Community code relating to medicinal products for human use
This Directive establishes a Community code which brings together, in a single instrument, all the provisions in force governing the placing on the market, production, labelling, classification, distribution and advertising of medicinal products for human use.
The code applies to all medicinal products for human use, except for:
- medicinal products prepared in a pharmacy in accordance with a medical prescription (‘magistral formula’);
- medicinal products prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia (‘officinal formula’);
- medicinal products intended for research and development trials;
- intermediate products intended for further processing;
- radionuclides in the form of sealed sources;
- whole blood, plasma or blood cells of human origin;
- innovative therapeutic medicinal products prepared on an as-needed basis, pursuant to specific quality standards, and used in the same Member State, in a hospital, under the professional responsibility of a doctor, to carry out a given medical prescription.
This code also applies to the manufacture of medicinal products exclusively intended for export, as well as intermediate products, active substances and excipients.
Marketing authorisation procedure
No medicinal product (with the exception, under certain conditions, of radiopharmaceuticals prepared at the time of use) may be placed on the market of a Member State unless an authorisation has been issued by the competent authorities of that Member State or by the European Medicines Agency (the ‘Agency’).
Only applicants established in the Community may be granted a marketing authorisation.
Certain particulars and documents must be included with the authorisation request, namely:
- the name and constituents of the medicinal product;
- the manufacturing method;
- therapeutic indications, contra-indications and side-effects;
- posology, method and route of administration;
- expected shelf-life, precautionary and safety measures during storage and administration of the medicinal product;
- disposal of waste;
- the risk to the environment;
- a description of control tests employed by the manufacturer;
- the results of pharmaceutical, pre-clinical and clinical tests;
- a summary describing the applicant’s system of pharmacovigilance;
- a copy of any marketing authorisation obtained in another Member State or non-member country.
Notwithstanding the previous paragraph and without prejudice to the law relating to intellectual and commercial property, applicants are not obliged to provide the results of pre-clinical or clinical tests or clinical trials if they can show that:
- the medicinal product is a generic of a reference medicinal product which has been authorised for not less than eight years in a Member State or in the Community;
- the active substances of the medicinal product have had a well established medicinal use in the Community for at least ten years, with an acceptable level of safety.
Homeopathic medicinal products may be subject to a special, simplified authorisation or registration procedure, provided they satisfy the following criteria:
- they are administered orally or externally;
- there is no specific therapeutic indication on the labelling of the medicinal product or in any information relating thereto;
- there is a sufficient degree of dilution to guarantee the safety of the medicinal product.
When examining a marketing application for a medicinal product (homeopathic or otherwise), the competent authority of the Member State:
- must verify whether the procedures for issuing a marketing authorisation have been complied with;
- may have the medicinal product, its raw materials and, if necessary, intermediate products or other constituents tested by a laboratory;
- may ask the applicant to complete the dossier by submitting certain items referred to in the Directive.
When a marketing authorisation is granted, the competent authority of the Member State concerned must inform the holder that it accepts the summary of the product’s characteristics. It must ensure that the information in the summary is consistent with that approved in connection with the issuing of the authorisation, and must prepare an evaluation report.
In the event of changes to the terms of marketing authorisations, the Commission adopts appropriate provisions by means of an implementing Regulation.
In exceptional circumstances and following consultation with the applicant, an authorisation may be granted subject to certain conditions relating mainly to the safety of the medicinal product, notification of any incident associated with its use, and the measures to be taken. Such authorisation is granted only where the applicant can show that he is unable to provide comprehensive information concerning the safety and efficacy of the medicinal product under normal conditions of use.
Once the authorisation has been delivered, the competent national authority may impose an obligation on the holder to perform a post-authorisation safety or efficacy study.
The authorisation is valid for five years and is renewable. Following issue of the authorisation the holder must take account of scientific and technical progress and ensure that the medicinal product is manufactured and checked by means of generally accepted scientific methods. The competent authority must approve any changes to the product. Once the marketing authorisation has been renewed, it is valid for an unlimited period.
The marketing authorisation application will be rejected if it appears that:
- the risk-benefit ratio is not seen as favourable (safety criterion);
- its therapeutic effect is insufficiently substantiated (this efficacy criterion does not apply to homeopathic medicinal products);
- its qualitative and quantitative composition is not as declared (quality criterion);
- the particulars and documents which accompany the application are inconsistent with the provisions of the Directive.
The duration of the procedure for granting an authorisation to place a medicinal product (homeopathic or otherwise) on the market may not exceed 210 days.
This Directive sets up a Coordination Group tasked with examining:
- any questions relating to the marketing authorisation of a medicinal product in two or more Member States;
- any pharmacovigilance issues for authorised medicinal products;
- any questions concerning amendments to marketing authorisations issued by Member States.
The role of secretariat of this Coordination Group will be carried out by the Agency.
Mutual recognition procedures and decentralised procedure
In order to be granted a marketing authorisation for a medicinal product in more than one Member State, the applicant must submit an application based on an identical dossier in those Member States (decentralised procedure). The applicant requests that one of the Member States act as “reference Member State” and prepare an assessment report on the medicinal product, a draft summary of the product characteristics as well as a draft label and package leaflet.
If the medicinal product has already been authorised at the time of the application, the authorisation holder may submit a request for recognition of this authorisation to other Member States (mutual recognition procedure). He must inform the Member State which has issued the authorisation (‘reference Member State’) of this, as well as the Agency. The reference Member State must forward the assessment report, the summary of product characteristics and the label and package leaflet to the Member States concerned by the application.
In both cases, within 90 days of the receipt of these documents, each Member State concerned must either recognise the decision of the reference Member State or, on the contrary, consider that the medicinal product may present a serious potential risk to public health.
In the latter case, a conciliation procedure is initiated. This may lead to referral to the Committee for Proprietary Medicinal Products (‘the Committee’) if the disagreement between the Member States is not resolved.
Matters may be referred to the Committee by a Member State, an authorisation holder or the Commission, when a medicinal product has been the subject of several market authorisation applications and the Member States have adopted divergent decisions in regard to those applications. It must issue an opinion within 90 days of the date on which the matter was referred to it by the Agency.
The Member States, the Commission, the applicant or the holder of the marketing authorisation may also refer the matter to the Committee in specific cases where the interests of the European Union (EU) are involved, before reaching a decision on a request for a marketing authorisation or on the suspension, withdrawal or amendment of an authorisation.
The authorisation holder may appeal against a negative decision by the Committee, in which case the Committee examines whether its opinion must be reviewed within 60 days.
Within 15 days of receipt of the Committee's opinion, the Commission must prepare a draft of the decision to be taken in respect of the application. It also assumes responsibility for drawing up a final decision, which is sent to all the Member States. The marketing authorisation holder or the applicant are informed accordingly.
Within 30 days of receipt of the final decision concerning a marketing authorisation, the Member States must comply with it and duly inform the Commission and the Agency.
Manufacture and importation
The following operations are subject to authorisation by the Member States:
- manufacture, dividing up, packaging or presentation of medicinal products within the territories of the Member States (with the exception of operations performed by a pharmacist solely for retail supply);
- all imports of medicinal products from Non-EU Member Countries.
The Member States must record information relating to the authorisation in a European database managed by the Agency.
In order to obtain manufacturing authorisation, the applicant must:
- specify the medicinal products to be manufactured and imported, and also the place where they are to be manufactured and/or controlled);
- have at his disposal appropriate premises, technical equipment and control facilities;
- have at his disposal the services of at least one qualified person responsible for ensuring that the requirements set out in the marketing authorisation and the legislation in force are met;
- provide particulars in support of his application.
The competent authority of the Member State may issue a manufacturing authorisation only after having made sure of the accuracy of the particulars supplied. Authorisation may be accompanied by certain obligations. The time taken for the procedure for granting manufacturing authorisation may not exceed 90 days, but the period may be suspended temporarily when the applicant is asked to supply additional data.
The holder of a manufacturing authorisation must:
- have at his disposal the services of staff who comply with the legal requirements existing in the Member State concerned;
- supply the authorised medicinal products only in accordance with the legislation of the Member States concerned;
- give prior notice to the competent authority of any changes he may wish to make to any of the particulars supplied in connection with his manufacturing application;
- allow the agents of the competent authority access to his premises;
- enable the qualified person mentioned above to carry out his duties, and inform the competent authority in the event that this person is replaced;
- comply with the principles and guidelines of good manufacturing practices for medicinal products and use only those active substances manufactured in line with good manufacturing practices and distributed in accordance with good distribution practices;
- immediately provide the competent authority and the authorisation holder with any information revealing that the medicinal products covered by his authorisation have been falsified or are suspected of having been falsified;
- check that the manufacturers, importers or distributors supplying him with active substances are registered with the competent authority in the Member State in which they are established;
- check the authenticity and quality of active substances and excipients.
Active substances may only be imported under certain conditions:
- they have been manufactured in line with good practice;
- they are accompanied by written confirmation from the competent authority in the third country in question.
Importers, manufacturers and distributors of active substances established in the EU must register their businesses with the competent authority of the Member State in which they are established.
Labelling and package leaflet
A number of specific particulars must appear on the outer packaging of medicinal products or, where there is none, the immediate packaging, including:
- name of the medicinal product, its dose and pharmaceutical form;
- qualitative and quantitative composition in respect of active substances;
- pharmaceutical form and contents by weight, volume or dose unit;
- method of administration;
- list of excipients, listed in the detailed indications;
- expiry date;
- special storage precautions, disposal of unused medicinal products or waste;
- authorisation number and manufacturing batch number;
- special warnings;
- safety measures enabling wholesalers and authorised persons to dispense medicinal products to the public (for medicinal products other than radiopharmaceuticals).
These particulars must be legible, easy to understand and indelible.
Prescription-only medicinal products must be provided with safety measures (unless they are exempted by the Commission). Medicinal products not requiring a prescription shall not need safety measures unless they are listed, by derogation, on a list drawn up by the Commission where a risk of falsification has been identified.
Member States may require the use of certain forms of labelling making it possible to ascertain the price of the medicinal product, the conditions for reimbursement by social security organisations, the legal status for supply, as well as identification and proof of authenticity of the medicinal product.
The packaging of all medicinal products must contain a package leaflet, unless the information required features directly on the outer packaging or on the immediate packaging.
The package leaflet must include certain particulars, including:
- details permitting identification of the medicinal product;
- therapeutic indications;
- information necessary before taking the medicinal product;
- the necessary and usual instructions for proper use;
- description of the side-effects observed during normal use of the medicinal product;
- reference to the expiry date indicated on the packaging;
- date on which the package leaflet was last updated.
Before issuing a marketing authorisation for a medicinal product, the competent authority must check that the outer packaging, the immediate packaging and the package leaflet comply with the Directive. The same applies to all proposed changes to the labelling or the package leaflet.
The labelling particulars must appear at least in the official language or languages of the Member State where the product is placed on the market.
Specific provisions will apply to the packaging and container of medicinal products containing radionuclides, and to the labelling and package leaflets of homeopathic medicinal products.
Classification of medicinal products
When granting a marketing authorisation, and on the basis of the criteria stipulated in the Directive, the competent authorities must specify the classification of the medicinal product as:
- a medicinal product subject to medical prescription;
- a medicinal product not subject to medical prescription.
On the basis of the criteria laid down in the Directive, the competent authorities may subdivide medicinal products belonging to the first category as follows:
- medicinal products on renewable or non-renewable medical prescription;
- medicinal products subject to special medical prescription;
- medicinal products on restricted medical prescription, reserved for use in certain specialised areas.
The authorities of each Member State must draw up a list of medicinal products which may only be issued on medical prescription specifying, if necessary, the category of classification. This list must be updated annually. The changes made to it must be communicated to the Commission.
The competent authorities must re-examine and, where necessary, amend the classification of a medicinal product where new facts are brought to their notice.
Wholesale distribution and resale of medicinal products
Member States must make the wholesale distribution of medicinal products subject to the possession of an authorisation to engage in activity as a wholesaler of medicinal products.
Authorisation is not required if a producer already possesses a manufacturing authorisation for the medicinal products concerned. However, possession of authorisation to engage in activity as a wholesaler in medicinal products does not give dispensation from the obligation to possess a manufacturing authorisation. Distributors that do not hold marketing authorisation and import a medicinal product from another Member State must inform the marketing authorisation holder and the competent authority of the Member State concerned of their intention to import said medicinal product.
Wholesale distributors of medicinal products must possess an authorisation to engage in activity as a wholesaler in medicinal products.
The holder of a distribution authorisation must comply with certain requirements, namely:
- providing officials with access in order to inspect premises, facilities and equipment;
- procuring medicinal products from persons holding a distribution authorisation;
- checking that medicinal products received have not been falsified;
- having an emergency plan which enables a medicinal product to be recalled;
- record-keeping (purchase/sales invoices, electronic format);
- implementing an effective risk management system.
Checks on the persons authorised to engage in the activity of wholesaler in medicinal products are carried out by the Member State which has granted the authorisation. A Member State must suspend or revoke the authorisation if the conditions of authorisation are no longer met. It must immediately inform the other Member States and the Commission thereof.
When a Member State considers that, in respect of a person holding an authorisation granted by another Member State, the conditions of authorisation are not, or are no longer met, it must forthwith inform the Commission and the other Member State involved. The latter must take the measures necessary and inform the Commission and the first Member State.
The time taken for the procedure for examining the application for authorisation may not exceed 90 days, unless the applicant has been asked to supply additional data.
The Directive lists the criteria which the holders of the distribution authorisation must meet. In particular, they must have suitable premises and qualified staff and must undertake to fulfil the obligations incumbent on them following issue of the authorisation; these include making the premises available for inspection, supplying medicinal products only to persons who are authorised to supply medicinal products to the public, keeping precise records of all purchase/sales invoices, and having an emergency plan which ensures effective implementation of any withdrawal from the market.
Member States must ensure that persons authorised or entitled to supply medicinal products to the public are able to provide information that makes it possible to trace the distribution path of every medicinal product.
The wholesale distribution of narcotic or psychotropic substances, medicinal products derived from blood, immunological medicinal products and radiopharmaceuticals is subject to more stringent requirements laid down by the Member States.
In consultation with the Committee for Medicinal Products for Human Use and the Pharmaceutical Committee established by Council Decision 75/320/EEC, the Commission must publish guidelines on good distribution practice.
Persons reselling medicinal products must be registered with the competent authority in their Member State and ensure that medicinal products are covered by a marketing authorisation or an authorisation from the competent authorities of a Member State.
Sale to the public by correspondence
Medicinal products may be sold to the public by correspondence, in compliance with Directive 98/34/EC, under the following conditions:
- the natural or legal person dispensing the medicinal products is authorised to do so in compliance with the legislation of the Member State in which they are established;
- the natural or legal person dispensing the medicinal products has provided the Member State in which they are established with certain information such as their name, date on which they commenced their activities, and the categories of medicinal products that they sell;
- medicinal products must be compliant with the national legislation of the destination Member State;
- the website through which the medicinal products are sold contains contact information for the competent authority, a link to the website of the establishment’s Member State and an official logo pertaining to the sale of medicinal products to the public by correspondence.
This Directive defines ‘advertising of medicinal products’ as any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of medicinal products, including advertising to the general public and advertising to persons qualified to prescribe or supply medicinal products, visits by medical sales representatives, supply of samples, sponsorship of promotional meetings and scientific congresses attended by persons qualified to prescribe or supply medicinal products, etc.
Member States must prohibit any advertising of a medicinal product for which a marketing authorisation has not been granted (this prohibition does not apply to homeopathic medicinal products).
The advertising of a medicinal product must encourage the rational use of the product and may not be misleading.
The Directive distinguishes between advertising to the general public and advertising to persons qualified to prescribe or supply medicinal products.
Member States must prohibit the advertising to the general public of medicinal products which:
- are available on medical prescription only;
- contain psychotropic or narcotic substances;
- are not intended for use without the intervention of a medical practitioner.
This prohibition does not apply to vaccination campaigns carried out by the industry and approved by the competent authorities of the Member States.
Medicinal products may be advertised to the general public if they are intended and designed for use without the intervention of a medical practitioner for diagnosis or for the prescription or monitoring of treatment, and if necessary with the advice of a pharmacist.
Member States must prohibit the direct distribution of medicinal products to the public for promotional purposes. They may also prohibit, on their territory, advertising to the general public of medicinal products the cost of which may be reimbursed.
All advertising to the general public of a medicinal product must be clearly identifiable as such and must include at least the following information:
- name of the medicinal product;
- the information necessary for correct use of the medicinal product;
- a specific and legible invitation to read carefully the instructions in the package leaflet.
The Directive bans the inclusion in advertising of medicinal products to the general public of any information which:
- gives the impression that a medical consultation or surgical operation is unnecessary;
- compares the medicinal product with other treatments or products;
- suggests that the health of the subject can be enhanced by taking the medicinal product or affected by not taking it;
- is directed exclusively or principally at children;
- refers to a recommendation by scientists, health professionals or persons who, because of their celebrity, could encourage the consumption of medicinal products;
- suggests that the medicinal product is a foodstuff, cosmetic or other consumer product;
- suggests that the safety or efficacy of the product is due to the fact that it is natural;
- could, by a description or detailed representation, lead to erroneous self-diagnosis;
- refers, in improper, alarming or misleading terms, to claims of recovery;
- uses, in improper, alarming or misleading terms, pictorial representations of changes in the human body caused by disease or injury, or of the action of a medicinal product on the human body.
Advertising aimed at persons qualified to prescribe or supply medicinal products (doctors, pharmacists, etc.) must include:
- essential information on the medicinal product;
- the supply classification of the medicinal product.
Member States may also require the inclusion of additional particulars: selling price or indicative price, conditions for reimbursement by social security bodies.
Any documentation relating to a medicinal product supplied to persons qualified to prescribe or supply it must include, besides the particulars listed above, the date on which it was last revised. The information must be accurate, up to date, verifiable and sufficiently complete.
The Directive also contains specifications concerning the training of medical sales representatives and the information requirements and constraints they must respect in their work (ban on granting significant pecuniary advantages or benefits as a promotion technique, restrictions on hospitality at sales promotions, restrictions on the distribution of free samples). For their part, persons qualified to prescribe or supply medicinal products may not solicit or accept any inducement prohibited by the Directive.
Member States must ensure that there are adequate and effective methods to monitor the advertising of medicinal products. These methods must in any event include provisions under which persons or organisations may take legal or administrative action against any advertisements considered to be incompatible with the Directive.
The marketing authorisation holder must fulfil certain obligations to ensure compliance with the Directive (he must provide the monitoring authorities with a sample of all advertisements emanating from his undertaking, meet specific information requirements, etc.).
Member States must lay down the penalties to be imposed should the provisions of the Directive be infringed.
Member States must establish a pharmacovigilance system to collect information useful for the surveillance of medicinal products with regard to risks they might pose to the heath of patients or public health, in particular adverse reactions in human beings, incorrect use and serious abuse of medicinal products. Member States shall use this pharmacovigilance system to scientifically evaluate this required information with the aim of preventing or reducing risks.
Member States must take all necessary measures to encourage doctors and other healthcare professionals to report suspected adverse reactions to the competent authorities.
Holders of marketing authorisations for medicinal products must implement a pharmacovigilance system equivalent to the system put in place by the Member States. Holders must:
- implement a risk management system for each medicinal product;
- monitor the results of risk reduction measures;
- update the risk management system.
As regards pharmacovigilance, the Member States have obligations of transparency and communication. They must therefore manage a national website on medicinal products which is linked to the European medicinal product website established by Regulation (EC) No 726/2004. The purpose of this website is to communicate, in particular, public assessment reports, risk management summaries and information on the adverse effects of medicinal products.
If marketing authorisation holders wish to disseminate information on pharmacovigilance issues, they must first inform the competent national authorities, the European Medicines Agency and the Commission.
Marketing authorisation holders must notify the Eudravigilance database, introduced by Regulation (EC) No 726/2004, of all suspected serious adverse effects brought to their attention in the EU or a third country, within 15 days of receiving such information. They must also notify the Eudravigilance database of any suspected serious adverse effect coming to light in the Union with 90 days of becoming aware of the occurrence.
For their part, the Member States must ensure that serious side-effect notifications are also brought to the attention of the Agency and the authorisation holder.
The Directive empowers a Member State to recommend the amendment, suspension or withdrawal of marketing authorisation following evaluation of the pharmacovigilance data.
A Member State or the Commission must initiate a European assessment procedure where emergency measures are considered necessary following the assessment of pharmacovigilance data, in any of the following situations in which the Member State or the Commission envisages:
- suspending or withdrawing a marketing authorisation;
- prohibiting the dispensing of a medicinal product;
- refusing the renewal of a marketing authorisation;
- notifying a new contra-indication.
The Agency must then determine whether the safety problem affects all medicinal products in the same range or the same therapeutic category, and initiate scientific assessment.
The Commission may request that provisional measures be taken. The procedure leads to harmonised measures being adopted throughout the European Union for the medicinal products concerned.
Monitoring of post-authorisation safety studies
This type of monitoring applies to non-interventional post-authorisation safety studies organised by the marketing authorisation holder.
Before carrying out a study, the marketing authorisation holder submits a draft protocol to the Pharmacovigilance Risk Assessment Committee and the competent national authority in their Member State. The study may only be undertaken after approval has been given by the Committee or competent national authority.
Once the study has been completed, a final report must be submitted to the competent national authority or the Pharmacovigilance Risk Assessment Committee. The Committee may also make recommendations, after which the Member States agree on a position to be adopted in this regard. The resulting agreement is then published on the website set up by the Regulation which established the European Medicines Agency.
Implementation, delegation and guidelines
The Commission adopts implementing pharmacovigilance measures concerning, in particular:
- the content of the permanent dossier in the pharmacovigilance system;
- minimum requirements for the pharmacovigilance quality system;
- minimum requirements for the monitoring of information in the Eudravigilance database.
In cooperation with the competent authorities and other interested parties, the Agency prepares guidelines on good pharmacovigilance practice for the competent authorities and marketing authorisation holders.
Medicinal products derived from human blood and plasma
Member States must take all the measures necessary to:
- prevent the transmission of infectious diseases by medicinal products manufactured on the basis of human blood or plasma;
- promote Community self-sufficiency in human blood or plasma by encouraging unpaid donations.
Monitoring and sanctions
The competent authorities of each Member State, in cooperation with the Agency, must ensure, by means of regular inspections (inspection of manufacturing establishments and laboratories, sampling, examination of documents), and if necessary by unannounced inspections, that the legal requirements governing medicinal products are complied with. This cooperation also involves sharing information with the Agency concerning inspections planned and carried out by manufacturers established in the EU or in non-Member States, as well as medicinal product wholesalers.
Inspections are carried out by officials authorised to:
- inspect establishments selling or manufacturing medicinal products, active substances or excipients;
- take samples;
- examine all documents relating to the inspection;
- inspect premises, archives, documents and the permanent dossier in the pharmacovigilance system for the marketing authorisation holder.
Member States may also request that an official laboratory analyse samples.
The Member States must ensure that the supply of a medicinal product is banned and the medicinal product is withdrawn from the market if it appears that:
- the product is harmful;
- it is lacking in therapeutic efficacy;
- the risk-benefit ratio is not favourable;
- the product’s qualitative and quantitative composition is not as declared;
- the controls have not been carried out.
The competent authority of a Member State must withdraw or suspend the manufacturing authorisation where the conditions required for obtaining such authorisation are no longer fulfilled and if the manufacturing of the medicinal product does not correspond to information provided.
The Member States must put in place a system aimed at preventing medicinal products suspected of being harmful to health from being dispensed to patients.
However, the competent authority may authorise the dispensing of a medicinal product in exceptional circumstances and for a transitional period to patients who are already being treated with that medicinal product.
|Act||Entry into force||Deadline for transposition in the Member States||Official Journal|
OJ L 311, 28.11.2001
|Amending act(s)||Entry into force||Deadline for transposition in the Member States||Official Journal|
OJ L 33, 8.2.2003
OJ L 159, 27.6.2003
OJ L 136, 30.4.2004
OJ L 136, 30.4.2004
Regulation (EC) No 1901/2006
OJ L 378, 27.12.2006
Regulation (EC) No 1394/2007
OJ L 324, 10.12.2007
OJ L 81, 20.3.2008
OJ L 168, 30.6.2009
OJ L 348, 31.12.2010
OJ L 174, 1.7.2011
Successive amendments and corrections to Directive 2001/83/EC have been incorporated into the basic text. This consolidated version is for information only.
- Directorate General Health and Consumers, Medicinal products for human use