001/83/EC

Waivers :

In addition, the regulators have considered cases where a PIP is not needed or requested:

  • Medicines not expected to be efficient or safe in the paediatric population of subset of paediatric population,
  • targeted disease does not exist in the paediatric population,
  • no additional benefit expected in the paediatric population versus the already available treatment.

In those cases, class waivers or specific waivers are possible. For the first case, the PDCO publishes a list of class waivers that are applicable. For the second option, it is requested to submit a specific waiver request to the PDCO.

Deferrals :

Finally, the regulators also provided cases where the paediatric requirements is not requested to be performed before submission of the Marketing Authorisation Application: the PDCO may grant deferral.

Such situations are expected for scientific or technical reasons or on Public Health grounds or when clinical results in adults are necessary prior to administer the product to the paediatric population.

In the case of deferral, a detailed calendar agreed with the PDCO is approved and must be followed by the MAH. In addition annual reports on paediatric deferred measures must be submitted by the owner of the PIP.

These waivers and deferrals might concern the full paediatric population or only  some subsets of the paediatric population.

Regulatory activities

Pre-MA

It is expected that PIP (initial version), deferral, product specific waiver requests, confirmation of applicability of class waiver are submitted to the PDCO via the IRIS portal. Paediatric regulation requests that these requests must be submitted at the latest at the date by when Pharmacokinetics studies are achieved.

PDCO will appoint a Rapporteur that will be in charge of the PIP assessment, product specific waiver or deferrals assessment within 60 days form validation. This period can be extended by a further 60-day assessment period as necessary. There is no fixed timelines for responses.

When a PIP is approved, the PIP becomes binding for the applicant that must submit PIP modifications if relevant (e.g. delayed timelines).

MA and Post MA Regulatory activities

Before submission of a MA for which a PIP is mandatory or for which deferral has been approved, the applicant should submit a request for compliance check to the PDCO. The PDCO will assess this request within 60 days and provide the applicant with a statement to be included in the MA dossier. In not performed before, the PDCO can be included during the validation period of the MAA that could lead to delayed start of the procedure.

Results of paediatric studies, waivers and deferrals are included in the Product Information.

Regulatory perspectives

Some studies[i],[ii],[iii] (cf. references below) confirmed the positive impact of the paediatric Regulation on the availability of medicines for children. Nonetheless, needs to have medicines in children still exist.

It is also interesting to note that EMA developed an inventory of the needs for paediatric medicines that is available in their website to help developers to identify opportunities.

The revision of the pharmaceutical legislation in the EU includes a new regulation that will replace existing regulations including Regulation 1901/2006/EC. Among other changes, one of the intention from the Regulators is to bring a more strict framework of exemptions and thus increase the development of medicines in the paediatric population.

Atessia supports companies in defining paediatric strategy and writing PIPs.

This article was written by Agathe DAUBISSE, Senior Regulatory Affairs Advisor


[i] Toma M, Felisi M, Bonifazi D, Bonifazi F, Giannuzzi V, Reggiardo G, de Wildt S, Ceci A and TEDDY European Network of Excellence for Paediatric Research (2021) Paediatric Medicines in Europe: The Paediatric Regulation—Is It Time for Reform? Front. Med. 8:593281. doi: 10.3389/fmed.2021.593281

[ii] Nordenmalm S, Tomasi P, Pallidis C More medicines for children: impact of the EU paediatric regulation Archives of Disease in Childhood 2018;103:557-564.

[iii] : Volodina A, Shah-Rohlfs R, Jahn A. Does EU and US paediatric legislation improve the authorization availability of medicines for children in other countries? Br J Clin Pharmacol. 2023;89(3):1056‐1066. doi:10. 1111/bcp.15553

Comprendre EUDAMED

Understanding EUDAMED: The European Database on Medical Devices

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:

Module :  Who needs to record information?Accessible to the public
1-ActorsEconomic operators must register as actors in EUDAMED and provide the required information.– EU and third-country manufacturers, – Authorized representatives, – System/procedure pack producers, – Importers.Available on a voluntary basis since December 2020 and will be mandatory from Q1 2026.
2-Devices Manufacturers must submit the basic-UDI and information of all devices they place on the EU market into EUDAMED.– Only manufacturers. Registration of medical devices under MDR. No obligation for legacy devices (if registered in EUDAMED, a new registration will be required for products under MDR, considered as new products).Available on a voluntary basis since October 2021 and will be mandatory from Q1 2026.
3- Notified Bodies (NB) and Certificates. Notified bodies must register in EUDAMED all information regarding issued, suspended, reinstated, withdrawn, or refused certificates and other restrictions imposed on these certificates. This information is accessible to the public.  – Notified Bodies.Available on a voluntary basis since October 2021 and will be mandatory from Q1 2026.
4-Vigilance  Module dedicated to all vigilance and post-market surveillance reports. – Safety information (Field Safety Notice, FSN), – Field Safety Corrective Action (FSCA), – Investigation report of incident causes and corrective measures (MIR), – Trend report, – Periodic Safety Update Report (PSUR).  – Manufacturer.Will be mandatory from Q3 2026.
5- Market SurveillanceCoordination of market surveillance actions between the various competent authorities.  – Competent authority only.Will be mandatory from Q1 2026.
6- Clinical Investigation/Performance Studies (CI/PS):  This module concerns the registration of clinical investigations (MD) and performance studies (IVD). – Clinical investigation report and summary, – Serious adverse event during clinical investigations.– Sponsor.Not yet available.


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. The dates present in the EUDAMED roadmap are provisional and in “Draft” mode. No dates are official at this stage.

Recently, on January 21, 2024, the European Commission published a proposal to amend regulation (EU) 2017/745 on medical devices (MDR) and regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) concerning the gradual deployment of EUDAMED. This proposal suggests a gradual implementation of EUDAMED modules once validated, potentially starting in Q4 2025. This proposal will need to be adopted and published in the Official Journal by May 2024.

Useful Documents and Guides:

– EUDAMED Release Note

– EUDAMED Roadmap

MDR Transition: New Responsibilities and Major Changes in the Medical Device Industry

Since 1994, medical devices have had to comply with the requirements of European Directives 93/42/EEC and 90/385/EEC. Conformity with this regulation allows the affixing of the CE marking, enabling the free circulation of medical devices within the European Union (EU).

The European Union has recently revised this regulation through the European Regulation 2017/745/EU for medical devices (MDR), which finally came into effect on May 26, 2021. The adoption of a regulation instead of a directive ensures uniformity in the regulatory framework through its direct application.

This new regulation imposes new responsibilities on economic operators involved in the supply chain of medical devices: manufacturer, authorized representative, importer, distributor.

What are the main changes introduced by this new regulation (MDR)?

– Redesignation of Notified Bodies (NB) under MDR and EU control of Notified Bodies (NB)

– Improved traceability through the Unique Device Identification (UDI)

– Inclusion of certain aesthetic devices with the same characteristics and risk profile as medical devices covered by the regulation

– Enhanced transparency through EUDAMED, the medical device database

– Strengthened requirements for clinical data and post-market surveillance

What transition periods will apply?

Initially, the MDR was to come into effect on May 26, 2020. Due to the COVID-19 health crisis in 2020, the EU decided to postpone this date through Regulation (EU) 2020/561.

The implementation date was thus postponed to May 26, 2021, with a transition period for manufacturers with medical devices already on the European market (“LEGACY DEVICES”) until May 26, 2024 (end of the issuance of certificates under the directive) and the availability of these medical devices on the market until May 26, 2025. However, for class I medical devices and new medical devices entering the European market, they had to comply with the MDR since May 26, 2021.

On March 20, 2023, the EU assessed a potential shortage risk for many medical devices and adopted Regulation EU 2023/607, amending Regulation (EU) 2017/745 concerning transitional provisions (Article 120).

The extension dates of certificates under Directive 93/43/EEC are extended based on the class of the medical device:

However, manufacturers covered by this extension must meet the following conditions:

1/ The devices continue to comply with Directive 90/385/EEC or Directive 93/42/EEC, as applicable. ;

2/ There are no significant changes to the design and intended use.;

3/ The devices do not present an unacceptable risk to the health or safety of patients, users, or other persons, considering other aspects related to public health protection. ;

4/ no later than 26 May 2024, the manufacturer has put in place a quality management system in accordance with Article 10(9); ;

5/ The manufacturer or authorized representative has lodged a formal conformity assessment request under the MDR for a medical device or a replacement device to a Notified Body by September 26, 2024, and the Notified Body and the manufacturer have signed a written agreement.

Special case for custom-made class III implantable devices – transitional period introduced:

The conformity assessment of custom-made class III implantable devices requires an assessment by a Notified Body.

Custom-made class III implantable medical devices can be placed on the market without the corresponding certificate until May 26, 2026, provided that the manufacturer has submitted an application to a designated Notified Body under the MDR before May 26, 2024, and has signed a contract with that Notified Body before September 26, 2024.

MDR requirements applicable from May 26, 2021:

However, it is important to note that certain MDR requirements shall apply to devices  since May 26, 2021, such as requirements related to post-market surveillance, market surveillance, vigilance, and the registration of economic operators.

Removal of the availability date:

Additionally, Regulation EU 2023/607 completely removes the availability deadline, allowing “LEGACY DEVICES” to be available without a deadline (still respecting the device’s usage limit date). This removal also applies to in vitro diagnostic medical devices marketed before May 26, 2022, in Regulation (EU) 2017/746 (IVDR).

Are CE certificates under the directives still valid during this extension period?

Certificates that expired before the entry into force of Regulation 2023/607 (March 20, 2023) should only be considered valid if:

– Either before the certificate’s expiration date, the manufacturer and Notified Body signed a conformity assessment agreement before the certificate’s expiration date.

– Or if a competent authority has granted a derogation.

Notified Bodies can no longer issue or modify CE certificates under the directives since May 26, 2021. Therefore, they are considered extended unless they have been withdrawn.

Manufacturers can issue a self-declaration confirming that they comply with the extension conditions, indicating the end date of the transition period (the medical devices covered by the extension must be clearly specified). At the manufacturer’s request, the Notified Body can also issue a confirmation letter.

It is important to remember that despite these delays, manufacturers must now act toward this new regulation. The submission period to Notified Bodies can take from 6 to 18 months, depending on the Notified Body and the medical device.

Atessia supports its clients through all stages of MDR compliance.

Quelle substitution des médicaments biologiques en France?

Biological medicinal products substitution in France?

Biological medicinal products are used in the treatment of numerous pathologies, such as diabetes, cancer and autoimmune diseases. Any biological medicinal product whose patent has fallen into the public domain can be copied: this is known as a “biosimilar”. A biosimilar is a medicinal product which, like any biological medicinal product, is produced from or derived from a cell or living organism, and whose efficacy and side effects are equivalent to those of its reference biological medicinal product. By February 2022, 67 biosimilar medicinal products had been authorized in the European Union. 

The marketing authorization of a biosimilar medicinal product

The marketing authorization of a biosimilar medicinal product must meet strict regulatory requirements to demonstrate that its pharmaceutical quality, efficacy and safety are clinically equivalent to those of the reference biologic medicinal product. The ANSM maintains the reference list of similar biological groups registered in France. It is presented by common name of the active substance. It includes all the medicines registered in France with the legal basis of a “similar biological” marketing authorization file within the meaning of b of 15° of article L5121-1. 

Since biosimilar medicinal products are derived from living organisms, they cannot be strictly identical to reference products. Consequently, the substitution principle, which applies to chemical medicinal products and their generics, cannot be applied automatically. 

However, in the light of advances in knowledge, interchangeability and substitution during initial prescription or treatment can now be envisaged under strict conditions and within the framework of the indications, dosage regimens and routes of administration common to the reference product. 

In order to guarantee proper use and safety during substitution, this substitution is  introduced gradually in France. The right of substitution for biosimilars is decided at national level by each member state. In France, the order of April 12, 2022 first sets out the first two groups of biosimilars that can be substituted in pharmacies within a specific framework: filgrastim and pegfilgrastim (immunostimulant-cytokine agents).  

More recently

More recently, the decree of October 31 and the decree of February 20, 2025 have expanded the list of similar biological groups that can be substituted by the community pharmacist and specified the conditions of substitution and information for the prescriber and the patient: 

  • Filgrastim (2022) 
  • Pegfilgrastim (2022) 
  • Ranibizumab (2024) 
  • Adalimumab NEW 
  • Enoxaparine NEW 
  • Epoétine NEW 
  • Etanercept NEW 
  • Follitropine alfa NEW 
  • Teriparatide NEW 

What’s the latest on biosimilar substitution in France? 

> Prescription 

The prescriber must inform the patient of the possibility of substitution by the pharmacist of the prescribed biological medicine. He can also indicate on the prescription which type of medical administration device is to be preferred for a given patient (adalimumab, etanercep, teriparatide). 

> Dispensing 

When dispensing, the pharmacist must inform the patient of the actual substitution and the associated useful information, in particular by recalling the rules for storing the specialty. He – mentions on the prescription the name of the medicine actually dispensed and informs the prescriber about the medicine dispensed. He records the name of the medicine dispensed by substitution and its batch number by all appropriate means in order to implement the traceability required for all biological medicines. Finally, he ensures the continuity of dispensing of the same medicine during subsequent dispensations. 

For the following specialties, the pharmacist must also: 

– substitute specialties with the same active substance dosage: Etanercept, adalimumab, enoxaparin, epoetin 

– not substitute with a biosimilar that would have a higher injection volume than the prescribed medication: Adalimumab 

For follitropin αlfa, the pharmacist: 

– dispense a specialty that allows the administration of the exact dosage prescribed in the event of substitution of multi-dose pens by single-dose pens and vice versa, 

– ensure that the patient has the appropriate pen in the event of dispensing of cartridges and support the patient in learning the new device, 

– in the context of ovarian stimulation, ensures understanding of the protocol implemented including the prescribed dosage regimen and the administration methods of the specialty dispensed. ; 

– supports the patient in learning the new device, 

> The patient has the possibility of returning to the specialty initially dispensed if necessary, “based on their feedback” (adalimumab, enoxaparin, epoetin, etanercep, follitropin alfa, teriparatide). 

> Finally, the laboratory provides dummy administration devices to healthcare professionals and patients (adalimumab, enoxaparin, epoetin, etanercep, follitropin alfa, teriparatide). 

Atessia is monitoring this evolving subject on a daily basis. 

Glossary : 

– Biological medicinal product (article L.5121-1, paragraph 14 of the French Public Health Code): “any medicinal product whose active substance is produced from or extracted from a biological source and whose characterization and quality determination require a combination of physical, chemical and biological tests as well as knowledge of its manufacturing process and control”. 

– Biosimilar” medicinal product (article L.5121-1, paragraph 15 of the French Public Health Code) “any biological medicinal product with the same qualitative and quantitative composition in active substance and the same pharmaceutical form as a reference biological medicinal product, but which does not meet the conditions laid down in 5° of this article to be considered as a generic, due to differences linked in particular to the variability of the raw material or the manufacturing processes, and requiring the production of additional preclinical and clinical data under conditions determined by regulation”. 

– Reference medicinal product: biological medicinal product approved in the EU that a company developing a biosimilar medicinal product chooses as a reference point for direct comparison of quality, safety and efficacy. 

– Interchangeability: refers to the possibility of replacing one medicinal product with another that is intended to have the same clinical effect. Interchangeability can be achieved in two ways: 

– Permutation: when a prescriber substitutes one medicinal product for another with the same therapeutic intent. 

– Substitution: the practice of dispensing a medicinal product in place of another equivalent and interchangeable medicinal product, without reference to the prescriber. 

This article was written by Estelle ICARD 

Ouvrir votre établissement pharmaceutique

How to open a pharmaceutical establishment in France?

  1. What status for my establishment? 

In France, the Public Health Code (PHC) defines different status: 

Status Authorised activities 
Manufacturer Manufacture of medicinal products, products or objects referred to in Article L. 4211-1 of the PHC 
Importer Import, storage, quality control and release of batches of medicinal products, products or objects referred to in Article L. 4211-1 from: States not members of the European Community or parties to the Agreement on the European Economic Area Or other Member States of the European Community or parties to the Agreement on the European Economic Area when the medicinal products, products or articles have been manufactured by an establishment not authorised under Article 40 of Directive 2001/83 of 6 November 2001 on the Community code relating to medicinal products for human use. 
Exploitant Exploitation of medicinal products other than investigational medicinal products, generators, kits and precursors mentioned in 3° of article L. 4211-1. 
Depositary Storage of medicinal products, products, objects or articles of which it is not the owner, with a view to their wholesale distribution and as is for the order and on behalf of: – one or more Exploitant of medicinal products, generators, kits or precursors mentioned in 3° of article L. 4211-1; – or of one or more manufacturers or importers of dressing objects or articles presented as complying with the Pharmacopoeia mentioned in 2° of article L. 4211-1 of the PHC. 
Wholesaler Purchase and storage of medicinal products, other than investigational medicinal products, with a view to their wholesale distribution as such 
Wholesale distributor of pharmaceutical products other than medicinal products Purchase and storage of intermediate products intended for further processing by an authorised manufacturer or of products, objects, articles, generators, kits or precursors referred to in 2° and 3° of Article L. 4211-1, with a view to their wholesale distribution and as such 
Export Wholesale Distributor Purchase and storage of medicinal products other than experimental medicinal products, products, objects, articles, generators, kits or precursors referred to in 2° and 3° of Article L. 4211-1, medicinal plants referred to in 5° of Article L. 4211-1, with a view to their export as such 
Humanitarian wholesale distributor Acquisition, free of charge or against payment, and storage of medicinal products other than investigational medicinal products, with a view to their wholesale distribution or export 
Distributors of investigational medicinal products Storage of investigational medicinal products manufactured or imported by companies or organisations defined in 1° or 2° of this Article (R.5124-2), with a view to their distribution as such for the order and on behalf of one or more sponsors defined in Article L. 1121-1 
Wholesale distributor of medicinal plants Storage and controls and operations necessary for the wholesale and bulk distribution, in sachet-doses, fragments or in a fresh or dried state of medicinal plants mentioned in 5° of Article L. 4211-1 
Wholesale distributor of gases for medical purposes,  Purchase and storage of packaged gases for medical use, with a view to their wholesale distribution and as such 
Wholesale distributor of the Armed Forces Health Service Wholesale distribution of the medicinal products, products or objects referred to in Article L. 5124-8; 
Pharmaceutical establishment for the protection of the population in the face of serious health threats Purchase, manufacture, import and export of products necessary for the protection of the population against serious health threats, with a view to their distribution. 
Pharmaceutical purchasing centre  Purchase and storage of medicinal products other than experimental medicinal products, with the exception of medicinal products reimbursed by compulsory health insurance schemes, with a view to their wholesale distribution as such to pharmacists who are the owners of a dispensing service either in their own name and on their own behalf, or in order and on behalf of pharmacists who are members of a dispensing or the structures mentioned in Article D. 5125-24-16 

Some status are cumulative for all or part of an activity related to its status for the same legal institution. Example: a pharmaceutical establishment may be granted Exploitant status and may be granted manufacturer status limited to batch certification. 

  1. Who issues the opening authorisation? 

The Public Health Code specifies that the authorisation to open a pharmaceutical establishment is issued by the Director General of the National Agency for the Safety of Medicines and Health Products (ANSM). This opening authorisation is made public on EudraGMP. The start of the activity therefore requires prior authorisation from the ANSM to ensure that the project complies with the regulations and to verify that the necessary resources are available and that they will be implemented. This can be a challenge, for example when early access is about to start, or when a drug is being launched. Indeed, the Exploitant must be designated. 

The opinion of the competent central council of the National Order of Pharmacists is required within 2 months for any opening of a pharmaceutical establishment, except for a pharmaceutical establishment dependent on the central pharmacy of the armed forces or the health supply establishments of the armed forces health service. At the end of the 2 months, the Director General of the ANSM can make a decision. 

  1. How to compile your file?  

For the opening of a pharmaceutical establishment, the ANSM website has 3 types of files available depending on the desired status:  

  • Manufacturer/Importer file 
  • Exploitant’s file 
  • Distributor file 

In the event of a combination of activities, as in our example above for example, 2 files must be completed. 

The application to be submitted must comply with the decision of 1 October 2019 on the submission of applications for authorisation to open and amend the initial authorisations of the pharmaceutical establishments mentioned in Article R. 5124-2 of the Public Health Code, except for establishments under the authority of the Minister for the Armed Forces (cf. Article R. 5124-5 of PHC). 

Such a project includes essential areas of vigilance to carry it out. The constitution of the file requires defining the appropriate status according to the desired activity, anticipating the implementation of the desired organization to write a file that is as compliant as possible with what will be carried out in the future establishment as well as with the regulations in force. The ANSM is particularly attentive to the aspects of pharmaceutical liability, compliance with GxP and security of the premises. Identifying the pharmacist in charge upstream is a crucial point. 

  1. What is the processing time? 

No pharmaceutical operation may be carried out within the establishment until the authorisation to open has been obtained.  

Depending on the desired activity, the applicant submits an application for authorisation to open a site to the ANSM via the dedicated secure platform “Démarches Simplifiées”. 

Under the Public Health Code, the Director General of the ANSM is required to notify his decision within 90 days. 

Once the file has been submitted by the Responsible Pharmacist in charge of the future establishment via « Démarches Simplifiées », the Responsible Pharmacist receives an email acknowledging receipt of the file. 

The admissibility period begins. It lasts for 30 days from the date on which the application is received by ANSM, and allows the content of the application to be analysed: missing documents, incorrect naming of documents, etc. If the ANSM does not receive any requests within 30 days, the application is considered “admissible” and the processing can begin. 

The ANSM may ask the applicant for any additional information. The 90-day period is then suspended from the date of notification to the Responsible Pharmacist of the request for additional information by the Director General of the ANSM, until receipt of the information requested. 

The ANSM may also carry out an inspection during the processing period to ensure the accuracy of the information provided by the applicant. 

If ANSM does not respond within 90 days, this is equivalent to: 

  • refusal of authorisation for manufacturer and importer applications.  
  • tacit authorisation for other establishments. 

In recent years, Atessia has opened, modified or relocated more than a dozen pharmaceutical establishments. 

This article was written by Isabelle BARBIEUX, Senior Quality Assurance Consultant. 

The Jardé Law and Research Involving Human Subjects (RIPH): How Are Pharmaceutical Companies Affected? 

Medical research is essential for the development of new treatments and the improvement of healthcare. 

In France, this research is governed by strict regulations designed to protect participants and ensure the integrity of human subjects. The Jardé Law, adopted in March 2012 and enforced since November 2016, is the legal framework for research involving human subjects (RIPH). 

It should be noted that clinical trials involving medicinal products are primarily regulated by the EU Clinical Trials Regulation (EU) 536/2014 (CTR), which came into effect on January 31, 2022. This regulation replaces Directive 2001/20/EC. As a reminder, any clinical trial with at least one active investigative site in France as of January 31, 2025, must be transitioned to the Clinical Trials Information System (CTIS) by its sponsor before this date. For clinical trials involving medicinal products, the Jardé Law introduces additional requirements to be considered. Other provisions include compliance with CNIL (GDPR), and procedures related to the use of medicinal products composed wholly or partially of genetically modified organisms (GMOs). 

Depending on whether the research concerns a medicinal product or another health product, such as medical devices (clinical investigation) and in vitro diagnostic medical devices (performance study), cell therapy preparations, tissues, organs, labile blood products (LBPs), or even research on dietary supplements or cosmetics, the applicable regulations vary. 

What is the Jardé Law? 

The Jardé Law, named after Deputy Olivier Jardé, is a regulation that governs the conditions under which research involving human participants can be conducted. It replaces the Huriet-Sérusclat Law of 1988 and aims to enhance the protection of participants while facilitating the conduct of clinical research. 

The main reference texts include: 

The Jardé Law, Law No. 2012-300 of March 5, 2012, relating to research involving human subjects. 

The ordinance, known as the “modified Jardé Law,” relating to research involving human subjects. 

Decree No. 2016-1537 of November 16, 2016, relating to research involving human subjects. 

The Public Health Code (Articles L1121-1 to L1126-11), which details the specific obligations for different categories of research. 

Classification of RIPH 

Research organized and conducted on human beings with the aim of developing biological or medical knowledge is referred to as “research involving human subjects” (RIPH). There are three types of RIPH: 

Category Legal Provisions Framework 
Category 1 Interventional research involving a risk to participants Articles L1121-1 and L1121-3 of the Public Health Code (CSP) These studies require prior authorization from the ANSM (French National Agency for Medicines and Health Products Safety) and a favorable opinion from a Committee for the Protection of Persons (CPP). 
Category 2: Interventional research with minimal risks and constraints Article L1121-2 of the CSP These studies require a favorable opinion from a CPP, but not authorization from the ANSM. 
Category 3: Non-interventional research Article L1121-1-1 of the CSP These involve observational studies where the risks are absent or negligible. A favorable opinion from a CPP is necessary, but these studies do not require authorization from the ANSM. 

What Are the Implications for the Industry? 

Participant Information 

The objective of the Jardé Law is to ensure the safety of participants. Special attention is given to the notions of informed consent and clear information. 

Manufacturers must ensure that participants fully understand the stakes, procedures, risks, and potential benefits of the study. These requirements are detailed in Articles L1122-1-1 to L1122-2 of the Public Health Code (CSP). 

Information for the ANSM 

Manufacturers must determine the category of their research during the design phase and ensure they obtain the necessary authorizations. Notably, for RIPH involving medicinal products, they cannot be classified as RIPH 2. An order specifies the criteria to remain within the scope of RIPH 2. For category 1 RIPH, this involves submitting a complete dossier to the ANSM and obtaining a favorable opinion from a CPP (Article L1121-4 of the CSP). Since 2022, for clinical trials on medicinal products, the CTR requires submission through the CTIS platform. Proper classification of your RIPH is a prerequisite for any procedure. 

Interactions with CPPs and the ANSM 

CPPs are French ethics committees. Interactions with CPPs and the ANSM are essential for the validation of research projects. Good communication and submission of complete dossiers are necessary, in accordance with Articles L1123-6 and L1123-7 of the Public Health Code. 

Procedures 

Before submitting the authorization request dossier (initial authorization and substantial modification) and/or human research opinion request, or routine care research, sponsors must obtain an IDRCB registration number for the research. This number identifies each research conducted in France. For a biomedical research authorization and opinion request concerning a medicinal product for human use, sponsors must obtain a research registration number in the European CTIS database (formerly: EudraCT). 

Subsequently, sponsors will electronically submit the biomedical research authorization and/or opinion request dossier to the ANSM and/or CPP, in accordance with the current orders setting the dossier formats for each type of research. Various “Notices to Sponsors” guide these procedures according to the situation. 

Conclusion 

The Jardé Law thus ensures the safety of participants in clinical research in France. 

For health manufacturers, understanding and complying with these regulations is not only a legal obligation but also a guarantee of the quality of the data generated, particularly for use in a Marketing Authorization Application (MAA) dossier. 

By integrating the requirements of the Jardé Law into their processes, manufacturers contribute to the development of innovative treatments while ensuring high ethical standards, in accordance with French regulations on this matter. 

Atessia can assist you in implementing these processes with its expertise in clinical trials. 

Article written by Zarine RAMJAUNY, Legal Consultant 

The Excellence of ATESSIA’s CMC: Your Partner in Technical and Regulatory Affairs

In a constantly evolving pharmaceutical industrial environment, regulatory requirements for quality data are becoming increasingly complex. Health authorities are continually updating guidelines, increasing CMC demands on regulatory affairs professionals. Faced with this complexity, revising the operational model and utilizing external expertise are essential solutions to overcome these challenges and meet market demands. 

Why Outsource CMC Activities? 

  1. Increasing Regulatory Requirements Health authorities are continuously raising the quality standards from development to drug registration and throughout the lifecycle of marketing authorizations (MA**). This trend imposes a significant workload from a CMC perspective, necessitating rigorous and expert management of regulatory dossiers. 
  1. Impact of Mergers and Acquisitions Corporate mergers and acquisitions increase the number of regulatory submissions to reflect changes in supply sources, production site transfers, etc. This dynamic requires increased flexibility and responsiveness to maintain compliance and the continuity of pharmaceutical operations. 
  1. Resource Management Optimization Increasingly complex regulatory requirements necessitate deep knowledge, leading to increased personnel needs and creating a talent shortage. The traditional operational model of pharmaceutical laboratories is often no longer optimized to handle the surplus work related to these CMC activities. Outsourcing complex technical and regulatory aspects reduces workload and improves overall efficiency. 

ATESSIA’s Unique Expertise 

ATESSIA was founded by Géraldine Baudot-Visser, a recognized expert in the technical-regulatory field. With a doctorate in pharmacy, extensive experience in R&D and regulatory affairs, Géraldine created ATESSIA to offer an innovative and client-centered approach. Her solid CMC expertise, acquired within major pharmaceutical laboratories and consulting firms, is at the heart of the service offering. 

Why Choose ATESSIA for Your CMC Needs? 

  1. Cutting-Edge Expertise and Knowledge ATESSIA has multidisciplinary expert teams with in-depth CMC knowledge. Our consultants possess practical experience and a fine understanding of regulatory authorities’ expectations, ensuring the quality of dossiers and compliance with current requirements. 
  1. Cost Reduction and Time Savings ATESSIA has the expertise to efficiently manage CMC activities and offers economical and fast solutions, best adapting to the market entry deadlines desired by its clients. 
  1. Guaranteed Quality Structured around the ISO 9001 standard, ATESSIA ensures impeccable quality at every stage of the product lifecycle. 
  1. Partner for Your R&D Activities ATESSIA has Research Tax Credit approval, enabling you to be supported in your research and development activities. 

Our Commitment to Excellence and Innovation 

At ATESSIA, we stand out with our agile and tailored approach, integrating feedback and specific needs of each client. Our flexibility and ability to integrate new technologies allow us to offer innovative solutions adapted to evolving market demands. 

Choosing ATESSIA for your CMC needs ensures expert and personalized support, capable of transforming your regulatory challenges into successes. Our commitment to excellence and innovation guarantees optimal results that ensure your competitiveness in the market. 

To learn more about our CMC services and other regulatory and pharmaceutical affairs offerings, and to discover how we can support you, contact us today. 

hello@atessia.fr

www.atessia.fr 

*CMC: Chemistry Manufacturing and Control

**MA: Marketing Authorization 

The Post-Approval Change Management Protocol or “PACMP” 

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 step-wise approach to evaluating modifications, initially allowing for an early evaluation of the modification strategy and, in a 2nd 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)”. 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 

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 and veterinary 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. 

Active substance Finished product 
Variation Type II/B.I.e.2: Introduction of a post approval change management protocol related to the active substance 
> Absence of conditions to be fulfilled. 
> Three supportive documentation to be provided: 
1. Detailed description for the proposed change. 
2. Change management protocol related to the active substance. 
3. Amendment of the relevant section(s) of the dossier 
Variation Type II/B.II.g.2: Introduction of a post approval change management protocol related to the finished product 
> Absence of conditions to be fulfilled. 
> Three supportive documentation to be provided: 
1. Detailed description for the proposed change. 
2. Change management protocol related to the finished product. 
3. Amendment of the relevant section(s) of the dossier. 
Variation Type IAIN/B.I.e.3: Deletion of an approved change management protocol related to the active substance 
> One condition to be fulfilled: 
1. The deletion of the approved change management protocol related to the active substance is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier. 
> Two supportive documentation to be provided: 
1. Justification for the proposed deletion. 
2. Amendment of the relevant section(s) of the dossier. 
Variation Type IAIN/B.II.g.3: Deletion of an approved change management protocol related to the finished product 
> One condition to be fulfilled: 
1. The deletion of the approved change management protocol related to the finished product is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier. 
> Two supportive documentation to be provided: 
1. Justification for the proposed deletion. 
2. Amendment of the relevant section(s) of the dossier. 
Variation Type II/B.I.e.4a): Changes to an approved change management protocol – Major changes to an approved change management protocol Variation Type II/B.II.g.4a): Changes to an approved change management protocol – Major changes to an approved change management protocol 
Variation Type IB/B.I.e.4b): Changes to an approved change management protocol – Minor changes to an approved change management protocol that do not change the strategy defined in the protocol 
> Absence of conditions to be fulfilled. 
> One supportive documentation to be provided: 
1. Declaration that any change should be within the range of currently approved limits. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
Variation Type IB/B.II.g.4b): Changes to an approved change management protocol – Minor changes to an approved change management protocol that do not change the strategy defined in the protocol 
> Absence of conditions to be fulfilled. 
> One supportive documentation to be provided: 
1. Declaration that any change should be within the range of currently approved limits. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
Variation Type IAIN/B.I.e.5a): Implementation of changes foreseen in an approved change management protocol – The implementation of the change requires no further supportive data 
> One condition to be fulfilled: 
1. The proposed change has been performed fully in line with the approved change management protocol. 
 
> Three supportive documentation to be provided: 
1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
4. Amendment of the relevant section(s) of the dossier. 
Variation Type IAIN/B.II.g.5a): Implementation of changes foreseen in an approved change management protocol – The implementation of the change requires no further supportive data 
> One condition to be fulfilled: 
1. The proposed change has been performed fully in line with the approved change management protocol, which requires its immediate notification following implementation. 

> Three supportive documentation to be provided: 
1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
4. Amendment of the relevant section(s) of the dossier. 
Variation Type IB/B.I.e.5b): Implementation of changes foreseen in an approved change management protocol – The implementation of the change requires further supportive data 
> Absence of conditions to be fulfilled. 
> Four supportive documentation to be provided: 

1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
3. Results of the studies performed in accordance with the approved change management protocol 
4. Amendment of the relevant section(s) of the dossier 
Variation Type IB/B.II.g.5b): Implementation of changes foreseen in an approved change management protocol – The implementation of the change requires further supportive data 
> Absence of conditions to be fulfilled. 
> Four supportive documentation to be provided: 
1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
3. Results of the studies performed in accordance with the approved change management protocol 
4. Amendment of the relevant section(s) of the dossier. 
Variation Type IB/B.I.e.5c): Implementation of changes foreseen in an approved change management protocol – Implementation of a change for a biological/immunological medicinal product 
> Absence of conditions to be fulfilled. 
> Five supportive documentation to be provided: 

1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
3. Results of the studies performed in accordance with the approved change management protocol 
4. Amendment of the relevant section(s) of the dossier. 
5. Copy of approved specifications of the active substance 
Variation Type IB/B.II.g.5c): Implementation of changes foreseen in an approved change management protocol – Implementation of a change for a biological/immunological medicinal product 
> Absence of conditions to be fulfilled. 
> Five supportive documentation to be provided: 
1. Reference to the approved change management protocol. 
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products. 
3. Results of the studies performed in accordance with the approved change management protocol 
4. Amendment of the relevant section(s) of the dossier. 
5. Copy of approved specifications of the finished product. 
The use of PACMP is strongly recommended by regulatory authorities and in line with the latest ICH guidelines (Q8, Q9, Q10, Q12 and Q14). As a result, an increase in this type of variation seems predictable for the years to come. 
 
Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Senior Consultant