What are the possible interactions between health industry players and healthcare professionals (HCPs) in France?

Promotional visit for medicinal products in France refers to promotional interactions with healthcare professionals (HCPs) conducted by authorized collaborators from the pharmaceutical industry.

The structural reform of health insurance established by the law of August 13, 2004, resulted in the first Charter of Medical Visit. The objective was to better regulate the commercial and promotional practices of laboratories that could harm the quality of care (creation of Article L.162-17-8 of the Social Security Code).

Since 2008, the scope of the charter has been broadened to include prescribers practicing in health institutions, and not just those from private practices. The latest version of the Charter, dated October 15, 2014, is now titled the “Charter on information provided for the promotion of medicinal products through prospecting or canvassing “

All pharmaceutical companies with an authorization to open as an “Exploitant” and having signed an agreement with the French Economic Committee for Health Products, CEPS, (reimbursable medicinal products), must commit to respecting the Charter, interpreted by a referential established by the High Authority for Health (HAS). The latest version of this reference system came into effect in March 2017. It is the practical application procedure of the Charter, and it is based on this procedure (certification reference system) that certifying bodies, accredited by the French Accreditation Committee (COFRAC), certify companies for their promotional activity. This procedure has two parts: one dedicated to the certification of the activity performed by the “Exploitant” companies themselves, on their own or in co-promotion, as well as the requirements that these companies must meet in the event of outsourcing all or part of their promotional activity. The second part is dedicated to the certification of the promotional activity performed by subcontracting companies.

Companies subject to this system must implement a quality management system that can sustainably meet the requirements of the Charter and its reference system:

  • Definition, implementation, and monitoring of the quality policy for this activity.
  • Initial/continuous training and knowledge evaluation of promotional collaborator  (7 regulatory themes and 2 scientific themes)
  • Respect for ethical rules towards patients, health professionals, competing companies, their own company, and health insurance.
  • Co-promotion and recourse to subcontracting (contract, responsibility, organization, and monitoring).

Pharmaceutical laboratories must prepare for annual certification audits (N: certification, N+1 surveillance, N+2 surveillance, N+3 renewal audit), regularly review their quality management system, monitor the activity of all cross-functional roles involved (marketing, regulatory affairs, medical, field staff: Medical Science Liaison (MSL) and promotional collaborators, etc.). Among the challenges, one is to ensure the regulatory compliance of promotional activity, which is one of the strategic pillars for companies.

Medicines are not the only ones concerned: the Quality Charter for professional practices for products and services reimbursable, published in the JO on March 8, 2022, will apply concomitantly to multiproduct companies, implying a double management of these Charters despite sometimes contradictory injunctions (see LunchWork Atessia x LexCase 20/04/22 “Quality Charter for professional practices for products and services reimbursable”).

It is interesting to note that the rules differ according to the product portfolio of the company: reimbursable or non-reimbursable medicinal products, Medical Devices, food supplements, cosmetics, biocides, everyday consumer products. Hospital visits are subject to additional rules.

The question of samples follows precise rules concerning both  the possible certification, the Law on the Regulation of Benefits, the requirement for transparency of links, the Good Manufacturing Practices (GMP).

What can promotional collaborator say? What can they give to doctors, and what must they give them? How to adapt the rules of the reference system with the digitalization of promotion and the advent of remote visits since the health crisis? And most importantly, what messages to deliver about the therapeutic indications of the marketing authorization , early or compassionate access, and off-label use, taking into account the therapeutic strategy established by the HAS? What part of the discourse should be devoted to job safety and side effects? How to talk about the results of clinical trials?

ATESSIA assists its clients in carrying out annual internal audits in preparation for the certification audits of Exploitant and their subcontractors, writing internal procedures, and training field teams.

Leslie Gorge, Regulatory & Pharmaceutical Affairs Consultant.

For more information

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The Chief Pharmaceutical Officer

The Chief Pharmaceutical Officer also called Responsible Pharmacist (RP) is a key role , essential to the organization of any pharmaceutical laboratory involved in the manufacture, exploitation and distribution of medicinal products for human use in France.

The Chief Pharmaceutical Officer ensures  the quality of the medicine and the safety of the patients. Their position, functions, and assignements are defined by the regulations. Their skills are validated by their peers based on practical experience. Their responsibilities are numerous. They must maintain their freedom of judgment and hold pharmaceutical authority within their structure. They can delegate some activities and must be replaced in case of absence.

Positions, functions and Assignements

The Chief Pharmaceutical Officer has a statutory position within a pharmaceutical establishment (manufacturer, operator, depositary or wholesaler-distributor).

They  organize and supervise all pharmaceutical activities: manufacturing and batch release, advertising, information, pharmacovigilance, follow up and withdrawal of batches, distribution, import and export, storage and transport.

The responsibilities attributed to the RP are broader than those of the qualified person within the European Union (directive 2001/83/EC, article 48). They have a personal responsibility for all pharmaceutical activities, unlike the qualified person who exercises operational responsibility for the activities they are responsible for (batch release, follow up and recall of batches, pharmacovigilance).

Their status as well as their functions and assignements are defined in the Public Health Code (Code de la Santé Publique CSP) in articles R.5124-16 to R.5124-41.

Validation of Skills and Practical Experience

Their skills and practical experience are validated by the National Council of the Order of Pharmacists. Decree No. 2022-324 of March 4, 2022, recently modified the terms of the practical experience required for the RP (CSP Articles R.5124-16 à R.5124-18).

The RP is appointed by the competent corporate body of the company and then declares themselves to the competent authority: the ANSM*.

The Responsibilities of the RP

The responsibilities of the RP are of three types:

  • Legal and criminal liability
  • They are a member of the management of the company.
  • They are the main contact of the Health Authorities.
  • They arepersonally responsible for the compliance of the pharmaceutical establishment with the Public Health Code.
  • Disciplinary responsibility
  • Respect for professional ethics
  • Compliance with their deontologic obligations
  • Civil liability

The RP shares civil and criminal liability with the manager(s) of the company.

Freedom of Judgment and Pharmaceutical Authority

Like any pharmacist, the RP preserves their freedom of professional judgment in the exercise of theirfunctions (CSP Article R.4235-3).

They have authority over all pharmaceutical staff (CSP Article R.5124-36) and appoints the delegate pharmacist(s).

Delegation and Replacement

The RP can delegate some pharmaceutical activities. The delegate pharmacist is bound, within the limits of their delegation, to the same obligations as the RP (CSP Article R.4235-68).

In the event of absence, the RP is replaced by an interim responsible pharmacist (CSP Article R.4235-70). The IRP then has the same functions, assignements, and responsibilities as the RP during the replacement period.

ATESSIA supports Chief Pharmaceutical Officer in the performance of their duties: regulatory intelligence, CMC support, advertising, pharmacovigilance, activities related to regulatory affairs and quality assurance, and offers Interim Responsible Pharmacists registered at the Pharmacists Council.

Article written by Christelle PETIT, Pharmaceutical Affairs Advisor and Director.

*ANSM : Agence Nationale de Sécurité du Médicament et des produits de santé (competent authority for medicines and health products)

The serialisation system

Securing the distribution of medicines represents an unprecedented challenge for public health. Although France has always benefited from a particularly secure drug distribution system and a strict legislative framework from the health authorities, the risk of falsified drugs is increasing on a global and European scale.

Faced with this major challenge, Directive 2011/62/EU of the European Parliament and of the Council of June 8, 2011 introduced the serialization system, which details were subsequently specified by Commission Delegated Regulation (EU) 2016/161 of October 2, 2015, in order to strengthen the safety of the distribution chain of medicinal products and to fight against their falsification. The obligations relating to the serialization of medicinal products and anti-counterfeiting devices are applicable since February 9, 2019.

Now 4 years after the entry into force of the European regulation, let’s look back at the implementation of the serialization system.

As a reminder, the serialization device is composed as follows:

  • A tamper-evident device for all drugs, affixed by the manufacturer and verified by the pharmacist to check the integrity of the product before dispensing (e.g. transparent adhesive tape);
  • A unique identifier (UI) on each box of mandatory prescription medication, affixed by the manufacturer and scanned by the pharmacist before dispensing to the patient (datamatrix).

The serialisation system contributes to the implementation of a European system to fight against the introduction of falsified medicines by providing additional security to guarantee the authenticity, safety and quality of medicines on the territory of the European Union. It completes the existing batch traceability by authenticating each box at the time of dispensing.

The implementation of this system required the collective commitment of all the stakeholders in the drug supply chain (manufacturers (CMOs) and Exploitants/Marketing Authorization Holders, wholesalers and distributors, pharmacies and hospitals, software publishers, etc.), as well as the Ministry of Solidarity and Health, the French National Agency for the Safety of Medicines and Health Products (ANSM) and the regional health agencies (ARS).

Indeed, this new system has required organizational changes at all levels, from drug production to delivery to the patient: adapting production lines to implement the unique identifier and the anti-tampering device, adapting the IT systems of all drug professionals, setting up governance bodies at national (NMVO) and European (EMVO) level, adapting procedures, etc.

The question of ultimate responsibility for implementing serialization has been the subject of numerous debates, which have now been settled, with the central issue of downloading unique identifiers at the time of manufacture and the possible outsourcing of this activity. The introduction of the OBP portal registration requirement and fees to finance the infrastructure of national (NMVS) and European (EMVS) repositories systems has also had an impact on the drug chain stakeholders.


Serialisation is a regulatory obligation for all pharmacies. Indeed, such a system can only operate with the participation of all pharmacies in the Member States in order to ensure that no falsified box is delivered to a patient in the European Union.

This obligation, which came into force on February 9, 2019, was reminded in the Order of February 26, 2021 on good dispensing practices for medicinal products in order to make the obligations incumbent on all pharmacists under European regulations more visible in a text of national scope.

However, to date, despite the health crisis and the strong mobilization of pharmacists, the connection of pharmacies to the system has been delayed and remains insufficient in France. As of February 6, 2023, only 17,901 pharmacies (86.2%) were complying with their obligations to serialize their medicines, with a target of 100% by December 31, 2022.

Given France’s considerable delay in implementing effective verification of the serialization system in pharmacies, a bill was adopted by the Senate on December 14, 2022, defining the financial penalties that may be imposed on pharmacy holders in the event of non-compliance with the obligation to deactivate the unique identifier.

On the page dedicated to serialisation in pharmacies on its website, the Ministry of Health stresses the importance of reaching this 100% objective as soon as possible to guarantee better safety and traceability of medicines for all French people.

Article written by Amélie NICOLAS-VERLEY, Regulatory and Pharmaceutical Affairs Advisor

The APQR review “à la française”

What is an APQR?

Both US and EU Good Manufacturing Practices (GMP) require manufacturers of all authorized medicinal products to perform Annual Product Quality Reviews (APQR in the US, PQR in EU). These reviews are conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. Such reviews are conducted and documented annually, (taking into account previous reviews), and include a number of review areas.

The Qualified Person is responsible for ensuring that each single batch is manufactured and controlled in compliance with the applicable regulation, in accordance with MA specifications and GMP, and is responsible for the APQR.

What’s special in France?

As it is the case everywhere, APQR duties involve the manufacturer and the MA Holder. But in France, there is another party involved, the Exploitant (see related article “The mysterious thing that an Exploitant is”). The Exploitant can sometimes be the MAH.

Moreover, French GMP specify that when the manufacturer, the MAH and the Exploitant are distinct, all of them are individually responsible for assessing the results of the APQR and evaluating the need to implement corrective and/or preventive actions or to perform any revalidation.

When the MAH is not the manufacturer and/or the Exploitant, contracts/Quality Agreements must be in place to define each party’s responsibilities in performing APQRs.

So, although mainly the manufacturer and the MAH are involved in performing the APQR, all parties including the Exploitant share responsibilities in reviewing the APQR. This means, for every single product exploited, that the APQR has to be received and checked by the Exploitant. This review has to be a critical review, and has to be documented in order to show that the Exploitant is continuously aware of the quality of the product, and is able to challenge the processes in case of any trend is identified.

APQR review is particularly critical as it is highly challenged by ANSM during routine inspections (both in the content and timelines of the review).It is therefore crucial for an Exploitant to have an effective APQR review process in place.

ATESSIA has a dedicated team performing APQR reviews that meet ANSM’s expectations and can help you in getting it right!

Article written by Raphaël DAUVERGNE, Regulatory and Pharmaceutical Affairs Advisors

The consulting profession at ATESSIA

In concrete terms, what does it mean to be a consultant in regulatory and pharmaceutical affairs at ATESSIA, Life science advisors?

At ATESSIA, we firmly believe that consulting is not a job that you do, but a talent that you keep developing. Our consultants have a strong technical background to meet the needs of our customers and a strong experience that allows them to solve complex problems. But it is also their behavioral and interpersonal skills that are necessary for them to succeed in this challenging profession. While the past has been almost exclusively focused on deliverables in the consulting world, at ATESSIA we believe that the present and future are entirely driven by the experience offered to our clients before, during and after the service is provided.

What qualities do we look for in our consultants?


“He who knows how to listen will become the one who is listened to” – Vizier Ptahhotep

A consultant must have the quality of active listening. Active listening to the needs of the customers enables us to set up innovative solutions in a culture of continuous improvement.

Listening to what the customer says about his needs and problems is the most useful way to be able to propose adequate solutions. In addition to being a good listener, it is also important to ask relevant and open-ended questions and not to impose a method or a solution without having really heard the client’s needs.

At ATESSIA our approach is thoughtful and detail oriented.


“The first rule before taking action is to take the place of the other. No real research for the common good will be out of there. “- Abbé Pierre

ATESSIA has chosen to position itself on the axis of human relations. We place the human being at the heart of our strategy, and we behave with empathy towards all our stakeholders. Empathy is an essential quality in the world of consulting, because if we do not put ourselves in the client’s shoes, we will not be able to understand his problem and thus respond to his request. In a world that has become more and more digitalized, we want to cultivate our human qualities that make all the difference.

Empathy is what reflects our signature: placing the human being at the heart of our customer relations.

Sense of urgency

“It doesn’t make sense to hire smart people and then tell them what to do. We hire smart people so they can tell us what to do.” – Steve Jobs

Agility and proactivity infuse everything we do, as well as the wisdom to consider options thoroughly. A sense of urgency allows the consultant to quickly identify potential problems, which then gives him the time to carefully craft solutions. In this unpredictable and ever-changing environment, our consultants respond with agility while remaining calm to get things done in an effective and efficient manner.


“Trust is a major element: without it, no project will succeed. – Eric Tabarly

ATESSIA’s consultants are committed to establishing a relationship of trust with their clients by understanding their environment and values and by being available and close to them when necessary. Firm believers in a customized approach, our consultants take into account the specificity of our clients’ businesses and the particularity of their operating methods. Our team overcomes obstacles, finds solutions, and delivers outstanding results. To achieve this, we remain transparent about our role and objectives. We pay particular attention to credibility, which depends on clearly communicating all the details of the mission while respecting the deadlines.

Critical thinking

“There is no fair wind for him who does not know where he is going” – Seneca

ATESSIA’s clients appreciate our ability to apply and communicate cutting-edge approaches in a clear and compelling manner. ATESSIA’s consultants base their thinking on the rational data of the cases. Our consultants are critical and independent thinkers who can effectively analyze data and draw conclusions based on the evidence at hand. This critical thinking involves breaking down information based on the available data and drawing logical conclusions based on the facts.

If you are interested in ATESSIA’s consulting world, contact us at hello@atessia.fr

Article written by Hiba MASSOUDY, Human Resources Manager

The mysterious thing that an Exploitant is

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.

If you’ve ever worked in a pharmaceutical company that has a subsidiary in France, there’s almost 100% chances that you haveheard about this absolutely unique-in-Europe status for a pharmaceutical establishment. So what does this mean and why are requests coming from French affiliates always so weird?

What is an Exploitant?

The term itself is so difficult to translate in a satisfactory way that it is almost always referred as “Exploitant” (with French accent, please).

The Exploitant is a distinct status from the MA Holder (however, they can be the same company) and cannot be defined as a distributor as well. Proof is, that WDAs issued by ANSM will not mention procurement/selling, but rather “Other – Exploitation”.

As long as there is a Marketing Authorization or an early access program in place (such as Early Access or Compassionate Use), no medicinal product can be distributed in France without an Exploitant being responsible for it.

The exploitant’s scope of activities covers:

  • Wholesaling – This means that the Exploitant is the one allowed to sell products to the rest of the distribution chain
  • Promotional activities – The Exploitant is the only entitled to use advertising material (under strict rules anyway)
  • Medical information – The Exploitant is responsible for providing necessary information to requestors, mainly prescribers, under stringent rules.
  • Pharmacovigilance – The Exploitant in the main contact for French agency
  • Batch follow-up and, if necessary, batch recall
  • Storage, if applicable

After this listing you may think that the Exploitant is responsible for almost everything, but the MA Holder still has certain responsibilities, and some are shared, like pharmacovigilance for example.

Some of the Exploitant duties (although not all) can be partly of completely subcontracted, but still fall under its supervision and responsibility. In case of subcontracting, the Exploitant will have to ensure that everything is done right.

In addition, the Exploitant is also the key when it comes to Market Access, Sales Reps Certification and pharmaceutical taxes.

Exploitants need to be authorized by ANSM prior to opening, and are regularly inspected, potentially financially sanctioned and can be closed by ANSM decision if any risk for Public Health.

Who’s the Responsible Pharmacist?

No matter how you call him/her (Chief Pharmaceutical Officer, and most often PR for “Pharmacien Responsable” in Molière’s language), he/she is the master person of an Exploitant. The one that personally undertakes all responsibilities, all sanctions.

The PR is necessarily a French Pharmacist, residing and working in France with a special level of experience that has to be recognized by the Order for Pharmacists.

How to enter the French Market and get your products “exploited”?

Securing a Marketing Authorization in France is a good start and an obvious prerequisite for entering the French Market indeed, but the having your product “exploited” is another key step.

You could either open your own Exploitant as your French subsidiary or rely on an already existing structure for exploiting your product.

Opening an Exploitant requires expertise in the following areas:

  • Describing the future Quality Management System. The QMS must be sufficiently described in order for ANSM to understand precisely enough how the Exploitant will operate and how it will handle a series of pharmaceutical operations like promotion, batch follow-up, pharmacovigilance;
  • Finding premises, and presenting related documentation as well as physical and IT securities in a way that will meet ANSM’s requirements;
  • Hiring a Responsible Pharmacist;
  • Managing all of the above in French, as the application file and relationships with the Authority can only be done in French;
  • Contracting Quality Agreements with partners (e.g. MAH) and sus-contractors (e.g. wholesaler) that meet French & EU regulation;
  • Certifying promotional activities within 9 months after the beginning of promotion.

Whatever the scenario, ATESSIA opened several Exploitant in France and can help you in defining your strategy, building you Exploitant opening file, or arranging third-party exploitation.

Article written by Raphaël DAUVERGNE, Regulatory and Pharmaceutical Affairs Advisor

Registering gene therapy medicinal products

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, Junior Regulatory and Pharmaceutical Affairs Advisor

How to manage a non-GMP raw material in your MA files?

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

How to proceed with non-pharmacopoeial excipients in the formulation of a medicinal product for human use?

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

Advertising for medicines: the keys to obtaining a visa in France

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)