The regulatory requirements for the pharmaceutical development of gene therapy medicinal product are described in Annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products. The following definition is included:

“Gene therapy medicinal product means a biological medicinal product which has the following characteristics:

a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.”

Both of these two conditions must be met so the product can be classified as a gene therapy medicinal product.

According to Regulation (EC) No 1394/2007, gene therapy medicinal products must be regulatory approved under an European centralised procedure, like all other advanced therapy medicinal products (ATMPs).

This procedure includes an in-depth evaluation of the marketing authorisation application file submitted by the pharmaceutical company, which is carried out by the EMA and involves various specific committees and working groups that provide recommendations. The EMA website provides procedural and guidance documents to help companies applying for a marketing authorisation for ATMPs.

In the following paragraph we discuss the main elements of the registration procedure for a gene therapy medicinal product.

As with “conventional” medicinal products, the marketing authorisation dossier is based on three main aspects: the quality, safety and efficacy of the medicinal product, in order to determine its benefit/risk ratio. The eCTD dossier is composed of five modules to which certain technical adaptations are added.

In particular, if the product is a gene therapy medicinal product containing genetically modified organism (GMO), Module 1 must also include an assessment of the possible risks that the medicinal product may pose to the environment, both in regards to its use and its disposal. Information on the risk related to the release of GMO should be annexed to this module and should be presented in accordance with the provisions of Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms.

The three main EMA committees involved in the evaluation of gene therapy medicinal products are the Committee for Advanced Therapies (CAT), the Committee for Medicinal Products for Human Use (CHMP) and the Pharmacovigilance Risk Assessment Committee (PRAC).

The CAT is a multidisciplinary committee within the EMA. Its main responsibility is to assess the quality, safety and efficacy of ATMPs. The CAT also provides scientific recommendations on the classification of ATMPs. The CHMP will then adopt a positive or negative opinion on the marketing authorisation of the medicinal product concerned.

During the evaluation of the marketing authorisation application, the CHMP chooses from among its members a “rapporteur” State and a “co-rapporteur” State, responsible for coordinating the evaluation of the dossier and drawing up evaluation reports for the other Member States (MS) in the procedure. The MS comment on these reports within the timeframe set out in the procedure’s timetable, which has a total duration of 210 days.

At the end of the procedure, the CHMP issues an opinion, which may be positive or negative. The CHMP’s opinion is then forwarded to the European Commission (EC). On the basis of this opinion, the final decision is taken by the EC, which has 67 days to take the administrative decision on whether or not to grant marketing authorisation.

During the pre-submission phase of the marketing authorisation dossier, the Committee for Orphan Medicinal Products (COMP) may also be called upon if the applicant wishes to obtain orphan designation for its product. Indeed, most medicines with ATMP status also claim orphan drug status. However, to obtain this status, which is associated with many advantages, certain conditions must be met. These conditions are defined in Regulation (EC) No. 141/2000 on orphan medicinal products.

The growing interest in obtaining orphan drug status is due to the significant advantages that industry can enjoy, in particular:

– Smaller-scale clinical trials (due to small populations), which are less costly;

– Accelerated marketing authorisation process;

– 10-year marketing exclusivity from the time of marketing.

The Paediatric Committee (PDCO) also intervenes at an early stage in the centralised procedure to ensure that the pharmaceutical company meets the requirements requested of it in terms of paediatric development.

In parallel, all of these committees are also supported within the EMA by advisory bodies, both technical and scientific, divided by area of activity. The EMA’s Gene Therapy Working Party (GTWP) supports the CAT and the CHMP in the scientific evaluation of this category of medicines.

In the event of questions from applicant laboratories, the EMA and the ANSM are able to provide scientific advice. In fact, a laboratory can call on the advice of the EMA (Scientific Advice Working Party (SAWP)) and/or that of the competent national authorities, either during the initial development of the medicinal product, or before the submission of a marketing authorisation application. In France, the industry can also apply to the ANSM’s guidance and innovation desk.

In addition, in March 2016, the EMA set up a special status called PRIME (meaning “Priority Medicines”) to improve the development and marketing of innovative products. The PRIME regulatory process is designed to allow for an accelerated assessment of these priority therapies, but it also aims to support laboratories in their development, as well as to help them use other systems for early access to treatments.

It should be noted that in order to meet unmet medical needs of patients and in the interest of public health, it may be necessary to grant marketing authorisations on the basis of less complete data than is normally required. In such cases, the granting of a conditional marketing authorisation may be recommended subject to certain specific obligations to be reviewed annually. The provisions for the granting of such an authorisation are laid down in Commission Regulation (EC) No 507/2006 on conditional marketing authorisations for medicinal products for human use. 

It should be noted that the various regulatory measures taken in recent years have proved to be effective and promote the development of gene therapy medicinal products. However, these measures still need to be adjusted in order to achieve their main objective of making safe and effective gene therapy medicinal products available to patients. This is the purpose of the ongoing revisions of the European pharmaceutical legislation.



Article written by Blandine LATROBE, Regulatory and Pharmaceutical Affairs Advisor

French always do it different In many domains, French people like to stand out, either in a positive or negative way. In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. As a result, understanding the regulatory specificities of France is key for entering the French market. ATESSIA can help you in this process and provide you assistance and expertise. Here are a few areas where France follows its own, often complicated and restrictive, rules.

The substances used in a medicinal product intended for the European market, including for export, are defined as raw materials for pharmaceutical use (RMP). They can be active (active substance) or inert (excipients).

Whether the medicinal products are intended for human or veterinary use, only active substances manufactured and distributed in accordance with European Good Manufacturing Practices (GMP – Part II) and Good Distribution Practices (GDP), introduced by article L.5138-3 of the French Heath Code, can be used.

Thus, when applying for a marketing authorization or for certain applications to modify the marketing authorization, the notice to applicants requires the submission of a signed QP declaration by the qualified person of the manufacturing site and/or of the certification of the batches of the finished product attesting that the active substance used is manufactured in accordance with good manufacturing practices.

Concerning the excipients used in medicinal products for human or veterinary use, there is no enforceable standard in the national or European regulations and they are not subject to the QP declaration in the marketing authorization file. It is up to the manufacturer or distributor of the finished product to define its quality system the applicable standard(s) for the manufacture or distribution of the excipient, according to its/their intended use(s). This exercise will be carried out in consultation with pharmaceutical users on the basis of the results obtained during a formal quality risk assessment (GMP point 5.29). It should be noted that ANSM recommends, at a minimum, the IPEC/PQG GMP & GDP reference systems.

However, it is recognized that for some raw materials, their pharmaceutical use may represent only a minor fraction of their other industrial uses (agri-food, cosmetics or others). Thus, their producers may not have the objective of meeting the specific requirements of pharmaceutical customers.

The EMA’s Q&A Part 1 reaffirms that compliance with the above-mentioned standards is a legal obligation and that, in the event of difficulties in guaranteeing a supply of satisfactory quality, alternative GMP sources must be sought out, qualified and, if necessary, registered. In the case of a source identified on European territory, the establishment must apply for authorization or registration from the competent authority of the Member State in which it is established. In case of import from a third country to the European territory, the source of the identified active substance will be conditioned by the provision of a written confirmation from the competent authority of the exporting third country.This document attests that the applicable standards are at least equivalent to the GMP defined by the European Union.

In exceptional circumstances these same EMA Q&A Part 1 introduces the possibility for manufacturing authorization holders (of the finished product) to assess and document the extent to which GMP is met, and to provide a risk-based justification for the acceptance of any deviation. At the MA level, the QP declaration should detail the rationale for stating that the standards applied provide the same level of assurance as GMP.The EMA will collect the experience gained with this approach, which can be used as a basis for discussion of possible future related changes to the guidelines.

However, at the national level, the ANSM does not, for example, explicitly provide for derogations or for exceptional circumstances, unlike the EMA for centralized MA. When informed in advance of a particular context (such as medicinal products of major therapeutic interest or the absence of a therapeutic alternative), the competent authorities could then request additional information or carry out an inspection to ensure that the establishment complies with the standards in force in the Union. Thus, this situation can only be transitory, since these alternative sources (in the EU or in third countries) and/or their principals can request an express request for an inspection of the raw materials from a competent authority of one of the member states in order to obtain a certificate of conformity.

The control of the supply chain is the key word. Deficiencies in the qualification and monitoring process of suppliers and/or manufacturers of raw materials are regularly the subject of injunctions issued by the ANSM against pharmaceutical establishments (2 for the year 2020 and 3 for the year 2021). For the alternative identified source, this may be a hindrance (compulsion to comply with the opposable standards) or an opportunity (to comply with them in order to enter the EU market for UPMPs). A mutualization of supplies (and on-site audits) can also be an interesting approach to encourage the source to seize this opportunity.


Article written by Lorraine BALIN, Senior Regulatory and Pharmaceutical Affairs Advisor

French always do it different In many domains, French people like to stand out, either in a positive or negative way. In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. As a result, understanding the regulatory specificities of France is key for entering the French market. ATESSIA can help you in this process and provide you assistance and expertise. Here are a few areas where France follows its own, often complicated and restrictive, rules.

– Excipients – inherently inactive – have a wide range of applications and are essential components in the formulation of medicines. However, few of these components are manufactured exclusively for pharmaceutical use. Often, the pharmaceutical use of an excipient represents only a minor fraction of its other industrial uses (food, cosmetics or others). However, the quality of excipients is crucial to ensure the quality, safety and efficacy of medicines.

– There is no registration or authorisation procedure prior to its use in a medicinal product. Implicit agreement for the acceptability of an excipient can only be obtained on the basis of a complete marketing authorisation dossier. Excipients used in the formulation of medicinal products can be classified into two main categories: known excipients (i.e. described in the literature, e.g. Handbook of Pharmaceutical Excipients, in the regulations, e.g. (EU) Regulation n°231/2003, or previously screened for risk/safety by an international organisation, e.g. JECFA, FAO, WHO) and unknown excipients, so-called “new excipients” (i.e. used for the first time in a medicinal product or via a new route of administration according to ICH M4Q).

– Among the known standard excipients used, the European guidelines of the EMA provide for two categories: those described in a pharmacopoeia (e.g. European, American, Japanese, French, British, etc.), and those not described in a pharmacopoeia. The latter are then subject to “in-house” control specifications, generally based on the excipient manufacturer’s own specifications, which may be consolidated by the MA holder depending on the use of the excipient in its formulation. It should be noted that in the case of mixed and co-processed excipients, a combination of one or more excipients described or not described in a pharmacopoeia may be considered.

– In Europe, the European Pharmacopoeia is the binding reference for substances for pharmaceutical use. Nearly 200 monographs for excipients are included. Increasingly, they include additional pharmaco technical specifications depending on the use of the excipient. The aim of the European Pharmacopoeia excipient monographs is to provide authorities and patients with a guarantee of acceptable quality. The national pharmacopoeias of the EU Member States are also considered as reference documents that can be used without providing a specific justification in the marketing authorisation dossier. A reference to the “current edition” of the European/national pharmacopoeia in the marketing authorisation dossier is expected to avoid subsequent maintenance changes to the marketing authorisation dossier.

– For the same excipient, depending on its various possible origins and uses, different additional requirements may also be necessary: e.g. with regard to a chemical risk (residual solvents according to ICH Q3C, elemental impurities according to ICH Q3D, nitrosamine impurities, etc.), with regard to a bacteriological risk (mycotoxins, endotoxins, sterility, etc.), or with regard to a viral risk (TSE/BSE).

– Although also accepted in Europe under certain conditions, references to monographs described in other pharmacopoeias (i.e. outside Europe and considered as third country or unofficial pharmacopoeias) must be duly justified in the marketing authorisation dossier. In this case, a copy of the monograph accompanied, if necessary, by the validation of the analytical procedures contained in this monograph and, if necessary, a translation should be provided in the marketing authorisation dossier. Updates to these monographs should be declared via the submission of MA variations to the authorities.

– In cases where the excipient used in the formulation is known but has no control monograph in a pharmacopoeia (e.g. surfactant for a skin solution), specifications should be set by the supplier to ensure that the quality of the raw material is maintained on a continuous basis, and reflects both the inherent properties of the excipient and its manufacturing process. These specifications are usually taken over by the user of the excipient and consolidated where appropriate. Consideration of the following parameters is recommended in establishing these internal control specifications: physical characteristics, identification tests, purity tests, assay and other relevant tests that may influence the performance of the pharmaceutical form. In addition, it should again be demonstrated that the methods used provide accurate, reproducible and repeatable results for the characteristic tested and are therefore validated.

– It should be remembered that it is the responsibility of the drug product manufacturer to ensure the quality of all raw materials used in the manufacture of a medicine. By regularly auditing the excipients producer, the end user is able to determine whether adequate controls are in place to ensure that the producer is capable of producing a product of appropriate quality. It should be noted that several guidelines and practical guides are available to manufacturers and users of pharmaceutical excipients from IPEC (The International Pharmaceutical Excipients Council) on the following topics: excipient compositional profiling, excipient qualification, excipient safety, development of certificates of analysis, determination and auditing of Good Manufacturing Practices (GMP) for manufacturers, development of technical agreements/specifications, etc.

– Finally, since 2015, the European regulation imposes on excipients manufacturers the obligation to comply with the appropriate GMP determined by the drug product manufacturer on the basis of a formalised risk assessment (reference document to be provided in case of inspection). An ANSM doctrine, currently being finalised, will soon explain the inspection procedures for excipient manufacturers with regard to the provisions of Article L.5138-3 of the Public Health Code.

ATESSIA assists you in the drafting of your MA and variation files in the context of your activities related to all types of pharmaceutical excipients.



Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Advisor

French always do it different In many domains, French people like to stand out, either in a positive or negative way. In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. As a result, understanding the regulatory specificities of France is key for entering the French market. ATESSIA can help you in this process and provide you assistance and expertise. Here are a few areas where France follows its own, often complicated and restrictive, rules.

Prior control of advertising

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

Regarding the content of promotional documents, in application of the Public Health Code and taking into account the state of scientific and medical knowledge, the ANSM will ensure the security of the message which must not induce bad prescribing or a danger to the public. Vector of proper use, advertising must also present the medicine objectively, and ensure compliance with the standards in force such as the MA** and the therapeutic strategies recommended by the HAS***. Finally, so that health professionals can form a personal idea of ​​the therapeutic value of the medicine, the ANSM checks that the target population and the benefit-risk ratio are clearly perceptible, in particular in the documents used by persons carrying out a promotional information activity. Many guidelines, which are mandatory in practice, have been drawn up by the authorities to help pharmaceutical firms in this delicate exercise.

Furthermore, advertising to the general public is only accessible for certain medicines:

– medicinal products not subject to compulsory medical prescription, non-reimbursable and not including in their marketing authorization a ban on advertising due to a risk to public health, in particular when the medicinal product is not suitable for use without medical supervision;

– certain vaccines on a list from the Ministry of Health;

– smoking cessation products.

It should also be noted that control of advertising is also exercised a priori for certain categories of medical devices presenting a significant risk to human health, the list of which is defined by a ministerial order.

An Immutable Authorization Schedule

But the real constraint lies in respecting the timetable governing this control, implying for pharmaceutical firms to anticipate and plan requests up to 6 months before the launch of a new medicine. Advertising is thus subject to strict filing periods (4 per year for documents for healthcare professionals, and 8 per year for advertisements targeting the general public), and files are processed by the authorities within a regulatory time limit of 2 months.

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

At the end of the evaluation period, the request will result in the granting of a prior authorization called the GP visa for advertising aimed at the public and the PM visa for advertising aimed at healthcare professionals, for a duration of 2 years. However, in the event of breaches of the requirement criteria on the content or presentation of the communication tool, the ANSM may issue a refusal. The applicant will then have no choice but to make a new request during the next slot. Each year, out of the 10,000 visa applications processed by the ANSM, around 10% are rejected in this way, and around two thirds of GP visas are modified before they are issued.

The dematerialization of applying

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


Article written by Gismonde PLAN, Senior Regulatory Affairs Advisor

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

** MA : Marketing Authorization

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

French always do it different In many domains, French people like to stand out, either in a positive or negative way. In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. As a result, understanding the regulatory specificities of France is key for entering the French market. ATESSIA can help you in this process and provide you assistance and expertise. Here are a few areas where France follows its own, often complicated and restrictive, rules.

What are direct-access medicines ?

In France, medicines are classified into different categories according to the way they are delivered.

Medicines that present difficulties in use or risks in the event of inappropriate use can only be obtained on presentation of a prescription from a doctor, dentist or midwife. They are known as mandatory medical prescriptions (prescription médicale obligatoire). In particular, they appear on lists I or II of poisonous substances, or even on the list of narcotics. The Director General of the ANSM has recently inherited this competence from the Ministry of Health, within the framework of the law on the “acceleration and simplification of public action” (ASAP).

Medicines not subject to mandatory medical prescription may be advised by the pharmacist, requested by the patient or prescribed by the doctor and are known as Optional Medical Prescription (prescription médicale facultative).

Among the optional prescription medicines, only certain medicines can be placed in front of the counter (“Over The Counter” (OTC)) of the pharmacy in order to allow the patient to serve himself. They are called in various ways: “self-medication medicines“(médicament d’automédication), “officinal medicines” (médicament de médication officinale), “free access medicines” (médicament en libre accès) or “direct access medicines“(médicament en accès direct). This is only possible if all the eligibility criteria are met, including the fact that they are not reimbursable by the health insurance system.

The list of these medicines that can be presented for direct access in pharmacies is defined and evolves according to the decisions published on the ASNSM website after evaluation of the express requests from laboratories.

Which medicines are eligible for direct access?

The inclusion of a medicinal product on this list is done according to the criteria of article R.5121-203 of the Public Health Code in order to guarantee the safety and security of patients.

A direct access medicinal product must be able to be used without the intervention of a doctor for the diagnosis, initiation or monitoring of a treatment due to its therapeutic indication: the symptoms must be easily recognisable, and must not risk hiding a serious condition. In addition, the medicine must have an easy dosage, a short treatment duration, and a leaflet adapted to the language of the general public. A whole process of adapting the marketing authorisation must therefore be devised to change the status of a drug.

A medicine with a major contraindication or a significant risk of drug interactions, or a medicine intended for the paediatric population whose safety level is not sufficient for self-medication, would not be eligible for safety reasons.

How to apply for direct access to a medicine?

When applying to the ANSM for a change in marketing authorisation with a view to placing optional prescription medicines on the direct access list, the procedures for submitting applications for inclusion on the “officinal medicines” (Médicament de Médication Officinale) list differ depending on the active substance and the indication of the medicine. It is necessary to carefully examine whether the active substance or the fixed combination is already referenced in the list, and whether the targeted indication has been identified as being suitable for self-medication. The regulatory and clinical aspects should therefore be considered together.

The composition of the type II MA variation dossier depends on this analysis. In any case, the ANSM will examine a whole range of aspects, the most important of which is safety of use.



Article written by Laure DEAN, Regulatory and Pharmaceutical Affairs Advisor

France is known for its strict regulatory provisions when it comes to medicines. The exception will not be made for the framework of relations between industries and health professionals, now known in France as the LEA. (anti-gift law)

So who is LEA?

Before, we used to say “anti-corruption law”, “DMOS”, “anti-gifts law”… These terms are no longer used. This system, which will soon celebrate its 30th anniversary (we are getting on in years), has just been revamped and we now speak of the “Benefits Framework System” or the “Benefits Framework Law” (the famous LEA in French) because it is a set of texts and a real arsenal put in place since October, 1st 2020 so that the State can better control relations between the health industries in particular, and health professionals in the broadest sense of the term. It should be remembered that it has to be considered in a very distinct way from the system of transparency of links, which pursues the objectives of publicising the advantages procured and agreements made in order to inform the general public and avoid any conflict of interest.

As we have just said, this system is not recent. It is true that over the years it has been considerably strengthened since it now concerns all health products, whether reimbursable or not, and its scope of application has gradually been extended to health professionals, students and their associations. But, in fine, its fundamental principle has remained the same: we are faced with a genuine “anti-corruption” mechanism applicable to relations between companies that market health products, such as medicines or medical devices, or provide health services, and health professionals (doctors, but also all other health professionals as well as osteopaths, chiropractors and psychotherapists). The aim is to ensure that HCPs are guided only by medical considerations in their choice of prescribing a product or health service and to prevent conflicts of interest.

More concretely, the general principle is the following:

• Prohibition for companies to provide health services, producing or marketing health products to grant direct or indirect benefits, in kind or in cash; and

• Prohibition on health professionals, associations of health professionals and civil servants/public officials covered by the scheme from receiving such benefits.

It should be noted that these prohibitions are punishable under criminal law and that there is joint responsibility between the companies granting undue advantages and the beneficiaries of these advantages.

But let’s make it a little more complex… The LEA provides derogations from this principle of prohibition and subjects all authorised interactions (remuneration, hospitality in the context of professional, scientific or promotional events, participation in research activities, provision of services, sponsorship, donations) to prior control by the competent authorities, i.e. the medical professions’ council of order where they exist or the Regional Health Agency. However, one condition for the implementation of these derogations is the establishment of an agreement working as a contract which will then be submitted to the competent authorities. These derogations should not be confused with items excluded from the definition of a prohibited benefit, such as benefits in cash or in kind that relate to the exercise of the beneficiary’s profession and benefits of negligible value (e.g. impromptu meals, samples, books). It should be remembered that any benefit in excess of 10 euros must also be declared on https://www.transparence.sante.gouv.fr/ as part of the transparency of links.

Two submission regimes are possible: submission for declaration OR for authorisation.

To guide us in the choice of the applicable submission regime, threshold values have been published by decree. These values are then defined for each type of benefit provided. It now remains up to you to define the category in which your benefit falls…

If the benefits granted are below the thresholds, a declaration must be made 8 days before the benefit is granted, either on Idahe 2 or EPS. The benefit cannot be implemented before this deadline.

If the benefits granted are above the thresholds, an application for authorisation must be made at least two months before implementation. At the end of the two months, the competent authority will issue a binding decision, not an opinion.

To sum up :

Few innovations have been published since the new system was introduced on October 1st 2020, but the day-to-day implementation of the system raises a large number of questions of interpretation. ATESSIA can assist you in setting up and adapting your processes to comply with this system.



Article written by Floriane LUCY, Regulatory & Pharmacist Affairs Advisor

On Wednesday 11 May 2022, our 4th Lunchwork of the year took place on the theme of nitrosamine impurities for which the regulatory deadlines are fast approaching. This event, organised around lunchtime and accessible free of charge to our ATESSIA INTELLIGENCE subscribers, brought together 70 participants from French and international pharmaceutical companies.

On this occasion, Lorraine BALIN, Senior Consultant for Regulatory and Pharmaceutical Affairs and Christelle PETIT, Director and Consultant for Pharmaceutical Affairs at ATESSIA respectively presented an overview of the European regulatory news on nitrosamines and led constructive exchanges with the participants

After a presentation of the root causes of the formation of nitrosamine impurities in medicines, the chronology of events relating to nitrosamines on a global scale from 2018 to the present day, the actions initiated in France and in Europe and their implementation methods, the impacts on the European Pharmacopoeia and CEPs, it was mainly the concrete management of a project to analyse and mitigate the risk of nitrosamines in chemical and biological medicines (new or already registered in Europe) and traditional herbal medicines (new only) that was discussed. The discussions were based on concrete cases (feedback from ANSM), from ATESSIA’s experience.

Our speakers recalled that knowledge of nitrosamine impurities was constantly evolving and insisted on the need to regularly monitor the texts issued by the health authorities on this subject, in order to take into account any new root cause of formation identified and any limit applicable to a specific nitrosamine defined by the authorities on the basis of safety data. Indeed, since 2018, health authorities have implemented various action plans in order to protect patients’ health, including a worldwide batch recall for medicines containing nitrosamines above the defined acceptable daily intake limit.

Tout en soulignant que les exigences en terme d’évaluation du risque de présence de nitrosamines ne s’appliquaient pas à ce stade aux spécialités radiopharmaceutiques, il a été rappelé que les médicaments traditionnels à base de plantes déjà enregistrés et les médicaments homéopathiques pourraient être intégrés ultérieurement dans le champ des spécialités concernées, en fonction de l’expérience acquise.

At the time of this lunchwork, pharmaceutical companies are involved in the conduct of step 2 (confirmatory testing: identification and quantification of nitrosamines actually present in the medicinal product) of the process of analysis and mitigation of the risk of the presence of nitrosamines in medicinal products of chemical and biological origin, and even for some of them in the conduct of step 3 (updating of marketing authorisations after prior validation of the control strategy by the authorities, for example : submission of a variation modifying the control specifications of the medicinal product) of this same process for medicinal products of chemical origin for which a common deadline of 26 September 2022 has been set in Europe. An additional period of time is granted for biological medicinal products (1 July 2023) for the completion of step 2 and 3.

Pending further clarification from the ANSM regarding the filing of variations to the marketing authorisation dossier, marketing authorisation holders are invited to communicate the results of the confirmatory tests and their proposals for a control strategy sufficiently in advance and to prepare their variations now so as to comply with the deadlines set to comply with the conclusions of the summary procedure according to Art5(3) of the CHMP on 26 September 2019.

ATESSIA assists its clients in the preparation, drafting and filing of variations to their marketing authorisations.


Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Advisor

On Wednesday April 20, 2022, our 3rd Lunchwork of the year took place. On the occasion of this lunchtime event, accessible free of charge to our ATESSIA INTELLIGENCE subscribers and having gathered more than 70 participants from many pharmaceutical companies and DM manufacturers, we had the pleasure to welcome the LEXCASE for a presentation dedicated to the new French Quality Charter of professional practices for reimbursable products and services.

Diane BANDON-TOURRET, Associate Lawyer, Victoire STORKSEN, Lawyer, and Lucie CLOUIN-MOTHE, Director of Operations of ATESSIA, gave an update on the new obligations, the stakes and what has still to be precised, in the management of this major turning point for the practices applied to the marketing of reimbursable products and services in France, especially medical devices.

After a review of the origins of the system, the history of the difficult negotiations between the various stakeholders, and the establishment of the legal framework, the speakers discussed the current status of the work of drafting the certification guide and the timeframe for implementation.

While stressing that all the texts are not yet available and that many things remain unclear, the speakers detailed the scope, the operators and products concerned and excluded, the semantic analysis and the definition of terms and of the different roles according to the new Charter, as well as the possible financial penalties.

Although it is possible to draw parallels with the Charter applicable to medicines in France, the two systems are clearly different in many respects. This observation can be made in many areas, such as the rules for organizing visits, the for ethics and for distributing samples. In this context, the simultaneous management of two Charters, with sometimes contradictory injunctions or additional restrictive terms, is likely to become a challenge for the companies that will be subject to both systems, beyond possible inequities between competitors who, due to their product portfolios, would not be subject to the equivalent requirements.

While waiting for more details, one thing to remember is that the Charter already applies, and even if many actions can only be undertaken once the entire system has been clarified and the certification guide is not yet available, there are already applicable measures! ATESSIA can assist you in setting up and adapting your processes to comply with these new standards.

Article written by Raphaël DAUVERGNE, Regulatory and Pharmaceutical Affairs Advisor