Medicinal Products [EU]

Table of Contents

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.

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

Summary

This Community code replaces and consolidates the following acts in a single act:

Directive 65/65/EEC, the basic Directive on authorisation for placing on the market, and certain subsequent amendments;
Directive 75/319/EEC, on additional conditions concerning placing on the market, and subsequent amendments;
Directive 75/318/EEC, on additional conditions concerning testing and placing on the market;
Directive 92/25/EEC, on wholesale distribution;
Directive 92/26/EEC, on classification for supply;
Directive 92/27/EEC, on labelling and package leaflets;
Directive 92/28/EEC, on the advertising of medicinal products.

These Directives and subsequent amendments to them are therefore repealed, and the Community code relating to medicinal products for human use incorporates all the existing provisions governing the production, placing on the market, distribution and utilisation 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.

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, including 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 and 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, and 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 will be granted if the applicant fulfils certain obligations, relating mainly to the safety of the medicinal product, notification of any incident associated with its use, and the measures to be taken.

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 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.

Mutual recognition of authorisations

An authorisation holder may submit a request for recognition of this authorisation to other Member States. 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 to the Member States concerned by the application.

Within 90 days of the receipt of the assessment report the Member State concerned must either recognise the decision of the other Member State or, on the contrary, consider that the medicinal product may present a 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 Community 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.

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 laid down in Directive 2003/94/EC.

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.

These particulars must be legible, easy to understand and indelible.

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 all 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;
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 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.

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.

Advertising

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.

Pharmacovigilance

Member States must take all necessary measures to encourage doctors and other healthcare professionals to report suspected adverse reactions to the competent authorities.

They must also establish a pharmacovigilance system, to collect information useful for the surveillance of medicinal products, in particular:

adverse reactions in human beings;
incorrect use and serious abuse of medicinal products;

and scientifically evaluate this information.

All marketing authorisation holders must designate a qualified person responsible for pharmacovigilance, who must establish and maintain a central information system concerning the side-effects of the medicinal product in question.

Marketing authorisation holders must notify the competent authority of all suspected serious side-effects which are brought to their attention by a healthcare professional, within 15 days of receiving such information.

They must also, at regular intervals (specified in the Directive) or at the request of the competent authority, transmit detailed reports on any other side-effects which have been brought to their attention.

After consulting the Member States, the Agency and the interested parties, the Commission must draw up guidance on the collection, verification and presentation of reports on side-effects.

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.
In the event of an emergency, the Member State concerned may also suspend the marketing authorisation of a medicinal product, provided certain information obligations are complied with.

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 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.

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 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.

General provisions

The Directive provides for an information and mutual communication procedure between the competent authorities of the Member States to ensure compliance with the Directive. In the case of disagreement concerning an inspection report drawn up by the competent authority of a Member State, the Member States concerned must endeavour to reach agreement.

A marketing authorisation holder must immediately inform the Member States concerned of any action he takes to suspend the marketing of a medicinal product or withdraw it from the market. This information is then forwarded to the Agency by the Member States concerned.

The Agency must also be notified by the Member States of any decisions authorising marketing, refusing or revoking a marketing authorisation, cancelling a decision refusing or revoking a marketing authorisation, prohibiting supply or withdrawing a product from the market.

All decisions by the competent authorities must be notified to the interested party, together with information as to the redress available.

Marketing authorisations and revocations of such authorisations must be published by each Member State in its official gazette.

At the request of the manufacturer, the exporter or the authorities of an importing third country, Member States must deliver a manufacturing authorisation certificate following the guidelines laid down by the Directive.

Two annexes are attached to the Community code:

Annex I on analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products;
Annex II is divided into three parts. It contains a list of repealed directives with their successive amendments, a list of transposition deadlines and a correlation table.

References

Act	Entry into force	Deadline for transposition in the Member States	Official Journal
Directive 2001/83/EC [adoption: codecision COD/1999/0134]	18.12.2001	–	OJ L 311 of 28.11.2001

Amending act(s)	Entry into force	Deadline for transposition in the Member States	Official Journal
Directive 2002/98/EC [adoption: codecision COD/2000/0323]	8.2.2003	8.2.2005	OJ L 33 of 8.2.2003
Directive 2003/63/EC	30.6.2003	31.10.2003	OJ L 159 of 27.6.2003
Directive 2004/24/EC [adoption: codecision COD/2002/0008]	30.4.2004	30.10.2005	OJ L 136 of 30.4.2004
Directive 2004/27/EC [adoption: codecision COD/2001/0253]	30.4.2004	30.10.2005	OJ L 136 of 30.4.2004
Regulation (EC) No 1901/2006	26.1.2007	–	OJ L 378 of 27.12.2006
Regulation (EC) No 1394/2007	30.12.2007	–	OJ L 324 of 10.12.2007
Directive 2008/29/EC [adoption: codecision COD/2006/0295]	21.3.2008	–	OJ L 81 of 20.3.2008
Directive 2009/53/EC	20.7.2009	20.11.2011	OJ L 168 of 30.6.2009

The successive amendments and corrigenda to Directive 2001/83/EC have been incorporated into the basic text. This consolidated version is of documentary value only.

AMENDMENT OF ANNEXES

Annex I, part IV – Advanced therapy medicinal products
Directive 2009/120/EC [Official Journal L 242 of 15.9.2009].

RELATED ACTS

Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use [Official Journal L 262 of 14.10.2003].