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

• CELEX: Directive 2001/83/EC
• Articles: 131

Article 1

For the purposes of this Directive, the following terms shall bear the following meanings:

1. Proprietary medicinal product: Any ready-prepared medicinal product placed on the market under a special name and in a special pack.

2. Medicinal product: Any substance or combination of substances presented for treating or preventing disease in human beings.

Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product.

3. Substance: Any matter irrespective of origin which may be:

- human, e.g.

human blood and human blood products;

- animal, e.g.

micro-organisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products;

- vegetable, e.g.

micro-organisms, plants, parts of plants, vegetable secretions, extracts;

- chemical, e.g.

elements, naturally occurring chemical materials and chemical products obtained by chemical change or synthesis.

4. Immunological medicinal product: Any medicinal product consisting of vaccines, toxins, serums or allergen products:

(a) vaccines, toxins and serums shall cover in particular:

(i) agents used to produce active immunity, such as cholera vaccine, BCG, polio vaccines, smallpox vaccine;

(ii) agents used to diagnose the state of immunity, including in particular tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, brucellin;

(iii) agents used to produce passive immunity, such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin;

(b) "allergen product" shall mean any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent.

5. Homeopathic medicinal product: Any medicinal product prepared from products, substances or compositions called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in absence thereof, by the pharmacopoeias currently used officially in the Member States.

A homeopathic medicinal product may also contain a number of principles.

6. Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose.

7. Radionuclide generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be obtained by elution or by any other method and used in a radiopharmaceutical.

8. Radionuclide kit: Any preparation to be reconsitituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration.

9. Radionuclide precursor: Any other radionuclide produced for the radio-labelling of another substance prior to administration.

10. Medicinal products derived from human blood or human plasma: Medicinal products based on blood constitutents which are prepared industrially by public or private establishments, such medicinal products including, in particular, albumin, coagulating factors and immunoglobulins of human origin.

11. Adverse reaction: A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function.

12. Serious adverse reaction: An adverse reaction which results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.

13. Unexpected adverse reaction: An adverse reaction, the nature, severity or outcome of which is not consistent with the summary of product characteristics.

14. Periodic safety update reports: The periodical reports containing the records referred to in Article 104.

15. Post-authorisation safety study: A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the marketing authorisation, conducted with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product.

16. Abuse of medicinal products: Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effets.

17. Wholesale distribution of medicinal products: All activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their depositories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned.

18. Public service obligation: The obligation placed on wholesalers to guarantee permanently an adequate range of medicinal products to meet the requirements of a specific geographical area and to deliver the supplies requested within a very short time over the whole of the area in question.

19. Medicinal Prescription: Any medicinal prescription issued by a professional person qualified to do so.

20. Name of the medicinal product: The name given to a medicinal product, which may be either an invented name or a common or scientific name, together with a trade mark or the name of the manufacturer; the invented name shall not be liable to confusion with the common name.

21. Common name: The international non-proprietary name recommended by the World Health Organization, or, if one does not exist, the usual common name.

22. Strength of the medicinal product: The content of the active substances expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form.

23. Immediate packaging: The container or other form of packaging immediately in contact with the medicinal product.

24. Outer packaging: The packaging into which is placed the immediate packaging.

25. Labelling: Information on the immediate or outer packaging.

26. Package leaflet: A leaflet containing information for the user which accompanies the medicinal product.

27. Agency: The European Agency for the Evaluation of Medicinal Products established by Regulation (EEC) No 2309/93.

28. Risk to public health: All risks with regard to the quality, safety and efficacy of the medicinal product.

TITLE II

SCOPE

Article 2

The provisions of this Directive shall apply to industrially produced medicinal products for human use intended to be placed on the market in Member States.

Article 3

This Directive shall not apply to:

1. Any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula).

2. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question (commonly known as the official formula).

3. Medicinal products intended for research and development trials.

4. Intermediate products intended for further processing by an authorized manufacturer.

5. Any radionuclides in the form of sealed sources.

6. Whole blood, plasma or blood cells of human origin.

Article 4

1. Nothing in this Directive shall in any way derogate from the Community rules for the radiation protection of persons undergoing medical examination or treatment, or from the Community rules laying down the basic safety standards for the health protection of the general public and workers against the dangers of ionizing radiation.

2. This Directive shall be without prejudice to Council Decision 86/346/EEC of 25 June 1986 accepting on behalf of the Community the European Agreement on the Exchange of Therapeutic Substances of Human Origin(20).

3. The provisions of this Directive shall not affect the powers of the Member States' authorities either as regards the setting of prices for medicinal products or their inclusion in the scope of national health insurance schemes, on the basis of health, economic and social conditions.

4. This Directive shall not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products as contraceptives or abortifacients. The Member States shall communicate the national legislation concerned to the Commission.

Article 5

A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health care professional and for use by his individual patients on his direct personal responsibility.

TITLE III

PLACING ON THE MARKET

CHAPTER 1

Marketing authorization

Article 6

1. No medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93.

2. The authorisation referred to in paragraph 1 shall also be required for radionuclide generators, radionuclide kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals.

Article 7

A marketing authorization shall not be required for a radiopharmaceutical prepared at the time of use by a person or by an establishment authorized, according to national legislation, to use such medicinal products in an approved health care establishment exclusively from authorized radionuclide generators, radionuclide kits or radionuclide precursors in accordance with the manufacturer's instructions.

Article 8

1. In order to obtain an authorization to place a medicinal product on the market regardless of the procedure established by Regulation (EEC) No 2309/93, an application shall be made to the competent authority of the Member State concerned.

2. A marketing authorization may only be granted to an applicant established in the Community.

3. The application shall be accompanied by the following particulars and documents, submitted in accordance with Annex I:

(a) Name or corporate name and permanent address of the applicant and, where applicable, of the manufacturer.

(b) Name of the medicinal product.

(c) Qualitative and quantitative particulars of all the constituents of the medicinal product in usual terminology, but excluding empirical chemical formulae, with mention of the international non-proprietary name recommended by the World Health Organization where such name exists.

(d) Description of the manufacturing method.

(e) Therapeutic indications, contra-indications and adverse reactions.

(f) Posology, pharmaceutical form, method and route of administration and expected shelf life.

(g) If applicable, reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of any potential risks presented by the medicinal product for the environment.

(h) Description of the control methods employed by the manufacturer (qualitative and quantitative analysis of the constituents and of the finished product, special tests, e.g. sterility tests, tests for the presence of pyrogenic substances, the presence of heavy metals, stability tests, biological and toxicity tests, controls carried out at an intermediate stage of the manufacturing process).

(i) Results of:

- physico-chemical, biological or microbiological tests,

- toxicological and pharmacological tests,

- clinical trials.

(j) A summary, in accordance with Article 11, of the product characteristics, one or more specimens or mock-ups of the outer packaging and the immediate packaging of the medicinal product, together with a package leaflet.

(k) A document showing that the manufacturer is authorised in his own country to produce medicinal products.

(l) Copies of any authorisation obtained in another Member State or in a third country to place the medicinal product on the market, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 11 or approved by the competent authorities of the Member State in accordance with Article 21. Copies of the package leaflet proposed in accordance with Article 59 or approved by the competent authorities of the Member State in accordance with Article 61. Details of any decision to refuse authorization, whether in the Community or in a third country, and the reasons for such a decision.

This information shall be updated on a regular basis.

Article 9

In addition to the requirements set out in Articles 8 and 10(1), an application for authorization to market a radionuclide generator shall also contain the following information and particulars:

- a general description of the system together with a detailed description of the components of the system which may affect the composition or quality of the daughter nucleid preparation,

- qualitative and quantitative particulars of the eluate or the sublimate.

Article 10

1. In derogation of Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property:

(a) The applicant shall not be required to provide the results of toxicological and pharmacological tests or the results of clinical trials if he can demonstrate:

(i) either that the medicinal product is essentially similar to a medicinal product authorized in the Member State concerned by the application and that the holder of the marketing authorization for the original medicinal product has consented to the toxicological, pharmacological and/or clinical references contained in the file on the original medicinal product being used for the purpose of examining the application in question;

(ii) or that the constituent or constituents of the medicinal product have a well established medicinal use, with recognized efficacy and an acceptable level of safety, by means of a detailed scientific bibliography;

(iii) or that the medicinal product is essentially similar to a medicinal product which has been authorized within the Community, in accordance with Community provisions in force, for not less than six years and is marketed in the Member State for which the application is made. This period shall be extended to 10 years in the case of high-technology medicinal products having been authorised according to the procedure laid down in Article 2(5) of Council Directive 87/22/EEC(21). Furthermore, a Member State may also extend this period to 10 years by a single Decision covering all the medicinal products marketed on its territory where it considers this necessary in the interest of public health. Member States are at liberty not to apply the six-year period beyond the date of expiry of a patent protecting the original medicinal product.

However, where the medicinal product is intended for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate toxicological and pharmacological tests and/or of appropriate clinical trials must be provided.

(b) In the case of new medicinal products containing known constituents not hitherto used in combination for therapeutic purposes, the results of toxicological and pharmacological tests and of clinical trials relating to that combination must be provided, but it shall not be necessary to provide references relating to each individual constituent.

2. Annex I shall apply by analogy where, pursuant to point (ii) of paragraph 1, (a), bibliographic references to published data are submitted.

Article 11

The summary of the product characteristics shall contain the following information:

1. Name of the medicinal product.

2. Qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used.

3. Pharmaceutical form.

4. Pharmacological properties and, in so far as this information is useful for therapeutic purposes, pharmacokinetic particulars.

5. Clinical particulars:

5.1. therapeutic indications,

5.2. contra-indications,

5.3. adverse reactions (frequency and seriousness),

5.4. special precautions for use and, in the case of immunological medicinal products, any special precautions to be taken by persons handling such products and administering them to patients, together with any precautions to be taken by the patient,

5.5. use during pregnancy and lactation,

5.6. interaction with other medicaments and other forms of interaction,

5.7. posology and method of administration for adults and, where necessary, for children,

5.8. overdose (symptoms, emergency procedures, antidotes),

5.9. special warnings,

5.10. effects on ability to drive and to use machines.

6. Pharmaceutical particulars:

6.1. major incompatibilities,

6.2. shelf life, when necessary after reconstitution of the medicinal product or when the immediate packaging is opened for the first time,

6.3. special precautions for storage,

6.4. nature and contents of the immediate packaging,

6.5. special precautions for disposal of unused medicinal products or waste materials derived from such medicinal products, if appropriate.

7. Name or corporate name and permanent address of the marketing authorization holder.

8. For radiopharmaceuticals, full details of internal radiation dosimetry.

9. For radiopharmaceuticals, additional detailed instructions for extemporaneous preparation and quality control of such preparation and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical will conform with its specifications.

Article 12

1. Member States shall take all appropriate measures to ensure that the documents and particulars listed in Article 8(3)(h) and (i), and Article 10(1)(a)(ii) are drawn up by experts with the necessary technical or professional qualifications before they are submitted to the competent authorities. These documents and particulars shall be signed by the experts.

2. The duties of the experts according to their respective qualifications shall be:

(a) to perform tasks falling within their respective disciplines (analysis, pharmacology and similar experimental sciences, clinical trials) and to describe objectively the results obtained (qualitatively and quantitatively);

(b) to describe their observations in accordance with Annex I, and to state, in particular:

- in the case of the analyst, whether the medicinal product is consistent with the declared composition, giving any substantiation of the control methods employed by the manufacturer;

- in the case of the pharmacologist or the specialist with similar experimental competence, the toxicity of the medicinal product and the pharmacological properties observed;

- in the case of the clinician, whether he has been able to ascertain effects on persons treated with the medicinal product which correspond to the particulars given by the applicant in accordance with Articles 8 and 10, whether the patient tolerates the medicinal product well, the posology the clinician advises and any contra-indications and adverse reactions;

(c) where applicable, to state the grounds for using the bibliography mentioned in point (a)(ii) of Article 10(1).

3. Detailed reports by the experts shall form part of the particulars accompanying the application which the applicant submits to the competent authorities.

CHAPTER 2

Specific provisions applicable to homeopathic medicinal products

Article 13

1. Member States shall ensure that homeopathic medicinal products manufactured and placed on the market within the Community are registered or authorized in accordance with Articles 14, 15 and 16, except where the products are covered by a registration or authorization which was granted under national law on or before 31 December 1993 (and whether or not that registration or authorization has been renewed after that date). Each Member State shall take due account of registrations and authorizations previously granted by another Member State.

2. A Member State may refrain from establishing a special, simplified registration procedure for the homeopathic medicinal products referred to in Article 14. A Member State shall inform the Commission accordingly. The Member State concerned shall allow the use in its territory of homeopathic medicinal products registered by other Member States in accordance with Articles 14 and 15.

Article 14

1. Only homeopathic medicinal products which satisfy all of the following conditions may be subject to a special, simplified registration procedure:

- they are administered orally or externally,

- no specific therapeutic indication appears 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; in particular, the medicinal product may not contain either more than one part per 10000 of the mother tincture or more than 1/100th of the smallest dose used in allopathy with regard to active substances whose presence in an allopathic medicinal product results in the obligation to submit a doctor's prescription.

At the time of registration, Member States shall determine the classification for the dispensing of the medicinal product.

2. The criteria and rules of procedure provided for in Article 4(4), Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply by analogy to the special, simplified registration procedure for homeopathic medicinal products, with the exception of the proof of therapeutic efficacy.

3. The proof of therapeutic efficacy shall not be required for homeopathic medicinal products registered in accordance with paragraph 1 of this Article, or, where appropriate, admitted in accordance with Article 13(2).

Article 15

An application for special, simplified registration may cover a series of medicinal products derived from the same homeopathic stock or stocks. The following documents shall be included with the application in order to demonstrate, in particular, the pharmaceutical quality and the batch-to-batch homogeneity of the products concerned:

- scientific name or other name given in a pharmacopoeia of the homeopathic stock or stocks, together with a statement of the various routes of administration, pharmaceutical forms and degree of dilution to be registered,

- dossier describing how the homeopathic stock or stocks is/are obtained and controlled, and justifying its/their homeopathic nature, on the basis of an adequate bibliography,

- manufacturing and control file for each pharmaceutical form and a description of the method of dilution and potentization,

- manufacturing authorization for the medicinal product concerned,

- copies of any registrations or authorizations obtained for the same medicinal product in other Member States,

- one or more specimens or mock-ups of the outer packaging and the immediate packaging of the medicinal products to be registered,

- data concerning the stability of the medicinal product.

Article 16

1. Homeopathic medicinal products other than those referred to in Article 14(1) shall be authorized and labelled in accordance with Articles 8, 10 and 11.

2. A Member State may introduce or retain in its territory specific rules for the toxicological and pharmacological tests and clinical trials of homeopathic medicinal products other than those referred to in Article 14(1) in accordance with the principles and characteristics of homeopathy as practised in that Member State.

In this case, the Member State concerned shall notify the Commission of the specific rules in force.

3. Title IX shall apply to homeopathic medicinal products, with the exception of those referred to in Article 14(1).

CHAPTER 3

Procedures relevant to the marketing authorization

Article 17

1. Member States shall take all appropriate measures to ensure that the procedure for granting an authorization to place a medicinal product on the market is completed within 210 days of the submission of a valid application.

2. Where a Member State notes that an application for authorization is already under active examination in another Member State in respect of that medicinal product, the Member State concerned may decide to suspend the detailed examination of the application in order to await the assessment report prepared by the other Member State in accordance with Article 21(4).

The Member State concerned shall inform the other Member State and the applicant of its decision to suspend detailed examination of the application in question. As soon as it has completed the examination of the application and reached a decision, the other Member State shall forward a copy of its assessment report to the Member State concerned.

Article 18

Where a Member State is informed in accordance with Article 8(3)(l) that another Member State has authorized a medicinal product which is the subject of an application for authorization in the Member State concerned, that Member State shall forthwith request the authorities of the Member State which has granted the authorization to forward to it the assessment report referred to in Article 21(4).

Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the first Member State and the summary of the product characteristics as approved by it or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health, it shall apply the procedures set out in Articles 29 to 34.

Article 19

In order to examine the application submitted in accordance with Articles 8 and 10(1), the competent authority of the Member State:

1. must verify whether the particulars submitted in support of the application comply with the said Articles 8 and 10(1) and examine whether the conditions for issuing an authorization to place medicinal products on the market (marketing authorization) are complied with.

2. may submit the medicinal product, its starting materials and, if need be, its intermediate products or other constituent materials, for testing by a State laboratory or by a laboratory designated for that purpose in order to ensure that the control methods employed by the manufacturer and described in the particulars accompanying the application in accordance with Article 8(3)(h) are satisfactory.

3. may, where appropriate, require the applicant to supplement the particulars accompanying the application in respect of the items listed in the Articles 8(3) and 10(1). Where the competent authority avails itself of this option, the time limits laid down in Article 17 shall be suspended until such time as the supplementary information required has been provided. Likewise, these time limits shall be suspended for the time allowed the applicant, where appropriate, for giving oral or written explanation.

Article 20

Member States shall take all appropriate measures to ensure that:

(a) the competent authorities verify that manufacturers and importers of medicinal products coming from third countries are able to carry out manufacture in compliance with the particulars supplied pursuant to Article 8(3)(d), and/or to carry out controls according to the methods described in the particulars accompanying the application in accordance with Article 8(3)(h);

(b) the competent authorities may allow manufacturers and importers of medicinal products coming from third countries, in exceptional and justifiable cases, to have certain stages of manufacture and/or certain of the controls referred to in (a) carried out by third parties; in such cases, the verifications by the competent authorities shall also be made in the establishment designated.

Article 21

1. When the marketing authorization is issued, the holder shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it.

2. The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently.

3. The competent authorities shall forward to the Agency a copy of the authorization together with the summary of the product characteristics.

4. The competent authorities shall draw up an assessment report and comments on the dossier as regards the results of the analytical and pharmacotoxicological tests and the clinical trials of the medicinal product concerned. The assessment report shall be updated whenever new information becomes available which is of importance for the evaluation of the quality, safety or efficacy of the medicinal product concerned.

Article 22

In exceptional circumstances, and following consultation with the applicant, an authorization may be granted subject to certain specific obligations, including:

- the carrying out of further studies following the granting of authorization,

- the notification of adverse reactions to the medicinal product.

These exceptional decisions may be adopted only for objective and verifiable reasons and shall be based on one of the causes referred to in Part 4 (G) of Annex I.

Article 23

After an authorization has been issued, the authorization holder must, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.

These changes shall be subject to the approval of the competent authority of the Member State concerned.

Article 24

Authorization shall be valid for five years and shall be renewable for five-year periods, on application by the holder at least three months before the expiry date and after consideration by the competent authority of a dossier containing in particular details of the data on pharmacovigilance and other information relevant to the monitoring of the medicinal product.

Article 25

Authorization shall not affect the civil and criminal liability of the manufacturer and, where applicable, of the marketing authorization holder.

Article 26

The marketing authorisation shall be refused if, after verification of the particulars and documents listed in Articles 8 and 10(1), it proves that:

(a) the medicinal product is harmful in the normal conditions of use, or

(b) that its therapeutic efficacy is lacking or is insufficiently substantiated by the applicant, or

(c) that its qualitative and quantitative composition is not as declared.

Authorisation shall likewise be refused if the particulars and documents submitted in support of the application do not comply with Articles 8 and 10(1).

CHAPTER 4

Mutual recognition of authorizations

Article 27

1. In order to facilitate the adoption of common decisions by Member States on the authorization of medicinal products on the basis of the scientific criteria of quality, safety and efficacy, and to achieve thereby the free movement of medicinal products within the Community, a Committee for Proprietary Medicinal Products, hereinafter referred to as "the Committee", is hereby set up. The Committee shall be part of the Agency.

2. In addition to the other responsibilities conferred upon it by Community law, the Committee shall examine any question relating to the granting, variation, suspension or withdrawal of marketing authorization which is submitted to it in accordance with this Directive.

3. The Committee shall draw up its own Rules of Prodecure.

Article 28

1. Before submitting the application for recognition of a marketing authorization, the holder of the authorization shall inform the Member State which granted the authorization on which the application is based (hereinafter "reference Member State"), that an application is to be made in accordance with this Directive and shall notify it of any additions to the original dossier; that Member State may require the applicant to provide it with all the particulars and documents necessary to enable it to check that the dossiers filed are identical.

In addition the holder of the authorization shall request the reference Member State to prepare an assessment report in respect of the medicinal product concerned, or, if necessary, to update any existing assessment report. That Member State shall prepare the assessment report, or update it, within 90 days of the receipt of the request.

At the same time as the application is submitted in accordance with paragraph 2, the reference Member State shall forward the assessment report to the Member State or Member States concerned by the application.

2. In order to obtain the recognition according to the procedures laid down in this Chapter in one or more of the Member States of a marketing authorization issued by a Member State, the holder of the authorization shall submit an application to the competent authorities of the Member State or Member States concerned, together with the information and particulars referred to in Articles 8, 10(1) and 11. He shall testify that the dossier is identical to that accepted by the reference Member State, or shall identify any additions or amendments it may contain. In the latter case, he shall certify that the summary of the product characteristics proposed by him in accordance with Article 11 is identical to that accepted by the reference Member State in accordance with Article 21. Moreover, he shall certify that all the dossiers filed as part of the procedure are identical.

3. The holder of the marketing authorization shall communicate the application to the Agency, inform it of the Member States concerned and of the dates of submission of the application and send it a copy of the authorization granted by the reference Member State. He shall also send the Agency copies of any such authorization which may have been granted by the other Member States in respect of the medicinal product concerned, and shall indicate whether any application for authorization is currently under consideration in any Member State.

4. Save in the exceptional case provided for in Article 29(1), each Member State shall recognize the marketing authorization granted by the reference Member State within 90 days of receipt of the application and the assessment report. It shall inform the reference Member State which granted the initial authorization, the other Member States concerned by the application, the Agency, and the marketing authorization holder.

Article 29

1. Where a Member State considers that there are grounds for supposing that the marketing authorization of the medicinal product concerned may present a risk to public health, it shall forthwith inform the applicant, the reference Member State which granted the initial authorization, any other Member States concerned by the application and the Agency. The Member State shall state its reasons in detail and shall indicate what action may be necessary to correct any defect in the application.

2. All the Member States concerned shall use their best endeavours to reach agreement on the action to be taken in respect of the application. They shall provide the applicant with the opportunity to make his point of view known orally or in writing. However, if the Member States have not reached agreement within the time limit referred to in Article 28(4) they shall forthwith refer the matter to the Agency with regard to the Committee's reference for the application of the procedure laid down in Article 32.

3. Within the time limit referred to in Article 28(4), the Member States concerned shall provide the Committee with a detailed statement of the matters on which they have been unable to reach agreement and the reasons for their disagreement. The applicant shall be provided with a copy of this information.

4. As soon as he is informed that the matter has been referred to the Committee, the applicant shall forthwith forward to the Committee a copy of the information and particulars referred to in Article 28(2).

Article 30

If several applications submitted in accordance with Articles 8, 10(1) and Article 11 have been made for marketing authorization for a particular medicinal product, and Member States have adopted divergent decisions concerning the authorization of the medicinal product or its suspension or withdrawal, a Member State, or the Commission, or the marketing authorization holder may refer the matter to the Committee for application of the procedure laid down in Article 32.

The Member State concerned, the marketing authorization holder or the Commission shall clearly identify the question which is referred to the Committee for consideration and, where appropriate, shall inform the holder.

The Member State and the marketing authorization holder shall forward to the Committee all available information relating to the matter in question.

Article 31

The Member States or the Commission or the applicant or holder of the marketing authorization may, in specific cases where the interests of the Community are involved, refer the matter to the Committee for the application of the procedure laid down in Article 32 before reaching a decision on a request for a marketing authorization or on the suspension or withdrawal of an authorization, or on any other variation to the terms of a marketing authorization which appears necessary, in particular to take account of the information collected in accordance with Title IX.

The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the marketing authorization holder.

The Member States and the marketing authorization holder shall forward to the Committee all available information relating to the matter in question.

Article 32

1. When reference is made to the procedure described in this Article, the Committee shall consider the matter concerned and issue a reasoned opinion within 90 days of the date on which the matter was referred to it.

However, in cases submitted to the Committee in accordance with Articles 30 and 31, this period may be extended by 90 days.

In case of urgency, on a proposal from its Chairman, the Committee may agree to a shorter deadline.

2. In order to consider the matter, the Committee may appoint one of its members to act as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks.

3. In the cases referred to in Articles 29 and 30, before issuing its opinion, the Committee shall provide the marketing authorization holder with an opportunity to present written or oral explanations.

In the case referred to in Article 31, the marketing authorization holder may be asked to explain himself orally or in writing.

If it considers it appropriate, the Committee may invite any other person to provide information relating to the matter before it.

The Committee may suspend the time limit referred to in paragraph 1 in order to allow the marketing authorization holder to prepare explanations.

4. The Agency shall forthwith inform the marketing authorization holder where the opinion of the Committee is that:

- the application does not satisfy the criteria for authorization, or

- the summary of the product characteristics proposed by the applicant in accordance with Article 11 should be amended, or

- the authorization should be granted subject to conditions, with regard to conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance, or

- a marketing authorization should be suspended, varied or withdrawn.

Within 15 days of the receipt of the opinion, the marketing authorization holder may notify the Agency in writing of his intention to appeal. In that case, he shall forward the detailed grounds for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of receipt of the grounds for appeal, the Committee shall consider whether its opinion should be revised, and the conclusions reached on the appeal shall be annexed to the assessment report referred to in paragraph 5.

5. Within 30 days of its adoption, the Agency shall forward the final opinion of the Committee to the Member States, the Commission and the marketing authorization holder together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions.

In the event of an opinion in favour of granting or maintaining an authorization to place the medicinal product concerned on the market, the following documents shall be annexed to the opinion.

(a) a draft summary of the product characteristics, as referred to in Article 11;

(b) any conditions affecting the authorization within the meaning of paragraph 4.

Article 33

Within 30 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law.

In the event of a draft decision which envisages the granting of marketing authorization, the documents referred to in Article 32(5)(a) and (b) shall be annexed.

Where, exceptionally, the draft decision is not in accordance with the opinion of the Agency, the Commission shall also annex a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to the Member States and the applicant.

Article 34

1. A final decision on the application shall be adopted in accordance with the procedure referred to in Article 121(2).

2. The rules of procedure of the Standing Committee established by Article 121(1) shall be adjusted to take account of the tasks incumbent upon it in accordance with this Chapter.

These adjustments shall involve the following:

- except in cases referred to in the third paragraph of Article 33, the opinion of the Standing Committee shall be obtained in writing,

- each Member State is allowed at least 28 days to forward written observations on the draft decision to the Commission,

- each Member State is able to require in writing that the draft decision be discussed by the Standing Committee, giving its reasons in detail.

Where, in the opinion of the Commission, the written observations of a Member State raise important new questions of a scientific or technical nature which have not been addressed in the opinion of the Agency, the Chairman shall suspend the procedure and refer the application back to the Agency for further consideration.

The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure referred to in Article 121(2).

3. A decision as referred to in paragraph 1 shall be addressed to the Member States concerned by the matter and reported to the marketing authorization holder. The Member States shall either grant or withdraw marketing authorization, or vary the terms of a marketing authorization as necessary to comply with the decision within 30 days of its notification. They shall inform the Commission and the Agency thereof.

Article 35

1. Any application by the marketing authorization holder to vary a marketing authorization which has been granted in accordance with the provisions of this Chapter shall be submitted to all the Member States which have previously authorized the medicinal product concerned.

The Commission shall, in consultation with the Agency, adopt appropriate arrangements for the examination of variations to the terms of a marketing authorization.

These arrangements shall include a notification system or administration procedures concerning minor variations and define precisely the concept of "a minor variation".

These arrangements shall be adopted by the Commission in the form of an implementing Regulation in accordance with the procedure referred to in Article 121(2).

2. In case of arbitration submitted to the Commission, the procedure laid down in Articles 32, 33 and 34 shall apply by analogy to variations made to marketing authorizations.

Article 36

1. Where a Member State considers that the variation of a marketing authorization which has been granted in accordance with the provisions of this Chapter or its suspension or withdrawal is necessary for the protection of public health, the Member State concerned shall forthwith refer the matter to the Agency for the application of the procedures laid down in Articles 32, 33 and 34.

2. Without prejudice to the provisions of Article 31, in exceptional cases, where urgent action is essential to protect public health, until a definitive decision is adopted a Member State may suspend the marketing and the use of the medicinal product concerned on its territory. It shall inform the Commission and the other Member States no later than the following working day of the reasons for its action.

Article 37

Articles 35 and 36 shall apply by analogy to medicinal products authorized by Member States following an opinion of the Committee given in accordance with Article 4 of Directive 87/22/EEC before 1 January 1995.

Article 38

1. The Agency shall publish an annual report on the operation of the procedures laid down in this Chapter and shall forward that report to the European Parliament and the Council for information.

2. By 1 January 2001, the Commission shall publish a detailed review of the operation of the procedures laid down in this Chapter and shall propose any amendments which may be necessary to improve these procedures.

The Council shall decide, under the conditions provided for in the Treaty, on the Commission proposal within one year of its submission.

Article 39

The provisions referred to in Articles 27 to 34 shall not apply to the homeopathic medicinal products referred to in Article 16(2).

TITLE IV

MANUFACTURE AND IMPORTATION

Article 40

1. Member States shall take all appropriate measures to ensure that the manufacture of the medicinal products within their territory is subject to the holding of an authorization. This manufacturing authorization shall be required nothwithstanding that the medicinal products manufactured are intended for export.

2. The authorization referred to in paragraph 1 shall be required for both total and partial manufacture, and for the various processes of dividing up, packaging or presentation.

However, such authorization shall not be required for preparation, dividing up, changes in packaging or presentation where these processes are carried out, solely for retail supply, by pharmacists in dispensing pharmacies or by persons legally authorized in the Member States to carry out such processes.

3. Authorization referred to in paragraph 1 shall also be required for imports coming from third countries into a Member State; this Title and Article 118 shall have corresponding application to such imports as they have to manufacture.

Article 41

In order to obtain the manufacturing authorization, the applicant shall meet at least the following requirements:

(a) specify the medicinal products and pharmaceutical forms which are to be manufactured or imported and also the place where they are to be manufactured and/or controlled;

(b) have at his disposal, for the manufacture or import of the above, suitable and sufficient premises, technical equipment and control facilities complying with the legal requirements which the Member State concerned lays down as regards both manufacture and control and the storage of medicinal products, in accordance with Article 20;

(c) have at his disposal the services of at least one qualified person within the meaning of Article 48.

The applicant shall provide particulars in support of the above in his application.

Article 42

1. The competent authority of the Member State shall issue the manufacturing authorization only after having made sure of the accuracy of the particulars supplied pursuant to Article 41, by means of an inquiry carried out by its agents.

2. In order to ensure that the requirements referred to in Article 41 are complied with, authorization may be made conditional on the carrying out of certain obligations imposed either when authorization is granted or at a later date.

3. The authorization shall apply only to the premises specified in the application and to the medicinal products and pharmaceutical forms specified in that same application.

Article 43

The Member States shall take all appropriate measures to ensure that the time taken for the procedure for granting the manufacturing authorization does not exceed 90 days from the day on which the competent authority receives the application.

Article 44

If the holder of the manufacturing authorization requests a change in any of the particulars referred to in points (a) and (b) of the first paragraph of Article 41, the time taken for the procedure relating to this request shall not exceed 30 days. In exceptional cases this period of time may be extended to 90 days.

Article 45

The competent authority of the Member State may require from the applicant further information concerning the particulars supplied pursuant to Article 41 and concerning the qualified person referred to in Article 48; where the competent authority concerned exercises this right, application of the time-limits referred to in Article 43 and 44 shall be suspended until the additional data required have been supplied.

Article 46

The holder of a manufacturing authorization shall at least be obliged:

(a) to have at his disposal the services of staff who comply with the legal requirements existing in the Member State concerned both as regards manufacture and controls;

(b) to dispose of the authorized medicinal products only in accordance with the legislation of the Member States concerned;

(c) to give prior notice to the competent authority of any changes he may wish to make to any of the particulars supplied pursuant to Article 41; the competent authority shall, in any event, be immediately informed if the qualified person referred to in Article 48 is replaced unexpectedly;

(d) to allow the agents of the competent authority of the Member State concerned access to his premises at any time;

(e) to enable the qualified person referred to in Article 48 to carry out his duties, for example by placing at his disposal all the necessary facilities;

(f) to comply with the principles and guidelines of good manufacturing practice for medicinal products as laid down by Community law.

Article 47

The principles and guidelines of good manufacturing practices for medicinal products referred to in Article 46(f) shall be adopted in the form of a directive, in accordance with the procedure referred to in Article 121(2).

Detailed guidelines in line with those principles will be published by the Commission and revised necessary to take account of technical and scientific progress.

Article 48

1. Member States shall take all appropriate measures to ensure that the holder of the manufacturing authorization has permanently and continuously at his disposal the services of at least one qualified person, in accordance with the conditions laid down in Article 49, responsible in particular for carrying out the duties specified in Article 51.

2. If he personally fulfils the conditions laid down in Article 49, the holder of the authorization may himself assume the responsibility referred to in paragraph 1.

Article 49

1. Member States shall ensure that the qualified person referred to in Article 48 fulfils the minimum conditions of qualification set out in paragraphs 2 and 3.

2. A qualified person shall be in possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course of study, or a course recognized as equivalent by the Member State concerned, extending over a period of at least four years of theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology.

However, the minimum duration of the university course may be three and a half years where the course is followed by a period of theoretical and practical training of a minimum duration of one year and including a training period of at least six months in a pharmacy open to the public, corroborated by an examination at university level.

Where two university courses or two courses recognized by the State as equivalent co-exist in a Member State and where one of these extends over four years and the other over three years, the three-year course leading to a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course or its recognized equivalent shall be considered to fulfil the condition of duration referred to in the second subparagraph in so far as the diplomas, certificates or other evidence of formal qualifications awarded on completion of both courses are recognized as equivalent by the State in question.

The course shall include theoretical and practical study bearing upon at least the following basic subjects:

- Applied physics

- General and inorganic chemistry

- Organic chemistry

- Analytical chemistry

- Pharmaceutical chemistry, including analysis of medicinal products

- General and applied biochemistry (medical)

- Physiology

- Microbiology

- Pharmacology

- Pharmaceutical technology

- Toxicology

- Pharmacognosy (study of the composition and effects of the natural active substances of plant and animal origin).

Studies in these subjects should be so balanced as to enable the person concerned to fulfil the obligations specified in Article 51.

In so far as certain diplomas, certificates or other evidence of formal qualifications mentioned in the first subparagraph do not fulfil the criteria laid down in this paragraph, the competent authority of the Member State shall ensure that the person concerned provides evidence of adequate knowledge of the subjects involved.

3. The qualified person shall have acquired practical experience over at least two years, in one or more undertakings which are authorized to manufacture medicinal products, in the activities of qualitative analysis of medicinal products, of quantitative analysis of active substances and of the testing and checking necessary to ensure the quality of medicinal products.

The duration of practical experience may be reduced by one year where a university course lasts for at least five years and by a year and a half where the course lasts for at least six years.

Article 50

1. A person engaging in the activities of the person referred to in Article 48 from the time of the application of Directive 75/319/EEC, in a Member State without complying with the provisions of Article 49 shall be eligible to continue to engage in those activities in the State concerned.

2. The holder of a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course - or a course recognized as equivalent by the Member State concerned - in a scientific discipline allowing him to engage in the activities of the person referred to in Article 48 in accordance with the laws of that State may - if he began his course prior to 21 May 1975 - be considered as qualified to carry out in that State the duties of the person referred to in Article 48 provided that he has previously engaged in the following activities for at least two years before 21 May 1985 following notification of this directive in one or more undertakings authorized to manufacture: production supervision and/or qualitative and quantitative analysis of active substances, and the necessary testing and checking under the direct authority of the person referred to in Article 48 to ensure the quality of the medicinal products.

If the person concerned has acquired the practical experience referred to in the first subparagraph before 21 May 1965, a further one year's practical experience in accordance with the conditions referred to in the first subparagraph will be required to be completed immediately before he engages in such activities.