Wael HAYEK

What are Good Manufacturing Practices (GMP) ? 

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Definition 

Good Manufacturing Practices are a set of principles and guidelines. The first GMPs were published in France in 1978. These guidelines are regularly updated to incorporate regulatory changes. 

The WHO defines Good Manufacturing Practices as “one of the elements of quality assurance, ensuring that products are manufactured and controlled in a uniform manner and to quality standards appropriate to their use and specified in the marketing authorization”. The aim is to guarantee the quality, safety and efficacy of medicinal products. 

These Good Manufacturing Practices provide an understanding of the requirements of European regulations relating to the manufacture of medicinal products. They are one of the standards applicable to health products with marketing authorisation for the European market, as well as to experimental medicinal products. 

The application of GMP by pharmaceutical establishments is verified by the competent authorities during inspections. 

GMP compliance certificates issued by the ANSM following these inspections are published in the European EudraGMDP database. 

Organisation of Good Manufacturing Practices 

The standard is made up of 4 different parts plus appendices and guidelines. The 4 parts are as follows:  

  • Part I: GMP for medicinal products for human use 
  • Part II: GMP for active substances used as starting materials in medicinal products 
  • Part III: GMP-related documents  
  • ICH Q9: “quality risk management” guideline 
  • ICH Q10: “pharmaceutical quality system” guideline 
  • Part IV: GMP specific to innovative therapy medicinal products 

The 10 Principles of Good Manufacturing Practice 

There are 10 fundamental principles applicable to pharmaceutical operations which are taken from these chapters and which must be applied in order to guarantee the compliance of medicines:  

  • Creating procedures: writing operating procedures and instructions to provide a “road map”; 
  • Documentation: provide a precise description of the work in progress to ensure compliance with procedures and traceability; 
  • Validation: proving the correct operation of the systems in place by ensuring validation circuits; 
  • System design: integrating processes, product quality and staff safety right from the design phase of buildings, systems and equipment; 
  • Maintenance: regular and efficient maintenance of systems, installations and equipment; 
  • Skills: developing and clearly demonstrating skills at the workplace; 
  • Contamination prevention: adopting regular and systematic hygiene and cleanliness practices; 
  • Quality first and foremost: regular checks on raw materials and processes (manufacturing, packaging, labelling, etc.); 
  • Quality audits: planning and carrying out regular audits to ensure GMP compliance and the effectiveness of the quality system. 

Conclusion  

Compliance with Good Manufacturing Practices is essential. It is a regulatory obligation for pharmaceutical establishments. It is crucial to ensure product compliance and safety. Furthermore, during inspections by the health authorities, failure to comply with these standards may result in decisions of varying severity, depending on the non-compliance observed. The consequences of inspections can range from administrative warnings to sanctions.  

What are CEPs ?

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CEP : what’s that? 

In Europe, three distinct possibilities exist for presenting information relating to the active substance, from a qualified manufacturer, used in a medicinal product in the marketing authorisation file (MA file): 

– present a complete documentation (sections 3.2.S.1 to 3.2.S.7.3 100% completed according to the requirements of NtA-Vol 2B); 

– present an Active Substance Master File (“ASMF“) which contains an open (non-confidential) part and a closed (confidential) part; 

– present a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP). 

In this article we will focus on defining what the CEP consists in and why this possibility for recording a source of active substance is particularly interesting. 

  • CEP definition 

The CEP is a document issued by the European Directorate for the Quality of Medicines and Healthcare (“EDQM“) following an official European procedure for Certification of suitability to the monographs of the European Pharmacopoeia (Ph. Eur.) (known as the “Certification procedure”). 

This document certifies that the quality of the substance in question can be adequately controlled by the corresponding Ph. Eur. monograph(s), supplemented if necessary by additional tests appearing on the CEP. It is thus based on the evaluation by EDQM experts of a file submitted by the applicant (in the same way as by the experts of the competent authorities for the MA application file). 

However, a CEP does not allow to confirm compliance with Good Manufacturing Practices (GMP) of the substance concerned and cannot replace the GMP certificate. A CEP can therefore be issued by the EDQM with or without inspection of the manufacturing site. Also a CEP does not replace a certificate of analysis and does not guarantee that a batch of the substance is of appropriate quality. Therefore, vigilance must remain required by the future user of the substance, with the implementation of controls upon receipt of the substance. 

The Certification procedure is applicable to substances for which a general or specific monograph has been adopted by the European Pharmacopoeia Commission (e.g. substance of synthetic origin [active substance or excipient], herbal drugs, herbal drugs preparations, etc.). This procedure does not apply to direct products of genetic expression (proteins), nor to products obtained from human tissues, nor to vaccines or products and preparations derived from blood. Furthermore, although this may have been the case in the past, the EDQM does not accept new CEP applications for substances of biological origin. 

A public list of CEPs with their status is available without access restriction in the EDQM certification database. 

Details of the content of the CEP application file are provided on the EDQM website. New requirements are now in force for the constitution of files by applicants with the entry into force of CEP 2.0 since September 1, 2023. 

  • The different categories of CEP 

There are currently several types of CEPs issued by EDQM depending on the evaluation carried out, including the following simple CEPs: 

– Certificate of chemical purity and microbiological quality (“Chemical CEP”) à e.g.: paracetamol 

– Certificate for herbal drugs and herbal drugs preparations (“Herbal CEP”)à e.g.: lavender oil 

– TSE certificate for substances of animal origin potentially subject to transmissible spongiform encephalopathy (“TSE CEP”) à e.g.: gelatin 

Combined CEPs may also be granted, as follows: 

– Certificate of chemical purity/microbiological quality and sterility à e.g.: sterile amoxicillin sodium 

– Double certificate (chemical + TSE) à e.g.: cholecalciferol 

– Double certificate (chemical + TSE) also covering sterility 

It is possible to claim a particular quality for a substance, this must be duly demonstrated in the file (e.g. sterile, micronised, crushed substance, etc.): this quality will be indicated in the subtitle on the CEP. Furthermore, it is possible to request a CEP for a particular polymorph (as a quality), even if the mention “the substance presents a polymorphism” does not appear in the “Characters” section of the corresponding specific Ph. Eur. monograph. 

  • Recognition of the CEP outside Europe 

Although it is not mandatory for the marketing of substances, the Certification procedure constitutes the preferred option for ensuring that a substance entering in the composition of a medicinal product complies with the specifications of the European Pharmacopoeia, as well as for demonstrating the compliance with TSE risk requirements. 

From a regulatory perspective, CEPs are accepted in all EU Member States and in States that have signed the Convention relative to the elaboration of a European Pharmacopoeia (including the United Kingdom), with the exception of Ukraine. 

According to the information received by the EDQM, the following countries accept CEPs, sometimes under conditions (non-exhaustive list): South Africa, Albania, Algeria, Saudi Arabia, Australia, Azerbaijan, Canada, Georgia, Ghana, Israel, Kyrgyzstan, Malaysia, Morocco, Moldova, New Zealand, Uzbekistan, Singapore, and Tunisia. CEPs are also accepted (under conditions) by the Taiwan Food and Drug Administration. 

CEPs may therefore be accepted in other countries (non-EU or Ph. Eur. members), at the discretion of the authorities of these countries. In such cases, the Competent Authorities will decide on the scope and conditions of acceptance of the CEP (e.g. submission of a partial or complete ASMF in addition to the CEP). The EDQM indicates that it is therefore important to check, in advance, the acceptability and conditions associated with the use of a CEP in these countries. 

Additional requirements may be applied by some non-EU states (e.g. signed, dated and version-controlled documents for specifications and analytical procedures). 

In terms of the MA file, section 3.2.S of the MA holder/applicant for the active substance should also be adapted by making the necessary references to the CEP and/or by providing the data specific to the manufacturer(s) of the finished product using the substance covered by a CEP in the relevant sections of the CTD. 

As a conclusion, the CEP is an essential document for marketing authorisation files in Europe and its evaluation by the EDQM encourages preferred use, the updating of which is less constraining in regulatory terms than other options (e.g. ASMF). Although recognised by a large majority of countries worldwide, it may not be sufficient in itself and may have to be subject to specific requirements of the country in which the MA is registered. 

Source: EDQM -FAQs (February 2024) 

Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Senior Consultant 

What is the European Pharmacopeia ?

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This article deals with the essential information you need to know about the European Pharmacopoeia (whose official acronym is “Ph. Eur.”), a unique reference work relative to the quality control of medicines in the 46 member countries of the Council of Europe. 

  • Presentation of the European Pharmacopoeia 

Ph. Eur. is a collection of official standards which, once published, provide a legal and scientific basis for the quality control of substances for pharmaceutical use and medicines during the development, production and marketing processes. It is available to users, in French and English, in paper format or online (paid service of the European Directorate for the Quality of Medicines and Healthcare (EDQM)). 

The legal basis of the European Pharmacopoeia is the “Convention relative to the elaboration of a European Pharmacopoeia” (European Treaty Series – No. 50) adopted by the Council of Europe in 1964. 

These official standards, presented in chapters and monographs, concern the qualitative and quantitative composition and the tests to be carried out on: medicines, the raw materials used in their production and synthesis intermediates. Therefore, all producers of medicines and/or substances for pharmaceutical use must apply these quality standards in a mandatory way in order to be allowed to market their products within the signatory States of the Convention. 

The role of the Ph. Eur. is to contribute to the protection of public health through the development of recognised common specifications relating to the quality of medicines and their components. These specifications must be appropriate because they constitute, for the patient, one of the fundamental guarantees in terms of the safety of use of medicines. Furthermore, their existence facilitates the free circulation of medicines within Europe and beyond. 

The monographs and other texts of the Ph. Eur. are developed to meet the needs of regulatory authorities (e.g. ANSM, EMA, etc.), services responsible for the quality control of medicines and their constituents as well as manufacturers of medicines and their various components (e.g. active substances, excipients, packaging materials). 

Ph. Eur. brings together member countries and observer countries. 

The member countries of the Ph. Eur. can participate in sessions of the European Pharmacopoeia Commission (EPC). Each Member State, represented by a national delegation, has one vote on all technical questions. A member country may also propose national experts in each of the Ph. Eur expert groups or working groups. 

Ph. Eur. observer countries can participate in the scientific work of the EPC, benefit from European experience in this area and access work relative to the quality control of medicines as well as the analytical methods used. 

The EPC is the decision-making body of the Ph. Eur. and is responsible, as such, for developing and keeping the content of the Pharmacopoeia up to date. This Commission meets behind closed doors three times a year in Strasbourg, in the premises of the EDQM. It is also the EPC which appoints the members of all Expert Groups and Working Groups in charge of developing and revising methods and texts. 

The Expert Groups cover the main scientific topics associated with the quality control of medicines and their constituents. Working Groups are appointed for a specific duration, in order to deal with a specific aspect of the work or a specific subject. 

  • Recognition of Ph. Eur. works worldwide 

The Ph. Eur. is widely used internationally. In fact, the EPC works in close collaboration with all users of the Ph. Eur. across the world considering that globalisation and expansion of international trade in the field of medicines have reinforced the need to develop quality standards of international scope. 

  • Interactions with Ph. Eur. 

The EPC defines a work program based on proposals from, for example, National Pharmacopoeia Authorities, expert groups, manufacturers and EDQM. Manufacturers wishing to participate in the development of a monograph, for example by providing data and samples for approved products and verifying the draft monograph, are encouraged to submit monograph proposals. 

It is possible for users to make proposals for revising monographs. However, these must follow the process defined on the EDQM website and be supported by sufficient data. 

The EDQM Knowledge database provides users with information on the status of general monographs/chapters. If the substance does not appear in this public database, this means that it is not covered by any monograph/general chapter of the Ph. Eur. 

  • The future of European Pharmacopoeia 

The Ph. Eur. has been actively engaged for almost 30 years in the Pharmacopoeia Discussion Group (PDG) alongside the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP) and, since October 5, 2023, the Indian Commission of Pharmacopoeia (IPC). The PDG aims to facilitate the international harmonisation of a selection of pharmacopoeial standards (in particular excipient monographs and certain general chapters) in order to alleviate for manufacturers the difficulties of carrying out analytical procedures according to different modalities, with different acceptance criteria, in order to comply with pharmacopoeial requirements which may vary depending on the regions of the world. 

Priorities for the future of the PDG, and therefore of the Ph. Eur., include the harmonisation of standards for elemental impurities and excipients as well as the modernisation of a large number of general methods and excipient monographs already harmonised. 

Sources: 

– EDQM website (February 2024) 

– EDQM-FAQs (February 2024) 

Article written by Isabelle MOUVAULT, Pharmaceutical Affairs Senior Consultant 

Poisonous Substances: What Use within the Pharmaceutical Industry? 

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Poisonous substances are defined in French legislation (and only in this legislation!) and include certain substances classified as dangerous according to categories defined by the Public Health Code. This classification imposes a number of constraints on marketing authorization holders based on these active substances. 

The regulation of poisonous substances thus encompasses substances, preparations, plants and medicines. 

Definitions 

Poisonous substances correspond to all narcotic, psychotropic, or potentially harmful substances. These substances are classified on List I or List II. Their dispensation in pharmacies is subject to mandatory medical prescription written by a doctor, dentist, or midwife, and for narcotic drugs, to the presentation of a prescription meeting all security techniques. 

Lists I and II of poisonous substances mentioned in Article L. 5132-1 of the Public Health Code include: 

– Certain substances classified as harmful to health in accordance with Article L. 1342-2; 

– Medicines that may directly or indirectly pose a danger to health; 

– Human medicines containing substances whose activity or side effects require medical supervision; 

– Any other product or substance presenting direct or indirect health risks. 

Medicines can be listed on List I, List II, or the list of narcotics, with this classification accommodating scenarios based on their quantitative composition of poisonous substances. 

List I means that a medicine can only be dispensed in a pharmacy for the duration mentioned on the prescription and can only be renewed if mentioned by the prescriber and for a maximum of one year. 

Medicines belonging to List II cannot be dispensed multiple times from the same prescription within 12 months, unless otherwise indicated by the prescriber. 

Finally, narcotic drugs are subject to a secure prescription and cannot be dispensed for a period exceeding 28 days. Some non-narcotic medicines are required to comply with some or all of the rules applicable to narcotics: these are narcotics-like medicines. 

Regulatory Evolution and Impact on Industry 

Since the adoption of stricter regulations regarding poisonous substances, the pharmaceutical industry has faced a more stringent framework. 

The measures outlined in the Public Health Code aim to strengthen control over all operations related to these substances, from production processes to wholesale distribution, import, and export. 

According to the Public Health Code, the production, manufacturing, transport, import, export, possession, offer, transfer, acquisition, and use of plants, substances, or preparations classified as poisonous are subject to strict conditions defined by decrees in the Council of State. This regulation requires full compliance with precise standards governing each stage of the supply chain. 

Decrees in the Council of State, established with the advice of the National Academies of Medicine and Pharmacy, have the power to prohibit certain operations or prescriptions related to poisonous substances, thus emphasizing the importance of safety and pharmaceutical regulation. 

Until 1st June  2021, poisonous substances were classified by order of the Minister of health, upon the proposal of the Director General of the National Agency for the Safety of Medicines and Health Products (ANSM). 

Since the decree of 1st February  2022, the ANSM is now responsible for: 

– Classifying substances and medicines intended for human medicine on Lists I and II of poisonous substances defined in Article L. 5132-6 of the Public Health Code; 

– Setting any exemptions to the regulation of poisonous substances regarding medicines intended for human medicine. Indeed, certain poisonous substances, below dose or concentration thresholds and used for a brief treatment duration, may be dispensed without a prescription; 

– Classifying any substance, intended or not for human medicine, as narcotics or psychotropics. 

Industrial pharmaceutical establishments must adapt to the regulatory specifics of this status, covering activities such as manufacturing, import, wholesale distribution, and research. Any failure to comply with these regulatory requirements can lead to severe sanctions, requiring strict compliance. 

These measures also affect stakeholders operating in the field of veterinary medicines. 

Regarding labelling, the regulation of poisonous substances adds requirements for medicines based on these substances in terms of primary and secondary packaging. The labelling must notably include a green or red frame so that the pharmacist can indicate the dosage to be followed. 

Finally, regarding possession, specific rules must also be followed. Poisonous substances are not eligible for direct access requests. As a reminder, the ANSM defines the list of medicines that can be presented for over-the-counter access at the front of the counter in pharmacies according to criteria chosen to guarantee health and patient safety (self-medication). 

Article written by Zarine RAMJAUNY, Legal counsel 

What are the mechanisms for early and compassionate access in France?  

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Atessia supports its clients daily in the practical modalities of implementing the French early and compassionate access system, whose subtleties require some explanations. 

On July 1, 2021, the new early and compassionate access system was introduced through 2 decrees, supplemented by 4 orders, with immediate effect. This new system is based on 2 mechanisms for access and coverage by health insurance: 

  • Early Access (AAP)  

Firstly, early access, which targets medicinal products that meet an unmet therapeutic need and may be innovative. The laboratory submits a request for early access authorization (AAP) to the High Authority for Health (HAS) and, for medicinal products not yet authorized under a Marketing Authorization (AMM), to the National Agency for the Safety of Medicines and Health Products (ANSM).  

These authorizations can apply to: 

  • A medicinal product prior to obtaining the AMM in the considered indication (Pre-AMM AAP = AP1), 
  • A medicinal product that already has an AMM in the considered indication, prior to common law coverage by health insurance (Post-AMM AAP = AP2) Interestingly, the product may or may not have an AMM for another indication. As per HAS doctrine, granting early access authorization is reserved for certain specialties meeting the following 5 cumulative eligibility criteria: 

1. Strongly presumed efficacy and safety in the considered indication. 

2. The disease to be treated is severe, rare, or disabling. 

3. There is no “appropriate treatment.” 

4. The implementation of treatment cannot be delayed. 

5. The medicinal product is presumed to be innovative.  

The authorities examine each of these criteria separately, in a relatively strict manner. 

This system also requires concrete commitments from laboratories, which should not be underestimated and need to be weighed with the parent company. 

  • From a REGULATORY standpoint: the laboratory must commit to filing an AMM request within 2 years for an AAP1 or a request for registration within the month following the AMM’s approval for an AAP2. Thus, the timing of the filing is crucial in the project. 
  • From a LOGISTICAL standpoint: the laboratory makes the product available within 2 months following the granting of the AAP (PUI) and ensures it can supply the product to allow continuity of treatments initiated during the entire AAP, for a minimum period of one year (including 3 months of coverage). 
  • From a FINANCIAL standpoint: the laboratory implements a PUT-RD, for data collection and transmission of periodic summary reports. The laboratory finances this data collection (cf. agreement to be signed with health establishments). 
  • The pharmaceutical laboratory is also required to assist prescribers in entering and monitoring the collection of real-life follow-up data of the medicinal product, providing them with the necessary means. 

Two types of compassionate access: 

This system targets two distinct cases, both involving a medicinal product to treat patients with diseases without appropriate treatment in a given therapeutic indication, without being intended to obtain an AMM in France. The requests are managed only by the National Agency for the Safety of Medicines and Health Products (ANSM). 

  1. Either this compassionate access is requested for an unauthorized and unavailable medicinal product in France by a hospital prescriber for a specifically named patient, provided that the ANSM can presume a favorable benefit/risk ratio for a severe, rare, or disabling disease: this is an individual and nominative compassionate access authorization (AAC). 
  1. Or it involves the regulation of a practice, initiated by the ANSM, to secure an off-label prescription practice of a medicinal product available in France, with an AMM for other indications, when it is subject to a well-established off-label prescription on French territory: this is a compassionate prescription framework (CPC).  

Exemptions to compassionate access have been foreseen in the following cases: 

  • Allowing nominative access to medicinal products in development for the indication: this is a “very early” compassionate access. 

The grant by the ANSM is subject to several eligibility conditions, which brings this system closer to early access and can be the gateway to it: 

  • The implementation of the treatment cannot be delayed; 
  • The patient cannot participate in any ongoing research; 
  • The company marketing the medicinal product must commit to filing an early access request within 12 months following the first “pre-precoce compassionate” authorization (18 months for rare diseases). 

For these mechanisms, the designation of a laboratory operating a medicinal product may be necessary, to ensure, if necessary, the import/distribution, pharmacovigilance, quality complaints, or medical information. 

The laboratories now have several years of experience with these new systems, and the emerging trends show the authorities’ willingness to make innovative medicinal products available to French patients and to respond to the personal situations of patients in therapeutic dead ends. 

Article written by Caroline LECUELLE, Consultant in Regulatory Affairs & Pharmaceuticals 

What are the differences between the Mutual Recognition Procedure and the Decentralized Procedure ? 

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From a legislative point of view, the mutual recognition procedure is defined by the Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. 

Directive 2004/27/EC subsequently laid the foundations for the decentralised procedure. 

These two procedures are available for all marketing authorisation applications that do not fall within the mandatory scope of the centralised procedure. They are applicable whenever an applicant wishes to register its medicinal product in more than one Member State.  

1/ The Mutual Recognition Procedure (MRP) 

Article 28.2 of Directive 2001/83/EC, as amended, specifies the scope of this procedure: the principle is to extend a national MA already obtained in one of the EU Member States, to one or more other Member States in which the laboratory wishes to market its product. The referent state (or “RMS”), which granted the existing MA, manages the procedure. 

Once the evaluation procedure has been completed, the MAs are issued by each of the competent authorities of the member states concerned. 

Timetable 

After a possible upgrade of the MA dossier, the RMS sends the MA dossier and its assessment report, including the SPC, package leaflet and labeling, to the CMS 14 days before the start of the procedure.  

The concerned Member States must then recognize the authorization already issued by the RMS within 90 days (without clock-stop).  

The procedure may, however, end on Day 60 if the RMS has no further comments.  

The MA (including the SPC, package leaflet and labeling) is recognized by the CMS. 

This period is followed by a 30-day national closing phase to issue the national MA. 

If a Member State has objections to recognizing the dossier’s assessment report, summary of product characteristics (SPC), package leaflet and labeling, on the grounds of a potentially serious risk to public health (as defined by Article 29(1) of Directive 2001/83/EC), the dossier is referred back to the CMDh for further discussion. This procedure lasts 60 days. If the CMDh is unable to reach a decision within 60 days, the application is sent to the CHMP for arbitration (art. 29(4) of Directive 2001/83/EC). This procedure also lasts 60 days. 


2/ The decentralized procedure (DCP) 

This procedure differs from the MRP in two main points :  

  • No marketing must first have been granted in the EU,  
  • The dossier is submitted simultaneously in all Member States.  

In this case, the laboratory asks a member state to act as reference state (“RMS”) for the evaluation among the states in which it wishes to authorize its medicinal product. 

Timetable 

The RMS draws up a preliminary assessment report on the dossier submitted and the draft summary of product characteristics (SPC), package leaflet and labeling. 

This report is submitted to the CMS and the applicant for comments on Day 70 of the procedure. 

On Day 105 of the procedure, the clock stops to allow the applicant to submit answers to the questions raised by the Member States at the end of phase 1. 

When the answers have been submitted, the clock starts again on Day 106, and on Day 120 of the procedure, the RMS circulates at the same time an update of all documents (assessment report, SPC, package leaflet and labeling) to the applicant and the CMS. 

A second phase of Questions and Answers begins, and the procedure may be closed on Day 150 if all comments have been resolved.  

Otherwise, a new 60-day phase begins to finalize outstanding issues.  

The DCP therefore lasts a maximum of 210 days. This period is followed by a 30-day national closing phase to issue the national MA. 

As with the MRP, if there is no consensus between member states, the dossier is referred back to the CMDh for further discussion. This procedure lasts 60 days. If the CMDh is unable to reach a decision within 60 days, the application is sent to the CHMP for arbitration (art. 29(4) of Directive 2001/83/EC). This procedure also lasts 60 days. 

To sum up: 

MRP DCP 
Existing initial national MA  No MA granted in the EU 
No choice of the RMS (national MA already existing th the EU) The choice of the RMS is up to the applicant 
Request a recognition by the other Member States  Simultaneous application to all member states: the RMS evaluates the dossier for the first time (as for the CMS) 
Only one evaluation phase Two evaluation phases 
Decision within 90 days, or up to 150 days in the event of arbitration by the CMDh if no consensus can be reached between Member States. Decision in 210 days (excluding clock-stop period), or up to 270 days in the event of arbitration by the CMDh if no consensus can be reached between Member States. 
MA Dossiers identical in all member states 
Principle of recognition of the evaluation of the Reference Member State (RMS) by the other Member States concerned (CMS) 
The choice of the States involved in these procedures is up to the applicant 
National closing phase of 30 days planned to issue the national MA 
A European Public Assessment Report (PAR) for each medicinal product approved via the MRP/DCP is published in the directory « Mutual Recognition Index » by the RMS on the HMA website. 

ATESSIA supports laboratories throughout the registration process: from the registration strategy to the draft and submission of the marketing authorization applications. 

Article written by Fabien MEDINA, Pharmaceutical and Regulatory Affairs Senior Advisor. 

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

What about the classification of Marketing Authorization variations? 

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What about the classification of Marketing Authorization variations? 

When a holder wishes to register a medicine in a country, he submits a marketing authorization application (MAA) file to the health authorities. 

Once marketing authorization (MA) has been obtained, this file is not intended to remain unchanged. For each change impacting the product, whether (for example) a change in manufacturing, control, therapeutic indication, packaging, the holder must submit a variation request to the health authorities. 

A variation is therefore a modification of the marketing authorization. 

Modifications to the terms of an European marketing authorization are provided for by Directive 2001/83/EC and Regulation (EC) No 726/2004, and detailed by Regulation (EC) No 1234/2008 of November 24, 2008 concerning the examination of modifications to the terms of an MA for medicinal products for human use and veterinary medicinal products (hereinafter referred to as the “Modifications” regulation) 

This regulation has been applicable since January 1, 2010 to MAs obtained through centralized, decentralized and mutual recognition procedures, and since August 4, 2013 to MAs obtained through national procedures. 

There are 3 types of variations: 

– Type IA variations, also called minor. These are modifications whose repercussions on the quality, safety and efficacy of the medicinal product are considered minimal or non-existent. These modifications may be implemented by the holder without prior review by the authorities. However, not later than 12 months from the date of implementation, the holder must notify this modification simultaneously to all relevant Member States, the competent national authority or the EMA (as applicable) . 

Of note, there are type IAIN variations (IN = immediate notification). They can also be implemented by the holder without prior examination by the authorities. However, notification to the competent authorities must be made within 14 days of implementation. 

– Type IB variations. Also minor, they are defined as variations which are neither minor of type IA, nor major of type II, nor extensions. Within type IB variations, we also find the so-called “unforeseen” variations, which are not included in the initial regulation and which are mentioned in article 5. 

– Type II variations, called major. These are modifications which are not extensions of Marketing Authorization and which may have significant consequences in terms of quality, safety and efficacy. 

Modifications to the terms of a marketing authorization also include extensions of marketing authorization and urgent restriction measures for safety reasons. 

Variations are categorized according to the type of change by the Guidelines relating to the characteristics of the different categories of modifications, to the conduct of the procedures provided for in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of amendments to the terms of a marketing authorization for medicinal products for human use and veterinary medicinal products and the documentation to be submitted under these procedures. There are changes classified as administrative (A), relating to quality (B), or relating to safety, efficacy or pharmacovigilance (C). Changes D concern the plasma master records and the vaccine antigen master records. 

The aim is twice: correctly position each change according to its type and category. To benefit from the type indicated in the classification, you must be able to provide the required documentation and meet the conditions mentioned, otherwise the variation request is likely to be recategorized or even rejected. 

Once these definitions have been established, note that MA holders have the possibility of submitting several modifications concerning one or more MAs in a single request, under the conditions determined by the regulation. It is called a grouping. It is important to mention that not all variations can be “grouped” together. A regulatory strategy must be put in place. 

Finally, the worksharing or task distribution procedure is strongly recommended. It allows MA holders to submit, in a single application, the same type IB, type II modification or the same group of modifications corresponding to one of the cases referred to in Annex III of the regulation provided that it does not include a request for extension, when these elements relate to several MAs held by the same holder, whatever the type of procedure (all combinations being possible), or to several purely national MAs from the same holder in more than one Member State. It was established to avoid duplication of work to evaluate these modifications: they are examined by a single authority, called the “reference authority” and chosen from among the competent authorities of the Member States and the EMA, to on behalf of other authorities concerned. 

Do not hesitate to call on ATESSIA to support you in the development of the regulatory strategy and writing your variation request files, whatever the registration procedure. 

Article written by Véronique LEWIN, Senior Consultant in Pharmaceutical Affairs – CMC