The current regulations on medicines have contributed to the fact that drugs are found in the market with proven guarantees of quality, safety and efficacy. However, in the light of the experience gained, the European Union has considered it necessary to adopt new measures to promote the functioning of the internal market, without forgetting at any time the achievement of a high level of protection for human health, for which progress is made in the incorporation of harmonised criteria and procedures for the evaluation and authorisation of medicinal products and is deepened in measures aimed at the continued assessment of the safety of medicinal products.

Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices sets out these criteria and procedures, the instrument being the instrument for which the most recent provisions are transposed. Community medicines.

This royal decree completes the transposition of Directive 2004 /27/EC of the European Parliament and of the Council of 31 March amending Directive 2001 /83/EC of the European Parliament and of the Council of 6 November 2001, establishing a Community code on medicinal products for human use, which harmonises and collects in a single text the Community legislation on medicinal products for human use, and Directive 2004 /24/EC of the European Parliament and of the Council of March 31, for which it is amended, as regards traditional medicinal products on the basis of plants, Directive 2001 /83/EC.

The transposition of Directive 2004 /27/EC implies the amendment, inter alia, of Royal Decree 767/1993 of 21 May 1993 governing the assessment, authorisation, registration and conditions of the supply of medicinal products for human use and other industrially manufactured medicinal products, and other special medicinal products. Therefore, and since the amendment concerns a large number of precepts, it is necessary to draw up a new provision integrating the original rules and their subsequent amendments.

The fundamental aspects of Directive 2004 /27/EC, which are the subject of transposition in this royal decree, concern the need to improve the functioning of the procedures for the authorisation of medicinal products, revised the procedure for national authorisation and in particular mutual recognition procedure, in order to strengthen the possibility of cooperation between Member States and also, for the same purpose, a new authorisation procedure The European Commission is responsible for the implementation of the assessment and transparency and publicity of decisions.

The need to ensure adequate monitoring of the therapeutic effects and safety profile of each new medicinal product makes the marketing authorisation to be renewed five years after it has been granted. Once that authorisation has been ratified, the period of validity should normally be unlimited without prejudice to the continued assessment of the risks through appropriate pharmacovigilance systems and studies on the use of medicinal products in the European Union. actual conditions of use.

Furthermore, the European legislative framework provides for the possibility of an authorised medicinal product not being marketed, stating that any authorisation which does not make the marketing of the medicinal product effective for three years Consecutive loss of validity. However, exceptions to this rule should be provided where they are justified on grounds of public health or general interest.

In order to avoid a duplication of rules, it is decided to apply to the modifications of the national marketing authorisations the same criteria for the classification of the Community procedures and the Regulation is adopted (EC) No 1084/2003 of 3 June 2003 concerning the examination of amendments to the terms of the marketing authorisations for medicinal products for human use and veterinary medicinal products granted by the competent authority of a Member State, as well as its successive updates.

Another key aspect of the medicine is its identification and information on the label and the package leaflet, as a guarantee of its correct use, promoting safety and effectiveness in its use. Directive 2004 /27/EC on labelling and package leaflet aims to define common rules in this field, leaving a wide margin for national legislation, in particular with regard to guarantees of authenticity and proper identification, to ensure a high level of consumer protection and to allow the correct use of medicinal products on the basis of comprehensive and comprehensible information.

The transposition of this directive implies the amendment of Royal Decree 2236/1993 of 17 December on the labelling and package leaflet of medicinal products for human use, affecting a large number of provisions, Therefore, it has been considered appropriate and following the Community criterion of unifying the legislation in a text, to collect this subject with the procedure of authorisation, registration and conditions for the supply of medicinal products for human use.

With the same criteria of unification, the special medicines that had their own legislation and which are now integrated into this same standard are included in this royal decree. Thus, the Royal Decrees 479/1993 of 2 April, which regulates the radiopharmaceutical medicinal products for human use, 478/1993 of 2 April, on the treatment of medicinal products derived from human blood and human plasma, 288/1991, is hereby repealed. March, on which the immunological medicinal products for human use are regulated, 2208/1994 of 16 November, which regulates homeopathic medicinal products for human use in industrial manufacture and 1800/2003 of 26 December, which regulates gases The latter was subject to the procedure for information on rules and regulations. techniques, provided for in Directive 98 /34/EC and the content of which has been included in this provision.

Directive 2004 /24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001 /83/EC on the harmonisation of the laws of the Member States Member States as regards traditional herbal medicinal products and ensures the necessary guarantees of quality, safety and efficacy of these medicinal products, avoiding the existing differences which could have an impact on the protection of public health.

The main novelty is to establish a simplified registration procedure for traditional herbal medicines. The peculiarity of this procedure is that in order to obtain a registration as a traditional herbal medicinal product, the extensive traditional use will be taken into account, so the clinical and pre-clinical tests that are usually required General for the registration of a medicinal product for human use, they will not be necessary even if the competent authorities could request additional information to assess the safety, if deemed necessary. For the effective implementation of this procedure, a transitional period is established until 30 April 2011, in line with Community requirements. This adjustment to the new regulation is a derogation from the legislation in force so far, without the sector being adversely affected, since plants traditionally regarded as medicinal products should be form of presentation provided that they do not have the consideration of medicinal products and are offered without reference to therapeutic, diagnostic or preventive properties, may be sold freely, subject, in the event of a meeting of the required criteria, to food law.

On the other hand, Order SCO4661/2003 of 26 November, by which Annex II to Royal Decree 767/1993 was amended, incorporating into Spanish law the Commission Directive 2003 /63/EC of 25 June 2003. 2003 is repealed and its content is incorporated as Annex I of this royal decree. Directive 2003 /63/EC is of major importance for establishing standard requirements for the marketing authorisation dossier for medicinal products in all Member States. This was achieved with the implementation of the common technical document (DTC). This harmonised document is currently the fundamental basis for the subsequent implementation of telematics instruments for the automated processing of applications. The use of management tools is in turn an essential element for the objective of giving public access to the decisions of the Spanish Agency for Medicines and Health Products, as well as to the information of medicines. rigorous and objective accompanying each authorization.

With this royal decree, the national legislation on the procedure for authorization to place the medicinal products on the market is repealed, which transposed several Community directives that were repealed and codified by the Directive 2001 /83/EC.

As Annex II, the data to be included in the technical information sheet of the medicinal product are collected.

The information to be included in the labelling of medicinal products is included in Annex III.

In Annex IV, the symbols, acronyms and legends that must appear on the labelling of the medicinal products are laid down.

Annex V collects the data that must contain at least the package leaflet and which is prepared in accordance with the technical information sheet of the medicinal product.

This royal decree is adopted in the development of Law 29/2006, of July 26, of guarantees and rational use of medicines and medical devices, and it has the character of legislation of pharmaceutical products for the purposes of Article 149.1.16 of the Constitution; guaranteeing, in respect of the processing of personal data, the respect of the Organic Law 15/1999, of 13 December, of Protection of Personal Data, and its rules of development.

Finally, in the process of drawing up this standard, the Autonomous Communities and the sectors affected have been consulted, among others.

In its virtue, on the proposal of the Minister of Health and Consumer Affairs, with the prior approval of the Minister of Public Administrations, in agreement with the Council of State and after deliberation of the Council of Ministers at its meeting of the October 11, 2007,

D I S P O N G O:

CHAPTER I

General provisions

Article 1. Object.

This royal decree aims to regulate medicines for human use manufactured industrially and in particular:

a) The requirements of the request for marketing authorization.

(b) The procedures for the authorisation, suspension and revocation of the authorisation, as well as for amendments to the conditions of authorisation.

c) The Summary of Product Characteristics, Labelling and Package Leaflet.

d) The particular conditions for certain classes of medication.

e) The obligations of the holder.

f) Community procedures.

g) Registration on the registration of medicinal products, including special medicinal products covered by Chapter IV.

Article 2. Definitions.

For the purposes of this provision:

1. Medicinal product: any substance or combination of substances which is present as a property holder for the treatment or prevention of diseases in humans, or which may be used, or administered to human beings in order to restore, correct or to modify physiological functions by exerting a pharmacological, immunological or metabolic action, or to establish a medical diagnosis;

2. Active substance: any matter, whatever its origin-human, animal, plant, chemical or other-to which an appropriate activity is attributed to constitute a medicinal product.

3. Excipient: that matter which, included in the galenic forms, is added to the active substances or to their associations to serve them as a vehicle, to enable their preparation and stability, to modify their organoleptic properties or to determine the physico-chemical properties of the medicinal product and its bioavailability.

4. Raw material: any substance-active or inactive-used in the manufacture of a medicinal product, whether it remains unchanged, modified or disappeared during the course of the process.

5. Galenic form or pharmaceutical form: the arrangement to which the active substances and excipients are adapted to constitute a medicinal product. It is defined by the combination of the way in which the pharmaceutical product is presented by the manufacturer and the way in which it is administered.

6. Presentation: each of the combinations in which the medicinal product is ready for use, including composition, pharmaceutical form, dosage, and format.

7. Format: number of units contained in the package and/or the contents of the package.

8. Name of the medicinal product: identifies the medicinal product and consists of the name of the medicinal product, dose and pharmaceutical form and where appropriate, the indication of the recipients: infants, children or adults.

9. Common name: the Spanish Official Denomination (D.O.E) attributed to each active principle by the Spanish Agency for Medicinal Products and Sanitary Products, in its absence, the International Common Denomination (D.C.I.) recommended by the Organization World of Health or, failing that, the usual common name.

10. Dose of the medicinal product: the active substance content, expressed in quantity per unit of intake, per unit of volume or weight depending on the presentation.

11. Summary of product characteristics: document authorised by the Agency, where the authorised conditions of use for the medicinal product are reflected and the essential scientific information for healthcare professionals is collected.

12. Immediate packaging: the packaging or any other form of packaging that is in direct contact with the medicinal product.

13. Outer packaging: the packaging in which the primary packaging is located.

14. Labelling: the information contained in the outer packaging and in the immediate packaging.

15. Package leaflet: written information to the patient or user, accompanying the medicinal product.

16. Special medicines: medicines that require special treatment for the purpose of demonstrating their quality, safety and efficacy.

17. Line extension: the second and successive applications for authorisation and registration in the register of other pharmaceutical forms, routes of administration and/or doses of an already authorised medicinal product, as well as those modifications requiring the the submission of a new application for authorisation, in accordance with the European standard governing the modification of the authorisation of medicinal products granted by the competent authority of a Member State.

18. Blood product: medicinal products based on blood constituents industrially prepared by public or private establishments; such medicinal products include, in particular, albumin, coagulation factors and immunoglobulins of origin human

19. Immune medicine: It is all medication consisting of vaccines, toxins, serums and allergens:

(a) Vaccines, toxins or serums, comprising in particular:

1. The agents used to trigger an active immunity such as the anticoleric vaccine, BCG, the anti-polio vaccine, the antivariolic vaccine.

2. º The agents used to diagnose the immunity status, in particular the tuberculin and the PPD tuberculin, the toxins used in the Schick and Dick tests, the bruceline.

3. The agents used to cause passive immunity, such as diphtheria antitoxin, anti-lymphocytic globulin, antilymphocytic globulin.

(b) Allergen products comprising any medicinal product intended to detect or cause an acquired and specific alteration in the immunological response to an allergenic agent.

20. Individual vaccines: are prepared with immunising agents, at specific concentration and dilution based on the corresponding optional prescription for a given patient.

21. Allergen: any product intended to identify or cause a specific and acquired modification of the immunological response to an allergenic agent.

22. Radiopharmaceutical: any product which, when prepared for use for therapeutic or diagnostic purposes, contains one or more radionuclides (radioactive isotopes).

23. Generator: any system that incorporates a radionuclide (radionuclide parent) that in its disintegration causes another radionuclide (radionuclide son) to be used as an integral part of a radiopharmaceutical.

24. Reactive equipment: any industrial preparation that must be combined with the radionuclide to obtain the final radiopharmaceutical.

25. Precursor: any industrially produced radionuclide for the radioactive marking of other substances prior to administration.

26. Extemporaneous preparation of a radiopharmaceutical: it is the preparation at the time of use of a radiopharmaceutical ready for use from the radioisotopic marking of a team or autologous samples of the patient itself (cells, proteins), with a radionuclide precursor or a radionuclide produced by a radionuclide generator. This preparation can only be done on request by medical prescription and if the standards of correct extemporaneous preparation of radiopharmaceuticals that are subsequently published are complied with.

27. Herbal medicinal products: the medicinal product containing exclusively as active substances, plant substances, plant preparations or combinations thereof.

28. Traditional herbal medicinal product: the herbal medicinal product which meets the conditions laid down in Article 51.

29. Plant substances: plants, mainly whole, fragmented or cut, the parts of plants, algae, fungi and lichens not treated, normally in a dry but also fresh form. Certain exudates which have not undergone a specific treatment are also considered as plant substances. Plant substances are defined precisely by the part of the plant used and the botanical name according to the binomial system which includes gender, species, variety and author.

30. Vegetable preparations: those obtained by subjecting the plant substances to treatments such as extraction, distillation, pressing, fractionation, purification, concentration or fermentation. Crushed or ground vegetable substances, tinctures, extracts, essential oils, squeezed juices and treated exudates are included.

31. Homeopathic medicinal product: Obtained from substances called homeopathic strains, in accordance with a homeopathic manufacturing process described in the European Pharmacopoeia, or in the Spanish Royal Pharmacopoeia or, failing that, in a pharmacopoeia used officially in a country of the European Union. A homeopathic medicinal product may contain several active substances.

32. Medicinal gases: is the gas or mixture of gases intended to come into direct contact with the human organism and which, acting mainly by pharmacological, immunological or metabolic means, is provided with properties to prevent, diagnose, treat, relieve, or cure diseases or ailments. Medicinal gases used in inhalation therapy, anesthesia, "in vivo" diagnosis, or for the preservation and transport of organs, tissues and cells for transplantation, provided that they are in contact with them.

Liquefied medicinal gases, liquid oxygen, liquid nitrogen and liquid nitrogen protoxide, as well as any other with similar characteristics and use, may be manufactured in the future.

33. Marketing authorisation holder: is the natural or legal person responsible for placing the medicinal product on the market for which it has obtained the marketing authorisation. For this purpose, a register of marketing authorisation holders shall be established.

34. Representative of the marketing authorisation holder: the natural or legal person, normally known as the local representative, designated by the marketing authorisation holder to represent him in Spain.

35. Generic medicinal product: the medicinal product having the same qualitative and quantitative composition in active substances and the same pharmaceutical form, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate studies of bioavailability.

Article 3. Scope and exclusions.

1. This royal decree applies to medicinal products for human use and to special medicinal products for human use, manufactured industrially or in the manufacture of which an industrial process is involved in the procedures and requirements for the use of the submission of applications for authorisation, the assessment of applications, requirements for marketing authorisation, technical information, labelling and package leaflet including prescription and dispensing conditions, as well as the inclusion of authorised medicinal products in the relevant official register.

2. They are excluded from the scope of this royal decree:

(a) The advanced therapy medicinal products referred to in Article 47 of Law 29/2006 of 26 July, prepared in full and used, without profit, in centres linked to the National Health System, and which the preparation is carried out in centres approved for this purpose by the Ministry of Health and Consumer Affairs and are medicinal products in clinical research or are medicinal products which the Spanish Agency for Medicines and Health Products considers to be satisfy the guarantees of quality, safety, efficacy, identification and information.

b) Full blood, plasma, and blood cells of human origin.

3. This provision is not applicable in respect of applications, assessment and authorisation for medicinal products referred to in Annex I to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 on the establishing Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing the European Medicines Agency. However, if the provisions of Article 21.3 and Annexes III and IV apply to them.

Article 4. Character of the marketing authorisation.

1. No medicinal product manufactured industrially can be placed on the market without the prior marketing authorization granted by the Spanish Agency for Medicines and Health Products or by the European Commission, and registration of the medicines, in accordance with the procedures laid down for each case.

Any modification, transmission, suspension and revocation of the authorization to place a medicinal product on the market must be authorised and entered in the register of authorised medicinal products which, for these purposes, will have the same the registration, constitutive character, except in the case of medicinal products authorised by the European Commission.

2. Where a medicinal product has obtained an initial marketing authorisation, any dosage, pharmaceutical form, route of administration and additional presentation, as well as any modifications and extensions to be introduced also to obtain an authorization. All such marketing authorisations shall be considered as belonging to the same overall marketing authorisation, in particular for the purposes of the application of the data exclusivity periods, as well as for the modifications. subsequent authorisation affecting a whole set of medicinal products of the same holder containing the same active substance.

CHAPTER II

Medicines authorization

Section 1. Requests

Article 5. Requirements of the applicant for a marketing authorisation.

The applicant for the marketing authorisation for a medicinal product must be established in the European Union. The applicant may designate a legal representative with whom the actions resulting from the processing of the application for authorisation of the medicinal product or its subsequent amendments shall be understood. The applicant may also indicate in the application the marketing authorisation holder proposed for Spain.

Article 6. Application for marketing authorisation for industrially manufactured medicinal products.

1. Applications for authorization to place medicinal products on the market shall be submitted in any of the places provided for in Article 38.4 of Law No 30/1992 of 26 November 1992 on the Legal Regime of Public Administrations and the Joint Administrative Board, addressed to the Spanish Agency for Medicines and Health Products.

And as provided for in Article 38.9 of the aforementioned Law, applications may be submitted by telematic means.

2. The application model shall be adjusted to the one established by the Spanish Agency for Medicines and Health Products at any time, in accordance with the standard models approved by the European Commission.

3. The documentation shall be presented in Spanish at least. However, the Spanish Agency for Medicines and Health Products may establish that one or more parts of the scientific-technical documentation may be presented in another language.

4. Applications for authorisation of medicinal products shall be accompanied by the document supporting the payment of the fee.

5. The application, the model of which can be obtained through the website of the Spanish Agency for Medicines and Health Products, must include at least the data and documents listed below. The file shall be submitted in a standardised format in accordance with the provisions of Annex I to this Royal Decree:

(a) name or business name and address or registered office of the applicant and, where applicable, of the manufacturer, DNI/NIE or CIF;

b) name of the medication;

c) qualitative and quantitative composition of all the components of the medicinal product, including the international common name (INN) recommended by the World Health Organization, and its equivalence with the name Spanish official (DOE), where it has, or the indication of the relevant chemical name in the absence of the above. In the case of plant substances and preparations, they shall be declared in accordance with the provisions laid down for them;

d) assessment of the risk that the medicinal product could pose to the environment. This impact must be studied and the special provisions intended to limit it should be foreseen, on a case by case basis;

e) description of the build mode;

f) therapeutic indications, contraindications and adverse reactions;

g) dosage, pharmaceutical form, form and route of administration and period or time of validity envisaged;

(h) indications on the precautionary and safety measures to be taken when the medicinal product is stored, when administering it to patients and when removing residual products, together with any indication of any risk potential that the medicinal product could present for the environment;

i) description of the control methods used by the manufacturer;

j) test result:

1. Pharmaceutical (physicochemical, biological or microbiological).

2. Preclinical (toxicological and pharmacological).

3. Clinics.

Documents and information relating to the results of the pharmaceutical, pre-clinical and clinical trials shall be accompanied by detailed summaries and expert reports, which shall form part of the relevant application and shall be integrated into the authorisation file. These reports should be drawn up and signed by persons possessing the necessary technical and professional qualifications, endorsed in a curriculum to be accompanied by the report;

k) a detailed description of the pharmacovigilance systems and, where appropriate, of the risk management plan to be created by the applicant;

(l) a declaration by the applicant that clinical trials carried out outside the European Union comply with the ethical principles and standards of good clinical practice provided for in Royal Decree 223/2004 of 6 February, regulating clinical trials with medicinal products;

m) a summary of the characteristics of the product in accordance with Annex II, a model of the design and contents of the outer packaging and the immediate packaging, as well as the package leaflet in accordance with the rules of procedure for the purpose of ensuring adequate understanding by citizens;

n) a supporting document that the manufacturer is authorised in his country to manufacture medicinal products;

n) where appropriate, a copy of the marketing authorisation obtained for the medicinal product in another Member State or in a third country together with the technical information sheet and the package leaflet approved or proposed where appropriate, together with the list of the Member States in which an application for authorisation is being considered. As well as any refusal of an application for authorisation, both in the European Union and in a third country, and the reasons for such a decision. Without prejudice to the provisions of Article 62.3 of this Regulation, the updating of this information should be carried out whenever the applicant or holder of the authorisation has been made aware of facts affecting or altering the information provided or working on the request;

(o) a supporting document that the applicant has a qualified person responsible for pharmacovigilance, as well as the necessary infrastructure in Spain to report on any adverse reaction suspected to be or that occurs in Spain, or in a third country.

Article 7. Specific requirements for the authorisation of generic medicinal products.

1. For generic medicinal products as defined in Article 2.35, the different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance unless they have significantly different properties in terms of safety and/or efficacy, in which case the applicant shall provide additional data to demonstrate the safety and/or effectiveness of the diversity of salts, esters or derivatives of an active substance authorized. The different oral pharmaceutical forms of immediate release will be considered as the same pharmaceutical form. The applicant may be exempt from presenting the bioavailability studies if it can demonstrate that the generic medicinal product satisfies the relevant criteria as defined in the relevant detailed guidelines.

2. Without prejudice to the right relating to the protection of industrial and commercial property, the applicant shall have no obligation to provide the results of the pre-clinical and clinical trials if it can demonstrate that the medicinal product is generic of a a reference medicinal product which is or has been authorised under this provision for at least eight years by a Member State or in the European Union by a centralised procedure. For these purposes, reference medicinal product is defined as that authorised on the basis of a complete dossier.

3. Generic medicinal products for a reference medicinal product, authorised under this provision, shall not be placed on the market until 10 years after the date of the initial authorisation of the reference medicinal product.

This 10-year period shall be extended to a maximum of 11 years if, during the first eight years of the 10-year period, the holder of the marketing authorisation for the reference medicinal product obtains an authorisation for one or more new therapeutic indications and, during the scientific evaluation prior to their authorisation, it is established that these indications will provide a significant clinical benefit in comparison with existing therapies.

4. Where the reference medicinal product is not authorised in Spain, the applicant shall indicate in the application the name of the Member State in which the reference medicinal product is or has been authorised and the date of authorisation. The Spanish Agency for Medicinal Products and Health Products shall ask the competent authority of the other Member State for confirmation within one month that the reference medicinal product is or has been authorised, together with the complete the reference medicinal product and, if necessary, any other documentation which it considers relevant.

5. Generic medicinal products must be designated by the official Spanish name of the active substance and, failing that, by the usual or scientific name of the substance, accompanied, where appropriate, by the name or mark of the holder or manufacturer; may also be referred to as a mark provided that it cannot be confused with a Spanish official name or an international common name or mislead as to the therapeutic properties or the nature of the medicinal product.

Generic drugs will be identified by the following name of the acronym EFG.

Article 8. Specific requirements for the authorisation of medicinal products with combined application with supplementary data.

When the medicinal product does not comply with the generic medicinal product requirements of paragraph 1 of the previous Article, where bioequivalence cannot be demonstrated by means of bioavailability studies or when there are differences in the active substances, therapeutic indications, dosage, pharmaceutical form or route of administration in respect of those of the reference medicinal product, the results of the appropriate preclinical and/or clinical trials shall be provided supplementary.

Article 9. Specific requirements for the authorisation of similar biological medicinal products to another reference.

1. Applications for authorisation shall include the results of appropriate pre-clinical and clinical trials where a biological medicinal product similar to a reference biological product does not meet the conditions of the definition of generic medicinal products, due to differences related to raw materials or differences in the process of manufacture of the biological medicinal product and the reference biological medicinal product.

2. The documentation shall comply with the criteria set out in the common technical document (DTC) agreed in the European Union and set out in Annex I as well as the detailed guidelines specific to each subject.

Article 10. Specific requirements for the authorisation of medicinal products based on sufficiently proven active substances.

1. The applicant shall have no obligation to provide the results of pre-clinical and clinical trials of its own if it can demonstrate that the active substance of the medicinal product has been well established for at least 10 years within the Union European and present recognised effectiveness, as well as an acceptable level of safety under the conditions set out in Annex I.

2. In this case, the results of the tests will be replaced by a literature-scientific documentation that provides adequate scientific evidence.

3. The provisions of this Article shall not apply to products which are required to comply with the conditions laid down in Articles 7, 8 and 9.

Article 11. Requests for new authorized active principles associations.

Applications for medicinal products containing the association of active substances present in the composition of authorised medicinal products, but which have not yet been combined for therapeutic purposes, should provide the results of pre-clinical and/or clinical trials relating to the new partnership, without the need to provide the documentation relating to each individual active substance.

Article 12. Requests for authorisation of medicinal products with the express consent of the holder of a prior authorisation or of a registration file.

1. Following the granting of a marketing authorisation, the holder of the marketing authorisation may consent to the use of the pharmaceutical, preclinical and clinical documentation on the dossier of his medicinal product by another applicant for the study of a Subsequent application of a medicinal product having the same qualitative and quantitative composition in active substances and the same pharmaceutical form. This situation shall be certified by both parties in the documentation accompanying the application, meaning the accuracy of both dossiers in all pharmaceutical, pre-clinical and clinical aspects, except for the identification and Design of the product label.

2. The applicant for a pending file may also consent to the submission of another application based on identical pharmaceutical, pre-clinical and clinical documentation, accompanied by the second dossier certified by both parties. parts of this authorisation and the accuracy of both documentation in all pharmaceutical, pre-clinical and clinical aspects, except in the identification and design aspects of the labelling of the medicinal product.

Article 13. Period of exclusivity for new indications of sufficiently known active substances.

When a new indication is authorized for a sufficiently known active principle, a period of one year of data exclusivity shall be granted, not cumulative to other data protection periods, provided that they are significant clinical and/or preclinical studies in relation to the new indication.

Section 2. Authorization Procedure

Article 14. Objectives of the authorisation procedure.

1. The purpose of the authorisation procedure is to verify that the medicinal product:

a) Reaches established quality requirements.

b) It is safe, not producing under normal conditions of use toxic or undesirable effects disproportionate to the benefit it seeks.

c) It is effective in approved therapeutic indications.

d) It is correctly identified and is accompanied by accurate information for use.

2. The assessment of the positive therapeutic effects of the medicinal product shall be assessed in relation to any risk related to the quality, safety and efficacy of the medicinal product for the health of the patient or public health, benefit-risk ratio

3. The provisions of this Article shall also apply to changes in the authorisation and shall remain applicable, as long as the product is on the market, in accordance with the new evidence concerning its security and effectiveness will be obtained.

4. At any time the Spanish Agency for Medicines and Health Products may verify that the requirements of paragraph 1 above are met.

Article 15. Confidentiality guarantees.

The documentation for the authorization request and expert reports will be confidential.

Article 16. Admission to processing and validation of the application.

1. The Spanish Agency for Medicinal Products and Sanitary Products, within 10 calendar days of the submission of the application, shall verify that the application meets the requirements laid down, and shall notify the applicant of its admission to the the applicable procedure and the identification of the file, as well as the time limit for the notification of the decision.

2. Where the application does not meet the requirements laid down, the applicant shall be required to remedy the deficiencies within the maximum period of 10 calendar days, with the indication that if he does not do so, his/her application shall be closed. a decision to be taken in accordance with the terms laid down in Article 42 of Law No 30/1992 of 26 November 1992.

3. The maximum time limit for the notification of the decision of the authorisation procedure for medicinal products shall be 210 calendar days, which shall begin to be computed from the day following the date of submission of a valid application.

4. Where the medicinal product covered by the application has previously been authorised in another Member State, the same holder may not apply to the Spanish Agency for Medicinal Products and Sanitary Products, nor shall he be admitted to the proceedings, unless if the application is submitted in accordance with the mutual recognition procedure laid down in Article 72, or if it is a line extension of an authorised medicinal product in Spain through the national procedure.

5. Where the medicinal product covered by the application is being evaluated in another Member State, it shall be communicated by the applicant to the Spanish Agency for Medicinal Products and Sanitary Products. The Agency shall inform the person concerned that it shall process its application by mutual recognition procedure or by decentralised procedure, in accordance with Articles 72 and 73, by filing its application if appropriate.

Article 17. Assessment of the pharmaceutical, preclinical and clinical documentation and issue of the relevant report.

1. The Spanish Agency for Medicinal Products and Health Products shall carry out the evaluation of the dossier and issue an assessment report. To this end, it may require additional documentation or clarifications from the applicant on any extreme subject of the application, setting a period of three months, which may exceptionally be extended to six months, for the submission of such an application. documentation. Where the Spanish Agency for Medicinal Products and Health Products makes use of this option, the period provided for in the third paragraph of the preceding Article shall be suspended until the required supplementary data are provided.

2. The assessment report shall be reasoned and shall cover the pharmaceutical, preclinical and clinical aspects of the medicinal product.

3. In the evaluation process, the Spanish Agency for Medicinal Products and Sanitary Products may subject the medicinal product, its raw materials, intermediate products and other components to the examination of its Official Control Laboratories. request the collaboration of another national laboratory accredited for that purpose by the Agency itself, to an official Community or third country control laboratory.

Article 18. Opinion of the Committee for the Evaluation of Medicinal Products for Human Use.

The Spanish Agency for Medicinal Products and Medicinal Products may request the Committee for the Evaluation of Medicinal Products for Human Use to give its opinion on applications for new authorisations for medicinal products, and applications for Major modifications of marketing authorisations in accordance with Article 63, for which the assessment report and, where appropriate, the proposal of the technical information sheet and the prospectus shall be referred to that Committee.

In any case, the opinions of the Committee for the Evaluation of Medicinal Products for Human Use will not be binding.

Article 19. Grounds and procedure for refusal.

1. The application for authorisation of a medicinal product may be refused for the following

:

a) the benefit-risk ratio is not favourable;

(b) the therapeutic efficacy is not sufficiently justified;

(c) the medicinal product does not have the declared qualitative and quantitative composition or lack the appropriate quality;

(d) the data and information contained in the documentation of the application for authorisation are incorrect or in breach of the rules of application in this field.

2. Where the result of the assessment is unfavourable for any of the reasons provided for in the previous paragraph, or there are substantial differences in the information of the medicinal product in respect of the proposal made by the applicant, the Sub-Directorate General for Medicinal Products for Human Use of the Spanish Agency for Medicinal Products and Health Products shall make it clear to the person concerned that, within a period of 15 days, he may make the allegations and present the documentation Consider appropriate.

3. The Agency shall amend the assessment report and if appropriate, in accordance with the previous Article, it shall be referred to the Committee for the Evaluation of Medicinal Products for Human Use, in order to issue the appropriate opinion.

Article 20. Resolution.

1. Completion of the instruction of the procedure shall be given to a reasoned decision which shall be notified to the person concerned with the expression of the resources which are obtained in accordance with the rules in force.

2. Where the results of the assessment are favourable, the Spanish Agency for Medicinal Products and Sanitary Products shall issue a decision authorising the placing on the market, without prejudice to the obligations arising from the rules on financing public.

3. The approval of a medicinal product shall contain the conditions of authorisation and shall form part of the administrative data, the information sheet, the labelling and the package leaflet.

4. The authorisation document shall contain at least the following information:

a) Name of the medication.

b) Record number.

c) Therapeutic group.

d) Pharmaceutical form.

e) The path of administration.

f) Presentations authorized with their respective National Codes.

g) Conservation and expiration conditions.

h) Prescription and dispensing conditions.

i) Name and address of the authorization holder.

j) Name and address of the representative of the marketing authorisation holder, where appropriate.

k) Name and address of the manufacturer, both of the active substance and of the medicinal product if they differ.

l) Full qualitative and quantitative composition.

Article 21. Registration of the registration of medicinal products.

1. The authorization of the medicinal product shall be entered in the Register of Medicinal Products of the Spanish Agency for Medicinal Products and Sanitary Products.

2. Each registration number shall relate to a composition, a pharmaceutical form, a dose per unit of administration including all presentations for sale. Each of the presentations will be identified by its corresponding National Code.

In the case of a medicinal product to be administered with an exclusive applicator device that allows it to be used repeatedly, a presentation with an applicator device and another without it, may be permitted in the same register. assigning a National Code to each of the presentations.

May also be admitted under the same number of other cases when determined by the Spanish Agency for Medicines and Health Products.

3. In the case of medicinal products listed in the Annex to Regulation (EC) 726/2004, the placing on the market shall be communicated to the Spanish Agency for Medicinal Products and Sanitary Products for the purposes of their inclusion in the register of medicinal products. authorized.

Article 22. Transparency and publicity.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall ensure public access to its decisions on the authorisation or refusal to place a medicinal product on the market, its modifications, suspensions and revocations, when all of them are In accordance with the provisions of the Organic Law 15/1999 of 13 December on the Protection of Personal Data.

2. The reasoned assessment report shall also be publicly accessible, subject to the deletion of any commercial information of a confidential nature, in accordance with the guidelines to be adopted by the European Commission.

Article 23. Responsibility of the holder and the manufacturer.

1. The marketing authorisation holder for each medicinal product shall be responsible for the fulfilment of the obligations arising from the authorisation and shall have the material and personal means necessary to fulfil the obligations. derived from it.

2. The authorisation of a medicinal product shall be granted without prejudice to the civil or criminal liability of the manufacturer or manufacturers and the manufacturer or manufacturers involved in the process of manufacture of the product or its raw material, and the case of the marketing authorisation holder.

Article 24. Conditions for prescribing and dispensing of medicinal products.

1. The Spanish Agency for Medicines and Health Products will classify the medicine as:

a) Drug subject to medical prescription.

b) Drug not subject to medical prescription.

Within the medications, the dispensing of which requires medical prescription, the following subcategories exist:

1. Medicines subject to medical prescription for renewable or non-renewable dispensing.

2. Medicines subject to special medical prescription.

3. restricted medical prescription drugs, for use reserved to certain specialized media.

2. Medicinal products shall be subject to special medical prescription when:

a) Contain, in non-exempt doses, a substance classified as stupefacent or psychotropic in accordance with international conventions on the subject.

b) They may be subject, in the event of abnormal use, to a considerable risk of drug abuse, to cause toxicodependence or to be diverted for illegal uses.

c) Contain some substance which, due to its novelty or properties, is deemed necessary for inclusion in this group as a precautionary measure.

3. Medicinal products shall be subject to restricted medical prescription when:

a) Because of their pharmacological characteristics or novelty, or for reasons of public health, they are reserved for treatments that can only be used or followed in the hospital or approved care centers (Medicines for Hospital Use).

(b) Used in the treatment of diseases to be diagnosed in the hospital, or in establishments with adequate means of diagnosis or by certain medical specialists, although the Administration and follow-up can be performed outside the hospital (Prescription Hospital Diagnostic Medicines by certain medical specialists).

(c) Stilling for outpatients, but the use of which may result in very serious adverse reactions, which will require, where appropriate, prescribing by certain specialist doctors and special surveillance during the course of the Treatment (Medicines of Special Medical Control).

4. By way of derogation from the preceding paragraphs, the Spanish Agency for Medicinal Products and Sanitary Products may derogate from those paragraphs taking into account the following:

(a) the single maximum dose or the maximum daily dose, dosage, pharmaceutical form, certain packaging and/or

(b) other conditions of use which ensure the appropriate use of the medicinal product.

5. The Spanish Agency for Medicinal Products and Sanitary Products may amend the classification granted to a medicinal product on its own initiative, in accordance with the criteria set out in this Article, when new data are reassessed to justify it.

6. The Spanish Agency for Medicines and Health Products may qualify as non-prescription medicinal products for those intended for processes or conditions which do not require a precise diagnosis and whose assessment data No medical prescription is required for toxicological, clinical or use and route of administration.

7. Where, on the basis of clinical trials or significant preclinical studies, the authorisation of medicinal product subject to medical prescription has been modified by the medicinal product not subject to medical prescription or vice versa, a period of one year of data uniqueness for the same since modification authorization.

8. The Ministry of Health and Consumer Affairs shall establish the specific conditions and requirements for the application of each of these categories of prescription and dispensing.

Article 25. Advertising medicines.

1. Medicinal products which meet all the requirements listed below may be the subject of advertising intended for the public:

a) That they are not funded by public funds.

b) That by their composition and purpose they are intended and designed for use without the intervention of a physician who makes the diagnosis of the prescription or the follow-up of the treatment.

c) Not containing psychotropic substances or narcotic substances in their composition.

2. Compliance with these requirements will be verified on a prior basis by the Spanish Agency for Medicines and Health Products by granting the mandatory authorization.

Article 26. Authorisations subject to special conditions.

1. In exceptional circumstances, the Spanish Agency for Medicinal Products and Sanitary Products may authorise a medicinal product based on a request for which the pre-clinical or clinical data are incomplete, where the applicant can justify objective and verifiable, which cannot provide complete data on efficacy and safety under normal conditions of use of the product, for any of the following reasons:

(a) the cases for which the medicinal product is indicated are so rarely presented that the applicant cannot reasonably be required to provide the detailed evidence;

b) the current state of development of science does not allow to provide complete information;

c) the principles of commonly admitted medical deontology prohibit collecting this information.

2. In these circumstances, the authorisation granted by the Spanish Agency for Medicinal Products and Sanitary Products shall be reviewed annually and subject to the obligation on the part of the applicant to fulfil the following conditions as appropriate:

(a) To carry out, within the time limit set by the Spanish Agency for Medicines and Health Products, a specific programme of studies whose results will form the basis for a new evaluation of the relationship benefit/risk.

b) Qualify the medicinal product as subject to medical prescription and, if necessary, authorize only its administration if it is carried out under strict medical control, if possible in a hospital facility.

c) Include the information available on the technical tab explaining the limitations of the data, as well as the package leaflet and any other medical information, highlighting that, in relation to certain aspects, there is still no conclusive data on the medicinal product in question.

Article 27. Period of validity and renewal of the authorisation.

1. The authorisation of a medicinal product shall be valid for five years. That period may be renewed after a reassessment of the benefit/risk ratio. Once the authorisation has been renewed, it shall be indefinite, unless the reasons for pharmacovigilance justify its submission to a new renewal procedure.

2. The renewal procedure shall be initiated at the request of the holder of the authorisation of the medicinal product. The application shall be submitted to the Spanish Agency for Medicinal Products and Sanitary Products, at least six months before its validity expires.

3. The application for renewal shall be submitted in any of the places provided for in Article 38.4 of Law No 30/1992 of 26 November 1992 and in accordance with the format of application published by the Spanish Agency for Medicinal Products and Products Sanitary.

4. The Spanish Agency for Medicinal Products and Health Products shall notify the decision before the expiry of the validity of the authorisation. Where the decision is negative, the provisions of Article 68 shall be followed.

5. The authorisation shall be extinguished if no application for renewal of the authorisation is submitted within the prescribed period, unless the Spanish Agency for Medicinal Products and Sanitary Products agrees to maintain the validity of the authorisation. authorization.

Article 28. Effective marketing.

1. The holder of the authorisation shall communicate to the Spanish Agency for Medicinal Products and Sanitary Products the effective date of placing on the market of each medicinal product. Such communication shall be carried out for each marketing authorisation at least 15 days before the marketing authorisation is made.

2. The holder of the authorisation shall make an annual declaration of intention to place the medicinal product on the market. This communication will be made to the Spanish Agency for Medicines and Health Products during the month of October of the previous year, accompanied by a justification for the payment of the corresponding fee. In the event of failure to submit this declaration, it shall be understood that the suspension of the marketing authorisation is requested in accordance with Article 69.1, the corresponding procedure being initiated.

3. Each marketing authorisation for a medicinal product shall be valid if, within three years, the holder does not proceed to the effective marketing of the medicinal product. The three-year period shall begin to be counted from the day following the date of notification of the decision of approval issued by the Spanish Agency for Medicinal Products and Sanitary Products.

4. Authorisation to place a medicinal product on the market shall also lose its validity, if once authorised and marketed it is no longer effective on the market for three consecutive years.

5. Where a marketing authorisation holder expresses to the Agency his intention not to continue the placing on the market of a medicinal product, the Agency may make this situation public by urging other laboratories which may be interested in requesting a marketing authorisation for that medicinal product, on the basis of Articles 7, 8, 10 and 12, as appropriate.

6. However, when health reasons or health concerns are present, as in the case of a therapeutic loophole, either in the market in general or in the pharmaceutical supply of the National Health System, the Spanish Agency of Medicines and Sanitary Products will maintain the validity of the authorisation and will require the effective marketing of the medicinal product.

7. The Spanish Agency for Medicinal Products and Sanitary Products will make use of the above mentioned circumstances in the Register of Medicines.

CHAPTER III

Labelling and Package Leaflet

Section 1. General provisions of labelling and package leaflet

Article 29. Labelling objectives and package leaflet: Identification guarantees and information for the rational use of the medicinal product.

1. The labelling and package leaflet of the medicinal product shall be in accordance with the information on the technical information sheet.

2. The labelling and the package leaflet shall ensure the unequivocal identification of the medicinal product, providing the necessary information for correct administration and use by patients or users and, where appropriate, by healthcare professionals.

3. The labelling and package leaflet, in their design and content, shall facilitate the proper understanding and knowledge of the medicinal product by the citizen. The package leaflet must be legible, clear, ensuring its understanding by the patient and minimizing the technical nature.

Article 30. Authorisation of the information contained in the labelling and package leaflet.

1. The texts and other characteristics of the labelling and package leaflet are part of the application for the medicinal product and will require authorisation from the Spanish Agency for Medicinal Products and Health Products.

The modifications will also require prior authorisation from the Spanish Agency for Medicines and Health Products and will be resolved in accordance with the procedure laid down for the modifications of the authorisation.

2. The texts will be presented in Spanish at least. In addition, they may also be written in other languages, provided that the same information is available in all languages. In such cases, the application shall be accompanied by the supporting documentation of the fidelity of the translation.

3. In the case of orphan medicinal products, the information provided for in the labelling may be drawn up on duly substantiated request in an official language of the European Union, in cases determined by the Spanish Agency Medicines and Healthcare products.

4. Likewise, where the destination of the medicinal product is not the direct delivery to the patient, the Spanish Agency for Medicinal Products and Sanitary Products may dispense with the obligation to make certain information on the labelling and the package leaflet. as well as writing the prospectus in Spanish.

5. Without prejudice to the foregoing, in the cases referred to in paragraphs 3 and 4, the marketing authorisation holder shall make available to the Spanish Agency for Medicinal Products and Sanitary Products the information on the labelling and/or the package leaflet. Spanish, so that it can be made available to interested citizens and professionals.

Section 2. Medication Identification Guarantees: Labelling

Article 31. General requirements.

1. The labelling of the medicinal product shall include the detailed information in Annex III

2. The particulars to be provided on the labelling of medicinal products shall be clearly legible, clearly understandable and indelible. This data shall not mislead the nature of the product or the therapeutic properties of the product.

Article 32. Guarantees of authenticity and traceability of the labelling.

The outer packaging or in its defect the primary packaging shall incorporate the elements that allow the authentication of the product, as well as the information necessary to determine the traceability of the medicinal product from its (a) manufacture up to his or her supply to the citizen, including for that purpose the identification to be laid down in regulation.

Article 33. Incorporation of symbols and graphic motifs.

1. The symbols listed in Annex IV shall be included in the labelling.

2. The inclusion of other graphic reasons may be authorised which, in accordance with the technical information sheet, and not having an advertising character, are appropriate to facilitate the interpretation by patients and users of certain particulars in the Annex. III.

Article 34. Obligation to declare certain excipients.

On the labelling, in the declaration of the composition of the medicinal product, the excipients must be included in a compulsory declaration, the knowledge of which is necessary for the correct administration and use of the medicinal product.

Compulsory declaration excipients will be updated in accordance with scientific and technical progress and in accordance with what is established in the European Union.

Article 35. Guarantee of correct identification: name of the medicinal product.

1. The name with which the medicinal product defined in Article 2.8 is marketed, shall meet the requirements laid down in law and in no case shall be liable to mislead the therapeutic properties or the nature of the medicinal product.

The name may be a name of a fantasy which cannot be confused with the common name defined in Article 2.9 or the common or scientific name of the active substance, accompanied by a trade mark or name of the marketing authorisation holder or manufacturer.

2. Such names shall be avoided which may lead to errors in the prescription or supply of names already existing in the pharmaceutical market, the use of other previous names or the prescription habits.

3. In general, and in accordance with the above two paragraphs, the names of medicinal products shall not be admissible where:

(a) Your prescription or dispensation may result in phonetic or spelling confusion with that of another medicine or with medical, cosmetic or food products.

(b) It has been used in a medicinal product for which the authorisation has been revoked and not more than five years after revocation, except that they have the same composition in active substances.

c) Have an orthographic resemblance to an Official Spanish Denomination, with a Common International Denomination recommended or proposed by the World Health Organization, or with a common or scientific common denomination.

(d) For advertising medicinal products and other medicinal products with advertising directed to the public, the name of which may not be the same or to be confused with that of another medicinal product subject to medical prescription or financed by public funds.

Section 3. Medication Information Guarantees: Package Leaflet

Article 36. General requirements of the package leaflet.

1. The package leaflet is the written information that accompanies the medicine, addressed to the patient or the user. It identifies the holder of the authorisation and, where appropriate, the name of the representative of the marketing authorisation holder and the person responsible for the manufacture of the medicinal product, declares its composition and gives instructions for its use. administration, employment and conservation, as well as their adverse effects, interactions, contraindications and other data as set out in Annex V, in order to propose their most correct use and compliance with the prescribed treatment, as well as measures to be taken in case of intoxication.

2. The package leaflet must be drawn up and designed in clear and comprehensible terms to enable patients and users to act appropriately, where necessary with the help of healthcare professionals.

3. The package leaflet shall reflect the results of the consultations with the patient or user groups to ensure their readability, clarity and ease of understanding to promote the correct use of the medicinal product.

4. As a general rule, the package leaflet shall contain only the information concerning the medicinal product to which it relates. However, the Spanish Agency for Medicinal Products and Sanitary Products may, in certain circumstances, authorise the inclusion of information relating to different doses and available pharmaceutical forms of the same medicinal product.

5. The insertion of the package leaflet into all medicinal products is mandatory unless all the information required is included in the outer packaging or, failing that, in the immediate packaging.

6. The marketing authorisation holder shall ensure that, upon request of the patient organisations, the package leaflet is available in appropriate formats for blind or partially sighted persons.

Article 37. Omission of therapeutic indications.

The Spanish Agency for Medicinal Products and Sanitary Products may decide that certain therapeutic indications are not included in the package leaflet or the technical information sheet, in particular where the applicant for a generic medicinal product communicates that these indications are covered by the right of patents or data protection at the time when the generic medicinal product is authorised.

Article 38. Graphic motifs.

The inclusion in the prospectus of drawings, and other graphic reasons, which complement the written information of the prospectus as well as other information, may be authorised provided that, in accordance with the technical information sheet, justify on grounds of health education or promote greater understanding for the consumer or user to whom they are directed, and do not meet criteria for the promotion or advertising of the medicinal product.

Section 4. Special Provisions for Certain Drug Formats

Article 39. Packaging material for clinical packaging.

1. The outer packaging shall contain the data set out in the first part of Annex III, with the following exceptions:

a) Suppression of the National Health System's seal coupon.

b) Deleting the box or blank to indicate the prescribed dosage, duration of treatment and frequency of shots.

c) Include prominently in the caption: "Clinical pack, forbidden your sale to detail".

2. In the primary packaging the data shall be recorded in the second part of Annex III.

3. The number of leaflets to be included in the package shall be sufficient, depending on the number of units in the clinical package, to ensure the information of the possible patients or users, and contain the information set out in the package. Annex V.

Article 40. Packaging material for free samples.

The packaging material of the free samples, whatever the latter, shall have the same characteristics and conditions as those authorised for sales packages to the public, with the following exceptions:

a) The seal coupon of the National Health System will be deleted or cancelled.

(b) In the outer packaging the legend shall be marked indelibly and clearly: "Free sample, prohibited for sale".

CHAPTER IV

Particular provisions for certain classes of medications

Section 1. Third blood products

Article 41. Prior authorisation of batches of manufacture of blood products.

1. For reasons of public health, the Spanish Agency for Medicinal Products and Sanitary Products, in accordance with Article 45.3 of Law 29/2006 of 26 July, shall subject to prior authorization each batch of manufacture of the finished product and condition the marketing to their conformity.

2. With the exception of plasma derivatives which are involved as an excipient or as a reagent in the production of another medicinal product or medical device, the products in the clinical trials and the medicinal products referred to in paragraph 2 of this Article Article 24 of Law 29/20006 of 26 July.

3. Prior authorisation of the batch of manufacture shall involve the review of the production and control protocols accompanying the application and, where appropriate, the carrying out of the analytical tests deemed appropriate.

4. Where it is documented by the Spanish Agency for Medicinal Products and Sanitary Products that the lot has been certified by the competent authority of another Member State, the said authorisation shall be granted without further analysis.

5. Where no analysis is required, the manufacturing batch shall be deemed to have been authorised if within five working days of receipt of the application for authorisation in the Spanish Agency for Medicinal Products and the Health Product it does not require to the applicant who subsals or improves the application. The Spanish Agency for Medicinal Products and Health Products shall determine the telematic means for making such an application.

6. If the application involves carrying out the analysis of the lot for not having the certification referred to above, the application shall be resolved within a maximum of 60 days from the date of its submission.

Article 42. External trade in blood products.

1. The entry and exit of blood products, their raw materials and their intermediates, from the Spanish territory is subject to prior authorisation by the Spanish Agency for Medicines and Health Products.

2. In the case of the removal of blood products, a favourable report from the Directorate-General for Public Health, Ministry of Health and Consumer Affairs will be required.

Section 2

Article 43. Prior authorization of manufacture of vaccines and allergens.

1. For reasons of public health, the Spanish Agency for Medicinal Products and Sanitary Products, in accordance with Article 45.3 of Law 29/2006 of 26 July, shall subject to prior authorization each batch of finished product and condition the the following vaccines:

a) Viral vaccines.

b) Vaccines against tetanus, diphtheria and tosferin both monovalent and polyvalent.

c) The attenuated antitific vaccine.

2. The prior authorisation shall involve the review of the production and control protocols and, where appropriate, the carrying out of the analytical tests deemed appropriate.

3. Where the Spanish Agency for Medicinal Products and Sanitary Products is accredited to the Spanish Agency for a certificate that the lot has been certified by the competent authority of another Member State of the European Union, the said authorisation shall be granted without new analyses. After the period referred to in paragraph 4 of this Article without negative statement, and taking into account the special need for these strategic products, the lot shall be understood as the lot for placing on the market.

4. The file shall be settled within the maximum period of 60 calendar days from the receipt of the application.

5. In the case of the influenza vaccine, the time limits referred to in paragraphs 3 and 4 shall be 30 calendar days.

Article 44. Individualized vaccines.

For individual use vaccines, limitations of the scope of the requirements set out in Annex I may be established in accordance with the characteristics of these products.

Article 45. Usage recommendations.

In those vaccines that are authorized by centralized, decentralized, and mutual recognition procedures, and the technical information to be used in accordance with the official recommendations, these official recommendations Use must be accompanied by the technical information sheet during the promotion of the vaccine.

Section 3. Radiopharmaceutical Medicinal Products

Article 46. Authorisation of radiopharmaceutical medicinal products.

The generators of radionuclides, equipment, radionuclides precursors and radiopharmaceuticals manufactured industrially have the consideration of medicines and are subject to authorization and registration by the Spanish Agency of Medicines and Health Products

Article 47. Exemptions.

1. Authorization will not be required for the following cases:

(a) The extemporaneous preparation of a radiopharmaceutical medicinal product, understood as the preparation of a radiopharmaceutical at the time of its use, in an authorised radio unit, under the supervision and control of an optional specialist in radio, for its application to a legally empowered institution or institution for this purpose, if it is carried out exclusively from radionuclide generators, precursor radionuclides and equipment duly authorised and with the manufacturer's instructions.

b) Preparation at the time of use of autologous samples where radionuclides are involved, as well as the extraction of individual doses of radiopharmaceuticals ready for use, in an authorised radio-arm unit, under the supervision and control of an optional specialist in radio, for the purpose of applying them to a legally empowered institution or institution, if it is carried out exclusively from radionuclide generators, precursor radionuclides, industrially manufactured radiopharmaceuticals and equipment duly authorised and in accordance with the manufacturer's instructions.

(c) Radiopharmaceuticals used for positron emission tomography (PET radiopharmaceuticals) prepared in a radiolabelling unit authorised under the supervision and control of an optional radiopharmaceutical specialist, always that meet the following requirements:

1. º fully elaborated and used, non-profit, in centers linked to the National Health System,

2. Sean substances in clinical research phase or are drugs that the Spanish Agency for Medicines and Health Products considers to satisfy the guarantees of quality, safety, efficacy, identification and information, and to be developed in appropriate facilities.

Article 48. Specific requirements for the authorisation of radiopharmaceutical medicinal products.

1. Applications for the authorisation of radiopharmaceutical medicinal products, in addition to complying with Article 6, shall include a full detailed explanation of the internal radiation dosimetry. In the case of radionuclide generators, a general description of the system shall be included, together with a detailed description of the components thereof which may affect the composition or quality of the radionuclide son, as well as the qualitative and quantitative characteristics of the eluid or sublimate. In the case of radiopharmaceuticals which require an extemporaneous preparation, additional detailed instructions for the extemporaneous preparation and the quality control of this preparation should be included and, where appropriate, maximum storage time during which any intermediate preparation, such as an eluid, or the radiopharmaceutical ready for use meets the intended specifications.

2. The documentation shall comply with the criteria set out in the common technical document (DTC) agreed in the European Union and set out in Annex I. as well as the detailed guidelines for each subject.

Article 49. Compliance with health protection legislation.

The provisions of this royal decree shall be without prejudice to the provisions of the legislation on the health protection of the population and exposed workers, as well as persons on the occasion of medical exposures, against the risks of ionizing radiation.

Section 4. Traditional herbal medicinal products

Article 50. Registration of traditional herbal medicines.

Without prejudice to Article 51.3 of Law 29/2006 of 26 July, traditional herbal medicinal products may not be placed on the market without the prior registration of traditional medicinal products to plant base created by the Spanish Agency for Medicines and Health Products.

Article 51. Criteria to be met by traditional herbal medicinal products to be registered under the simplified procedure.

1. In order to obtain the simplified registration of a traditional herbal medicinal product, the following conditions must be met:

(a) that the medicinal products have appropriate indications exclusively for traditional herbal medicinal products, which, by virtue of their composition and purpose, are intended and designed for use without the control of a doctor; for the purposes of diagnosis, prescribing or monitoring of a treatment.

b) To be administered in accordance with a given dose or posology.

c) For use by oral, external or inhalation use.

(d) the period of traditional use, consisting of a minimum period of 30 years, of which at least 15 years has elapsed, has been used in the European Union.

e) That the information on traditional use is sufficient and in particular that the product proves not to be harmful under the conditions of use established and the pharmacological action or the efficacy of the herbal medicinal product, can derive from experience in traditional use.

2. Without prejudice to Article 2.28, a traditional herbal medicinal product may contain vitamins or minerals whose safety is well documented in accordance with Article 50. In such cases, the action of vitamins and minerals should be secondary to the active substances in plants as regards the specific indications authorised.

Article 52. Simplified registration procedure for traditional herbal medicines.

1. The application shall be accompanied by the following data and documents:

(a) Those referred to in points (a) to (i), including and (n) of Article 6.5.

b) The results of pharmaceutical (physico-chemical, biological or microbiological) tests.

(c) The technical information sheet of the product, without the information on the pharmacological properties where appropriate, a model of the packaging and labelling, as well as the package leaflet in accordance with the rules, for the purpose of ensuring the appropriate understanding by users.

(d) Supporting documentation of the authorisations or refusals obtained by the applicant in another Member State or in a third country for the medicinal product, specifying, where appropriate, the reasons for the decision.

e) In the case of an association of plant substances, plant preparations or combinations of both, information on the traditional use of the combination shall be included, in particular that the product proves not to be harmful in the conditions of use and that the pharmacological action or efficacy is derived from long-standing use and experience and if the individual active substances are not sufficiently known, the information shall also refer to them.

(f) Bibliographic references or expert reports showing that the medicinal product concerned or an equivalent product, as referred to in this paragraph, has been used for a minimum period of time 30 years before the date of application, of which at least 15 years have been used in the European Union or the medicinal product has obtained a favourable opinion from the Committee for Medicinal Products for Plants of the European Agency for Medicines that you consider to be a traditional herbal medicine.

The requirement to present evidence of pharmacological use over a period of 30 years shall be fulfilled even if the placing on the market of the product has not been based on a specific authorisation. It will also be fulfilled if the number or quantity of ingredients in the medicine has been reduced during that period.

g) bibliographic documentation, accompanied by an expert report, on the safety of the medicinal product. The Spanish Agency for Medicines and Health Products may request additional information to assess the safety of the traditional herbal medicinal product.

2. The documentation referred to in paragraphs (d), (f) and (g) of this Article shall not be required where the plant substances or preparations or their combinations are included in the list of plant substances and preparations and combinations thereof. of these, for use in traditional herbal medicinal products developed by the Committee for Medicinal Products for Plants of the European Medicines Agency.

Community monographs developed by the Committee for Medicinal Products for Plants of the European Medicines Agency will be referred to in the preparation of the documentation of the traditional use.

3. Where the application for registration of traditional herbal medicinal products is of a medicinal product which has been in use in the European Union for less than 15 years, but which may be eligible for other reasons for the simplified registration, the Agency Spanish Medicines and Sanitary Products will request an opinion on the traditional use of the medicinal product presented in the application to the Committee for Medicinal Products for Plants of the European Medicines Agency.

Where there is a Community monograph on the plants that are part of the proposed medicinal product, it shall be taken into account in the resolution of the application for registration.

4. The Spanish Agency for Medicines and Health Products, when assessing the application for registration of a herbal medicinal product, will take into account the records of traditional herbal medicines granted in other States. members on the basis of this legislation.

5. Where the registration of a traditional herbal medicinal product is requested, which has been registered as such in another Member State, the mutual recognition procedure shall apply, provided that a monograph has been published. of the medicinal plant for traditional use, or the herbal medicinal product consisting of substances, preparations or combinations thereof appearing on the list drawn up by the Committee for Medicinal Products for Plants of the European Agency For the use of medicinal products and published by the European Commission.

6. The maximum period for the notification of the decision of the procedure shall be six months from the day following the date of submission of a valid application. Otherwise, the application shall be deemed to be rejected, with the result of the administrative and administrative disputes arising.

Article 53. Grounds for refusal.

1. Without prejudice to the grounds for refusal laid down in Article 19, the application for the simplified registration of traditional herbal medicinal products shall be refused where the application of Articles 51 and 52 is not complied with, and where the information on traditional use is insufficient, especially if the pharmacological aspects or efficacy are not deducted from their long-standing use and experience or the product is harmful under normal conditions of use.

2. If a registration application refers to a plant substance or preparation or a combination of those listed in the list published by the European Commission, the application for registration may not be refused for the last two causes listed in the Annex. Previous section.

3. The Spanish Agency for Medicinal Products and Sanitary Products shall notify the applicant, the Commission and any competent authority that it is required of any decision on the refusal of a registration for traditional use and the reasons for the latter.

Article 54. Market-run.

In addition to the causes laid down in Article 68.1, where a substance, plant preparation or combination thereof is no longer listed in the list drawn up by the Committee for Medicinal Products on the basis of plants of the European Agency, Medicinal products, the respective inscriptions shall be left without effect in the register of traditional herbal medicinal products, unless within three months they submit the supporting documentation referred to in the Article 52.1 and the withdrawal from the market of traditional medicinal products of plants which contain any of these components.

Section 5. Homoeopathic Medicines

Article 55. Homeopathic medication classes.

Homeopathic medicines may be:

(a) With approved therapeutic indication, the authorisation and registration procedure of which shall follow the procedure laid down in Chapter II, taking into account their homeopathic nature.

(b) No approved therapeutic indications, the authorisation and registration procedure of which shall be the special simplified homeopathic medicinal product, established for this purpose by the Spanish Agency for Medicinal Products and Sanitary Products, provided that they comply with the requirements laid down for that procedure. Otherwise, they shall follow the procedure laid down in Chapter II, taking into account their homeopathic nature.

Article 56. Criteria to be met by homeopathic medicinal products to be registered under the special simplified procedure.

To obtain the simplified registration of a homeopathic medicine the following conditions will have to be met:

a) That your administration path be oral or external.

b) Absence of particular therapeutic indication on the label or any information relating to the medicinal product.

(c) That the degree of dilution ensures the safety of the medicinal product, in particular the preparation must not contain more than one part per 10,000 of the mother tincture or more than one hundredth of the lowest dose which may be use allopathic medicine from active substances whose presence in an allopathic medicinal product involves the obligation to present a prescription.

Article 57. Special simplified registration procedure for homeopathic medicinal products.

1. The application for registration, which may cover the whole range of medicinal products obtained from the same homeopathic strain or strains, shall be accompanied by the following data and documents:

(a) Scientific name of the homeopathic strain (s) or other name recognised in the Spanish Royal Pharmacopoeia, in the European Pharmacopoeia, or in its defect, in an official pharmacopoeia used in a country of the Union European.

b) Administration Vies, pharmaceutical forms and degrees of dilution to be recorded.

c) A description of the production and control of the homeopathic strain or strains.

d) Justification of your homeopathic use, based on an appropriate bibliography.

e) Description of the manufacturing and control procedure for each pharmaceutical form, as well as the dilution and dynamisation methods used.

f) Information about the stability of the medicine.

g) Preclinical tests or justification for their absence.

(h) bibliographic documentation, accompanied by an expert report, demonstrating the safety of the medicinal product.

2. Where the simplified registration of a homeopathic medicinal product which has been registered as such in other Member States is requested, the mutual recognition procedure shall be applied, the application of which shall comply with the provisions of the Article 16.4.

3. The maximum period for the notification of the decision of the procedure shall be 6 months from the day following the date of submission of a valid application. Otherwise, the application shall be deemed to be rejected, with the result of the administrative and administrative disputes arising.

Article 58. Labelling of homeopathic medicinal products.

1. The labelling and, where appropriate, the package leaflet of homeopathic medicinal products with therapeutic indication, shall comply with the general provisions concerning the labelling and package leaflet referred to in this royal decree and the provisions of this Directive. (a) specific rules to be adopted.

2. The labelling and, where appropriate, the package leaflet of homeopathic medicinal products without approved therapeutic indication, must necessarily include the following data:

(a) Scientific name of the strain or strains followed by the degree and type of dilution using the symbols of the pharmacopoeia used; if the homeopathic medicinal product is composed of several strains, the scientific name of the strains, with their degree of dilution in the labelling, may be supplemented by a name of fancy.

(b) Name and address of the health authorisation holder and, where applicable, the manufacturer.

c) Form and route of administration.

d) Expiration date expressed clearly (month and year). In addition, medicinal products with reduced stability after reconstitution, dilution or opening, shall indicate the time of validity of the reconstituted preparation, diluted or after opening and shall include a box for entry by the medicinal products. users.

e) Pharmaceutical form.

f) Content of the sales pack, by weight, volume or units of administration.

g) Special precautions for storage, if any.

h) Special warnings, when the medication requires them.

i) Manufacturing lot.

j) National Drug Code.

k) Legend "Homeopathic medication with no approved therapeutic indications".

l) A warning to advise the user to consult a doctor if symptoms persist.

Section 6. Medical Gases

Article 59. Authorization to place medicinal gases on the market.

Medicinal gases are permitted in accordance with the provisions of this royal decree, taking into account the following specificities:

1. They must comply with the quality technical characteristics required by the Spanish Royal Pharmacopoeia, the European Pharmacopoeia or, failing that, in other official pharmacopoeias of the Member States of the European Union or of another country, to which the Ministry of Health and Consumer Affairs recognizes quality requirements equivalent to those referred to in the pharmacopoeas.

2. Medicinal gases containing the same component with qualities adjusted to different pharmacopoeias shall be considered as distinct products for the purposes of their marketing authorisation.

3. Any other medicinal gas intended to be used for therapeutic purposes before being recognised by a pharmacopoeia as provided for in paragraph 1 of this Article shall be subject to the marketing authorization for the purposes of the assessment of their quality, safety and efficacy.

Article 60. Particular conditions.

By way of exception and for the care of their patients, medical centres may request a duly authorised pharmaceutical laboratory, the manufacture of a composition other than those authorised when they are met. the following conditions:

a) That you obey a doctor's written and motivated prescription for a particular patient.

(b) To be used in the manufacture of medicinal gases whose specifications are described in the pharmacopoeias provided for in paragraph 1 of the preceding article and in concentrations other than those authorised.

c) That the processing be carried out with the same quality guarantees as the authorised products.

(d) The labelling of the package should include at least the percentage composition, the identification of the prescriber and the care facility in which it will be used, the identification code of the patient, the social reason for the manufacturer's laboratory, the technical director of the manufacturer's laboratory, the expiry date and the storage conditions, if any, and the number of manufacturing and control protocols.

The laboratory must notify the Spanish Agency of Medicines and Health Products within a maximum of 15 days from the receipt of the request, and file the written request of the prescriber along with the manufacturing protocol and the product release certificate.

Article 61. Supply, delivery or dispensing.

1. A signed and dated certificate shall be accompanied during the transport of the liquefied medicinal gases to the storage tanks of hospital centres, other health centres or research or experimentation centres. the data on the labelling, which shall be available to the health authorities. The recipient will archive a copy of the certification per shipment.

2. The supply of liquefied medicinal gases for human use, in accordance with the provisions of Article 52 (2) of Law 29/2006 of 26 July, may be carried out as determined by the competent health authorities, the necessary safety and quality measures in the application of the medicinal gases by the appropriate healthcare or healthcare facilities.

3. Direct delivery to patients in the case of home therapy shall require the presentation of the appropriate medical order duly completed by the optional prescriber. The specific conditions of supply shall be developed regulatively.

CHAPTER V

Obligations of the holder of the medicinal product

Article 62. Obligations of the holder of the authorisation.

The holder of the authorisation of a medicinal product is required to respect the pharmacovigilance rules and, during the duration of the marketing authorisation to:

1. To observe the conditions under which the marketing authorisation was granted, in addition to the general obligations which the legislation in force points to, as well as those of any modification of the conditions of the authorisation laid down in the the following Chapter, including those of the manufacturing and control procedures. In no case will the modifications of the conditions of authorization be carried out without authorization.

2. Respect the continuity of the service. The marketing authorisation holder has an obligation to supply the market for authorised medicinal products.

3. Keep the file permanent update. The holder of the authorisation shall submit the periodic safety update reports, in order to keep the dossier up to date in the field of safety and in particular the information addressed to professionals. included in the technical information sheet and the information in the package leaflet ensuring adequate understanding of the package leaflet.

4. Contribute to the appropriate knowledge of the medicine and promote its rational use. The holder of the authorization is obliged to make available to the public, in particular to the health professionals, the updated information of the technical information sheet of the medicinal product with the legally established information, as well as to make public the results of the clinical trials, regardless of the outcome or not of their findings.

5. Collaborate on control programmes, ensure the adequacy of products on the market and report any possible withdrawal of lots from the market. The holder of the authorization of a medicinal product must communicate to the Spanish Agency for Medicinal Products and Health Products, the Autonomous Communities and the authorities of all the countries where it has been distributed, with the appropriate speed to case and setting out the grounds, any action taken to remove a lot from the market.

6. Participate in systems that guarantee the collection of the residues of medicinal products that are generated in the homes.

7. Any other legal or regulatory obligation established.

CHAPTER VI

Amendments to the conditions for authorization of medicines

Article 63. Modifications to the conditions of authorisation of the medicinal product.

1. Modifications to the conditions of authorisation of medicinal products are subject to prior authorisation by the Spanish Agency for Medicinal Products and Health Products in the following terms.

2. These modifications are classified into:

a) minor modifications that are divided into IA-type modifications and IB-type modifications.

b) major changes: type II.

3. Minor amendments are considered to be of minor importance as defined in Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of the amendments to the terms of the authorisations of the placing on the market of medicinal products for human use and veterinary medicinal products granted by the competent authority of a Member State.

4. Major modifications which are not typified as minor modifications are considered as minor in accordance with the provisions of the previous paragraph.

5. In accordance with Regulation (EC) 1084/2003 of 3 June 2003, the conditions for the authorisation of a medicinal product shall not be considered to be the line extensions of the marketing authorisations of that medicinal product. require a new marketing authorization.

6. Amendments shall not be permitted during the processing of applications for marketing authorisation, except those imposed by the Spanish Agency for Medicinal Products and Sanitary Products and/or the European Commission.

7. The Spanish Agency for Medicinal Products and Sanitary Products shall notify the European Medicines Agency of the resolutions of amendments to the authorisations considered to be relevant.

Article 64. Procedure for minor modifications.

1. The procedure for minor modifications will be governed, as established in this royal decree and by the instructions on the subject approved by the Spanish Agency for Medicines and Health Products.

2. In applications for the modification of type IA, the Spanish Agency for Medicines and Health Products shall verify that it conforms to the group defined as IA and that the documentation submitted complies with the requirements for the modification concerned.

Within the maximum period of 30 days, from the day following the filing of the application, the Spanish Agency for Medicinal Products and Sanitary Products shall notify the person concerned that his application has been accepted, and this proceed to its implementation. If not, the application shall be refused, by means of a reasoned decision. When the decisions are notified, the remedies shall be expressed in accordance with the provisions of the rules applicable to the case.

3. In the type IB amendments, the Spanish Agency for Medicinal Products and Health Products shall verify that it conforms to the group defined as IB and that the documentation submitted complies with the requirements for the modification concerned.

Within 15 days, from the day following the filing of the application, the Spanish Agency for Medicines and Health Products shall inform the person concerned of his admission to the proceedings or, if necessary, request the subhealing of the request.

In the case of admission to the application, within 30 days of the day following the communication to the person concerned provided for in the preceding paragraph, the Spanish Agency for Medicines and Health Products shall issue and notify the resolution authorizing the requested amendment, or a proposal for a decision to reject the application with the relevant hearing procedure, which shall be passed and shall be notified by reasoned decision. When the decisions are notified, the remedies shall be expressed in accordance with the provisions of the rules applicable to the case.

Article 65. Procedure for major modifications.

1. The procedure for major modifications will be governed, as established in this royal decree and by the instructions on the subject approved by the Spanish Agency for Medicines and Health Products.

2. In the major modifications or type II the Spanish Agency for Medicines and Health Products, it will verify that the documentation submitted is in line with the modification that is intended to be implemented.

Within 15 days, from the day following the filing of the application, the Spanish Agency for Medicines and Health Products shall inform the person concerned of his admission to the proceedings or, if necessary, request the subhealing of the request.

3. In the case of admission to the application, within 90 days of the day following the communication to the person concerned, as provided for in the preceding paragraph, the Spanish Agency for Medicinal Products and Health Products shall notify the authorising or refusing the requested amendment, with an indication of the remedies against it.

At any point in the procedure prior to the resolution, the Spanish Agency for Medicines and Health Products may request information or supporting documentation from the person concerned, with the calculation of the time limit for the resolution, for a period not exceeding 60 days.

Article 66. Special modifications.

The following special modifications will be considered:

1. Urgent modifications for security reasons.

When new information is known to indicate an important public health risk associated with the use of the medicinal product or has a significant impact on the safety of the medicinal product, a change may be made. Provisional information on the medicinal product which will affect in particular some of the following data from the technical information: indications, posology, contraindications or warnings, special precautions for use and adverse reactions.

For this purpose, the specific procedures laid down in the pharmacovigilance rules for medicinal products for human use will be followed.

2. Annual modification for human influenza vaccines.

(a) General modifications that may affect human influenza vaccines shall be governed by the provisions of Article 65.

(b) In the particular case of the application for the adequacy of the strains to the annual recommendations established by the World Health Organization, the procedure laid down for the modifications of importance shall be followed. major, with the documentary specifics for the flu vaccine, issuing resolution within the maximum period of 60 days.

3. Amendment of the authorisation for reasons of general interest.

(a) The Spanish Agency for Medicinal Products and Sanitary Products for reasons of public interest, defense of the health or safety of persons, may modify the conditions of dispensing and/or prescription of a medicinal product.

(b) This procedure shall be processed with a hearing to the party concerned and the maximum period for the notification of the decision shall be 90 days. The opinion of the Committee for the Evaluation of Medicinal Products for Human Use will also be required.

(c) If the procedure is based on the safety of the medicinal product, the procedure shall be carried out in accordance with the provisions of the specific pharmacovigilance rules.

Article 67. Change of holder of the medicinal product.

1. The change of holder of the marketing authorisation for the medicinal product is subject to authorisation by the Spanish Agency for Medicinal Products and Sanitary Products.

2. Modifications to the authorisation of the medicinal product resulting from the change of holder shall be governed by the procedure laid down for the amendments.

CHAPTER VII

Procedures for suspending and revoking the authorization

Article 68. Causes of suspension and revocation.

1. The Spanish Agency for Medicines and Health Products may agree to suspend or revoke the authorisation of a medicinal product when:

(a) The medicinal product does not have the authorised quantitative or qualitative composition or when the quality guarantees are not complied with or when the required quality controls are not carried out.

b) Based on the safety data, the medicinal product has, under the usual conditions of use, an unfavourable benefit/risk ratio.

c) The medicinal product may not be therapeutically effective.

d) The data and information contained in the documentation of the application for authorization are erroneous or do not comply with the rules of application in this field.

e) For any other cause, pose a foreseeable risk to the health or safety of people or animals.

f) In any other case where the European Medicines Agency would have agreed.

Article 69. Procedure for suspension and revocation of trade.

1. The Spanish Agency for Medicines and Health Products may suspend or revoke the authorization of a medicinal product, for the reasons provided for in the previous article. In the case of suspension of the marketing authorisation, the marketing authorisation shall not interrupt the period laid down in Article 28 (3) and (4

.

2. The procedure shall be initiated by agreement of initiation and hearing of the person concerned, after which a decision shall be taken to notify the person concerned within the maximum period of six months, indicating the resources. Where the grounds for suspension or revocation are those referred to in paragraphs (b), (d) or (e) and concern the safety of the medicinal product, the procedures laid down in the pharmacovigilance rules for medicinal products shall be followed. human use.

3. The Spanish Agency for Medicinal Products and Sanitary Products shall notify the European Medicines Agency of the resolutions of suspension and revocation of the conditions of the authorisation which are considered to be relevant.

Article 70. Suspension and revocation procedure at the instance of a party.

1. Where the holder of an authorisation for a medicinal product intends to suspend or cease the marketing of a medicinal product, he shall notify the Spanish Agency for Medicinal Products and Sanitary Products at least two months before the date on which he is scheduled to to stop the marketing of the medicinal product, motivating that request. In the case of suspension of the marketing authorisation, the marketing authorisation shall not interrupt the period laid down in Article 28 (3) and (4

.

2. However, the above, when health reasons or health concerns are present, as in the case of a therapeutic loophole, either in the market in general or in the pharmaceutical supply of the National Health System, the Spanish Agency of Medicines and Sanitary Products will maintain the validity of the authorisation and will require the effective marketing of the medicinal product.

CHAPTER VIII

Community Procedures

Article 71. Definitions and general requirements of Community procedures.

1. Mutual recognition means the Community procedure laid down for the granting of a marketing authorisation for a medicinal product in more than one Member State where the medicinal product has already been evaluated and authorised in one of the Member States.

2. Decentralised, the Community procedure laid down for the granting of a marketing authorisation for a medicinal product in more than one Member State where the medicinal product does not have an authorisation in any Member State Member of the European Union at the time of application.

3. Both procedures require the applicant to submit an application based on an identical dossier in all Member States involved in the procedure. The file shall contain the information and documents referred to in Articles 6, 7, 8, 9, 10, 11, 12 and Annex II.

The submitted documents shall include a list of the Member States concerned by the application.

Article 72. Mutual recognition procedure.

1. Where the holder of a medicinal product already authorised in Spain intends to apply for authorisation in another Member State or other Member State, Spain may act as a reference Member State in the procedure.

2. In the event that Spain acts as a reference Member State, the marketing authorisation holder shall request the Spanish Agency for Medicinal Products and Sanitary Products to draw up a report on the evaluation of the medicinal product, or update the existing assessment report for that drug.

3. The Spanish Agency for Medicinal Products and Health Products shall draw up or update that report within 90 days of receipt of a valid application.

4. The assessment report, as well as the technical information sheet of the authorised medicinal product, the labelling and the package leaflet, shall be sent to the Member States concerned and to the applicant.

5. Within 90 days of receipt of the documents referred to in the preceding paragraph, the Member States concerned shall approve the documents submitted by the Spanish Agency for Medicinal Products and Sanitary Products, to which inform of their acceptance. The Agency shall ensure the general agreement and finalise the procedure and inform the applicant accordingly. Within 30 days, all Member States involved must resolve in accordance with the general agreement.

6. When an application for authorization to place an authorised medicinal product on the market in another Member State is submitted to the Spanish Agency for Medicinal Products and Sanitary Products, the mutual recognition procedure shall apply to it, It is understood that Spain is a Member State concerned in the proceedings. In this case, the procedure described above shall apply from the documentation submitted by the Member State acting as a reference Member State, in accordance with the provisions of the previous paragraph.

Article 73. Decentralised procedure.

1. Where it is intended to obtain a marketing authorisation for a medicinal product in more than one Member State, the applicant shall request one of them to act as a reference Member State.

2. When Spain acts as a reference Member State, the Spanish Agency for Medicinal Products and Sanitary Products will prepare a draft assessment report, a draft technical fiche and a draft labelling and package leaflet, within 120 days. days from receipt of a valid application, and shall send them to the other Member States concerned and to the applicant.

3. Within 90 days of receipt of the documents referred to in the preceding paragraph, the Member States concerned shall approve the documents submitted by the Spanish Agency for Medicinal Products and Health Products, informing them of their acceptance. The Agency shall ensure the general agreement and finalise the procedure and inform the applicant accordingly. Within 30 days, all Member States involved shall be required to resolve in accordance with the general agreement.

4. Where in a decentralised procedure it is another State acting as a reference Member State, Spain being involved as a State concerned, the Spanish Agency for Medicinal Products and Health Products shall apply the procedure described above. previously, on the basis of the documentation submitted by the reference Member State, in accordance with the provisions of the previous paragraph.

Article 74. Discrepancy in arbitration decisions and procedures.

1. Where, in a Community procedure, Spain, as a member state concerned, is unable to approve within the 90-day period provided for in Articles 72.5 and 73.3 the assessment report, the summary of the product characteristics, the labelling and the Package leaflet to be considered that there is a serious potential risk to public health, it shall give reasons for its decision in detail and shall communicate its reasons to the Member State of reference as well as to the other Member States concerned and to the applicant.

2. In the case of Spain being a reference member and receiving a communication of disagreement from another Member State, the Spanish Agency for Medicinal Products and Health Products shall communicate the disagreement to the other Member States concerned and to the applicant.

It shall also immediately communicate the reasons for disagreement to the Coordination Group to examine issues relating to the marketing authorisation for medicinal products in two or more Member States.

3. All Member States involved in the procedure shall endeavour to agree within the framework of the coordination group on the measures to be taken. They shall provide the applicant with the possibility to issue orally or in writing.

If within 60 days of the communication to the coordination group, the Member States reach an agreement, the Member State of reference, as the case may be, the Spanish Agency for Medicines and Health Products, ensure the general agreement and terminate the procedure and inform the applicant accordingly.

4. If, within the period laid down in the previous paragraph, the Member States do not reach an agreement, the Member State of reference, as the case may be, the Spanish Agency for Medicinal Products and Sanitary Products, shall inform the European Medicines Agency with the the purpose of initiating the arbitration procedure by referring a detailed description of the questions on which the Member States have not been able to reach an agreement and the reasons for their disagreement. A copy of this information shall be sent to the applicant, which shall forward a copy of the dossier to the European Medicines Agency without delay.

5. However, in the event that the Spanish Agency for Medicinal Products and Sanitary Products has approved the assessment report, the technical information sheet, the labelling and the package leaflet, it may, at the request of the applicant, authorise the placing on the market of of the medicinal product prior to the decision of the European Commission. In this case the authorisation shall be granted subject to the outcome of the arbitration procedure.

Article 75. Harmonisation of Community authorisations.

1. Where the same medicinal product has been subject to different applications for authorisation and the Member States have taken dissenting decisions in respect of the authorisation, suspension or revocation, Spain, any Member State, the Commission, the applicant or holder of the authorisation may refer to the Committee for Medicinal Products for Human Use of the European Medicines Agency in order to apply the arbitration procedure.

2. In order to promote the harmonisation of medicinal products authorised in the European Union, the Spanish Agency for Medicinal Products and Sanitary Products shall forward annually to the Coordination Group a list of the medicinal products for which it considers that harmonised technical sheets should be drawn up. This coordination group shall take into account the various proposals submitted by all Member States and shall send a list to the European Commission for harmonisation.

Article 76. Decisions of Community interest.

1. In specific cases where the interests of the European Union are at stake, any Member State, as the case may be, the Spanish Agency for Medicinal Products and Sanitary Products, the Commission, the applicant or the holder of the authorisation shall use the Committee for Medicinal Products for Human Use of the European Union to apply the arbitration procedure before a decision is taken on an application for authorisation, on a suspension or revocation of an authorisation or any other authorisation modification, especially for cases relating to new security information based on the pharmacovigilance of the medicinal product. Such request shall be accompanied by all available information.

From the above, the applicant or the holder of the authorisation shall be informed when the Commission or any Member State makes use of the Committee for Medicinal Products for Human Use of the European Medicines Agency.

2. Where the use of the Committee for Medicinal Products for Human Use of the European Medicines Agency relates to a number of medicinal products or to a therapeutic category, the European Medicines Agency may limit the procedure to a specific part. of the authorization.

3. Where the Spanish Agency for Medicinal Products and Sanitary Products considers that the modification of the terms of a marketing authorisation granted in accordance with the provisions of this Chapter, or its suspension or withdrawal, are necessary for to protect public health, it shall without delay submit the matter to the European Medicines Agency for the adoption of a Community decision.

4. In exceptional cases, where urgent action is essential to protect public health, and until a final decision is taken, the Spanish Agency for Medicines and Health Products may suspend marketing and use in Spain of the medicinal product concerned. This measure shall be communicated to the Commission and to the other Member States the following day.

Additional disposition first. Application to other industrially manufactured medicines.

This royal decree will apply, in what is not established in its specific rule, to drugs with psychoactive substances with addictive potential.

Additional provision second. Application of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use.

The provisions of this Royal Decree shall apply to medicinal products for paediatric use, without prejudice to Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006, on medicines for paediatric use.

First transient disposition. Application of data protection periods.

In accordance with the first transitional provision of Law 29/2006, the period of data exclusivity set out in Article 7.2 and 7.3 of this royal decree shall apply only to the reference medicinal products which have been submitted an application for authorisation after 1 November 2005. The periods of data exclusivity for the reference medicinal products for which an application for authorisation has been submitted before 1 November 2005 shall be those which governed prior to the entry into force of Law 29/2006, (a) the abbreviation of EFG, provided that 10 years have elapsed since the authorisation in Spain of the reference medicinal product or is authorised as a generic medicinal product in another country of the European Union.

Second transient disposition. Renewal of authorization of medicinal products.

The medicinal products authorised for the entry into force of Law 29/2006 of 26 July, must be renewed at the appropriate date. The provisions of the rules in force in relation to periodic safety reports shall apply to them from that renewal.

Transitional provision third. Period of adequacy of the labelling and package leaflet.

1. The holders of a marketing authorisation shall request the amendments relating to the labelling and package leaflet, in accordance with the provisions of Chapter III, to the Spanish Agency for Medicinal Products and Health Products.

2. In general, the suitability of the labelling and package leaflet of the medicinal products must be made with the application of any type II modification, except those changes which affect the quality of the medicinal product only and, in all case, with any modification affecting the labelling and package leaflet, as well as any modifications that are pending approval.

3. If none of the amendments referred to in the previous paragraphs have been made, the application shall be made in conjunction with the application for renewal. In any event, the corresponding amendment must be requested to bring the labelling and package leaflet into line before the end of five years after the entry into force of Law 29/2006 of 26 July.

Transitional disposition fourth. Application of Chapter III on labelling and package leaflet to pending applications.

Chapter III of this Regulation shall apply to applications for marketing authorization which are in the process, as well as to modifications of medicinal products for human use manufactured industrially and to medicinal products which are are in a temporary suspension situation. However, the provisions of Article 36.3 of this Regulation may be completed as additional documentation prior to the decision of the application or, at most, six months after the authorization has been granted, by means of the corresponding.

Transient disposition fifth. Preservation of organs for transplants.

The solutions for the conservation of organs listed in the seventh provision of Law 29/2006, of 26 July, which were marketed in Spain at the entry into force of the Law, may continue on the market until the decision of the file and as a result of it, if within the year following the entry into force of this royal decree is presented in the Spanish Agency for Medicines and Health Products the application for authorization corresponding.

Transitional disposition sixth. Homeopathic medicines.

1. The homeopathic medicinal products covered by the second transitional provision of Royal Decree 2208/1994 of 16 November 1994 on homeopathic medicinal products for human use in industrial manufacture must be brought into line with the of this royal decree, as provided for in the following paragraphs.

2. The holders of medicinal products affected by the second transitional provision of Royal Decree 2208/1994 of 16 November 1994 must inform the Spanish Agency of Medicinal Products and Sanitary Products of their intention to adapt to the present situation. decree.

The communication must take place within three months of the entry into force of the order in which the Ministry of Health and Consumer Affairs will determine the minimum requirements and the procedure for the communication, the fee provided for in Article 111 (3.7) of Law 29/2006 of 26 July.

After that period, the medicinal products covered by the second transitional provision of Royal Decree 2208/1994 of 16 November 1994 for which the intention to adapt was not communicated, in accordance with the provisions of this Directive. paragraph, may not be placed on the market, and must be withdrawn from the market.

3. The Spanish Agency for Medicinal Products and Sanitary Products shall set a timetable for the holders of homeopathic medicinal products which have made the communication provided for in the preceding paragraph to submit applications and documents. necessary to adjust its provisional situation and assess the benefit/risk ratio of the product. That application shall be accompanied by the payment of the fee of point 3.5 or 3.6 of Article 111 of Law 29/2006 of 26 July, as appropriate.

4. In any case, in respect of homeopathic medicinal products which the Spanish Agency for Medicinal Products and Health Products considers as a priority review to ensure the appropriate benefit/risk ratio, the adequacy procedure provided for in this transitional provision must be completed within one year of the entry into force of the order referred to in paragraph 2.

Transitional disposition seventh. Medicinal products based on medicinal plants.

1. Traditional herbal medicinal products which are currently marketed under the Ministerial Order of 3 October 1973 laying down the special register for the preparation of medicinal plant species may be to be adapted to the forecasts of this royal decree, before 30 April 2011. After the period of adequacy, all authorizations granted or registered in accordance with the Order of 1973 shall be without effect, being prohibited the placing on the market as medicinal products, without prejudice to the plants traditionally considered as medicinal products, whatever form of presentation, provided that they are not considered as a medicinal product and are offered without reference to therapeutic, diagnostic or preventive properties, they may be sold freely in the terms of Article 51.2 and 3 of Law 29/2006 of 26 July of guarantees and rational use of medicines and medical devices.

2. Applications for authorisation or registration of traditional medicinal products on the basis of plants referred to in this provision shall be submitted within a maximum of three years from the entry into force of this royal decree.

Single repeal provision. Regulatory repeal.

As many provisions of equal or lower rank are repealed, they are opposed to what was established in this royal decree, and in particular:

(a) Royal Decree 767/1993 of 21 May on the assessment, authorisation, registration and conditions of supply of medicinal products for human use manufactured industrially.

(b) Royal Decree 2236/1993 of 17 December 1993 on the labelling and package leaflet of medicinal products for human use.

(c) Royal Decree 288/1991 of 8 March 1991 regulating immunological medicinal products for human use.

(d) Royal Decree 478/1993 of 2 April 1993 regulating medicinal products derived from human blood and plasma.

(e) Royal Decree 479/1993 of 2 April 1993 on the treatment of radiopharmaceutical medicinal products for human use.

(f) Royal Decree 2730/1981 of 19 October on the characteristics and registration of proprietary medicinal products.

g) Royal Decree 2208/1994 of 16 November, which regulates homeopathic medicinal products for human use in industrial manufacture.

(h) Royal Decree 1800/2003 of 26 December, which regulates medicinal gases, with the exception of medicinal products for veterinary use.

(i) Ministerial Order of 3 October 1973 establishing a special register for the preparation of medicinal plant species.

j) Articles 28 and 29 of Royal Decree 223/2004 of 6 February on the regulation of clinical trials with medicinal products.

Final disposition first. Legislation on pharmaceutical products.

This royal decree is issued under article 149.1.16 of the Spanish Constitution, which attributes to the State exclusive competence in the field of legislation on pharmaceutical products.

Final disposition second. Incorporation of European Union law.

This royal decree incorporates into Spanish law Directive 2004 /27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001 /83/EC establishing a code of conduct for the Directive 2004 /24/EC of the European Parliament and of the Council of 31 March 2004 on medicinal products for human use and Directive 2004 /24/EC of the European Parliament and of the Council of 31 March 2004 on medicinal products for human use 2001 /83/EC.

Final disposition third. Regulatory development.

The Minister of Health and Consumer Affairs is authorized to issue any provisions necessary for the implementation and development of this royal decree, as well as to update its annexes in accordance with the advance of knowledge scientists and technicians in accordance with the guidelines and guidelines of the European Union.

Final disposition fourth. Entry into force.

This royal decree will enter into force on the day following its publication in the "Official State Gazette".

Given in Madrid, 11 October 2007.

JOHN CARLOS R.

The Minister of Health and Consumer Affairs,

BERNAT SORIA ESCOMS

ANNEX I

Analytical, pharmacotoxicological and clinical standards and protocols for the conduct of drug testing

Index

Introduction and general principles.

Part I: Requirements for standard marketing authorization files.

1. Module 1: Administrative information.

1.1 Index.

1.2 Request Form.

1.3 Summary of Product Characteristics, Labelling and Package Leaflet.

1.3.1 Summary of Product Characteristics.

1.3.2 Labelling and Package Leaflet.

1.3.3 Bocets and Samples.

1.3.4 Summaries of the product characteristics already approved in the Member State.

1.4 Information about experts.

1.5 Special requirements for different types of requests.

1.6 Assessment of the risk to the environment.

2. Module 2: Summaries.

2.1 Overall index.

2.2 Introduction.

2.3 Overall Quality Summary.

2.4 Overview of non-clinical part.

2.5 Overview of the clinical part.

2.6 Non-clinical summary.

2.7 Clinical summary.

3. Module 3: Chemical, pharmaceutical and biological information for medicinal products containing chemical and/or biological active substances.

3.1 Format and presentation.

3.2 Content: Basic principles and requirements.

3.2.1 Active Principle (s).

3.2.1.1 General information and information on starting materials and raw materials.

3.2.1.2 Process of manufacturing the principle or principles.

3.2.1.3 Characterization of the active principle or principles.

3.2.1.4 Control of the active substance or substances

3.2.1.5 Reference materials or standards

3.2.1.6 Envase and active-principle closure system.

3.2.1.7 Stability of the active substance or substances.

3.2.2 Product terminated.

3.2.2.1 Description and composition of the finished product.

3.2.2.2 Pharmaceutical development.

3.2.2.3 Process of manufacturing the finished product.

3.2.2.4 Control of the excipients.

3.2.2.5 Control of finished product.

3.2.2.6 Standards or reference materials.

3.2.2.7 Envase and close the finished product.

3.2.2.8 Stability of the finished product.

4. Module 4: Non-clinical reports.

4.1 Format and presentation.

4.2 Content: Basic principles and requirements

4.2.1 Pharmacology.

4.2.2 Pharmacokinetics.

4.2.3 Toxicology.

5. Module 5: Clinical studies reports.

5.1 Format and presentation.

5.2 Content: Basic principles and requirements

5.2.1 Biopharma Studies Reports

5.2.2 Reporting of pharmacokinetics studies using human biomaterials

5.2.3 Reports of Human Pharmacokinetic Studies.

5.2.4 Reports of Human Pharmacodynamics Studies.

5.2.5 Reporting on efficacy and safety studies.

5.2.5.1 Reports of controlled clinical studies regarding the stated indication.

5.2.5.2 Reports of uncontrolled clinical studies, data analysis reports obtained in various studies and other reports from clinical studies.

5.2.6 Post-marketing experience reports.

5.2.7 Data collection and patient listings.

Part II: Marketing authorization issues and specific requirements.

1. Sufficient medical use checked.

2. Essentially similar medicines.

3. Additional information required in specific situations.

4. Similar biological drugs.

5. Fixed combination drugs.

6. Documentation for authorization requests in exceptional circumstances.

7. Mixed requests for marketing authorization.

Part III: Special Medicines.

1. Biological drugs.

1.1 Plasma-derived drugs.

1.2 Vaccines.

2. Radiopharmaceuticals and precursors.

2.1 Radiopharmaceuticals.

2.2 Radiopharmaceutical Precursors for Radioactive Marking Purposes.

3. Homeopathic medicines.

4. Herbal medicines.

5. Orphan drugs.

Part IV: Advanced therapy drugs.

1. Gene therapy drugs (of human and xenogenic origin).

1.1 Diversity of gene therapy drugs.

1.2 Specific requirements for module 3.

2. Somatic cell therapy (human and xenogenic) drugs.

3. Specific requirements for gene therapy medicinal products and somatic cell therapy (human and xenogenic origin) in relation to modules 4 and 5.

3.1 Module 4.

3.2 Module 5.

3.2.1 Studies of human pharmacology and efficacy.

3.2.2 Security.

4. Specific statement on xenotransplantation medicinal products.

INTRODUCTION AND GENERAL PRINCIPLES

1. The data and documentation to accompany any application for a marketing authorisation in accordance with Section 1 of Chapter II of this Royal Decree shall be submitted in accordance with the requirements set out in this Annex, Following the guidelines published by the Commission in the European Union Rules on Medicinal Products, Volume 2 B, Explanatory note for applicants, Medicinal products for human use, presentation and content of the dossier, Common Technical Document (DTC).

2. The data and documents should be presented in five modules: module 1 collects the administrative data specific to the European Community; module 2 includes quality, clinical and non-clinical summaries; module 3 provides information on chemical, pharmaceutical and biological; module 4 collects non-clinical reports; and module 5 contains clinical study reports. This presentation applies a common format for all the regions of the International Conference on Harmonization (ICH): the European Union, the United States and Japan. The five modules mentioned above must be submitted strictly in accordance with the format, content and numbering system which are set out in detail in Volume 2 B of the abovementioned Explanatory Note for applicants.

3. The presentation of the European Union DTC is applicable to all types of application for marketing authorisation for any procedure that is applied (centralised, mutual or national recognition) and whether it is based on an application complete or abbreviated. It also applies to all product types, including New Chemical Entities (NEQs), radiopharmaceuticals, plasma derivatives, vaccines, herbal medicines, etc.

4. When setting up the application dossier for marketing authorisation, applicants shall also take into account the scientific guidelines on the quality, safety and efficacy of medicinal products for human use adopted by the Committee of medicinal products for human use and published by the European Medicines Agency (EMEA), as well as the other Community pharmaceutical guidelines published by the Commission in the various volumes of the Rules on medicinal products for human use European Union.

5. As regards the quality (chemical, pharmaceutical and biological) part of the dossier, all monographs, including the general chapters and monographs of the European Pharmacopoeia and the Spanish Royal Pharmacopoeia, are applicable.

6. The manufacturing process must comply with the requirements of Royal Decree 1564/1992 of 18 December 1992, for which the system of authorization of pharmaceutical laboratories and importers of medicinal products and the guarantee of quality is developed and regulated. of its industrial manufacturing and of the principles and guidelines for good manufacturing practice, published by the Commission in the European Union's Rules on Medicinal Products, Volume 4.

7. All relevant information for the assessment of the medicinal product concerned shall be included in the application, whether favourable or unfavourable to the product.

In particular, all relevant data should be provided on all evidence or any incomplete or abandoned pharmacotoxicological or clinical trials relating to the medicinal product and/or complete indications related to indications therapeutic not covered by the application.

8. All clinical trials carried out in the European Union shall comply with the requirements set out in Directive 2001 /20/EC of the European Parliament and of the Council on the approximation of laws, regulations and Member States ' administrative procedures for the application of good clinical practice in the conduct of clinical trials on medicinal products for human use and in Spain to Royal Decree 223/2004 of 6 February on the conduct of trials Medicines and medicines. In order to be taken into account during the assessment of an application, clinical trials conducted outside the European Union relating to medicinal products intended for use therein shall be designed, carried out and reported. concerning clinical practices and ethical principles, in accordance with principles equivalent to those set out in Royal Decree 223/2004 of 6 February. They must be carried out in accordance with the ethical principles set out in the Helsinki Declaration, for example.

9. Non-clinical (pharmacotoxicological) studies should be carried out in accordance with the provisions on good laboratory practice set out in Royal Decree 822/1993 of 28 May laying down the principles of good practice laboratory and its application in the conduct of non-clinical studies on chemicals, on inspection and verification of good laboratory practice.

10. Tests carried out on animals must be carried out in accordance with Royal Decree 1201/2005 of 10 October on the Protection of Animals Used for Experimentation and other Scientific Finances.

11. In order to monitor the benefit/risk assessment, any new information not listed in the original application and all pharmacovigilance data shall be submitted to the competent authority. Once the marketing authorisation has been granted, all amendments to the data in the dossier shall be submitted to the competent authorities in accordance with the requirements set out in Regulations (EC) No 1084/2003 and (EC) No 1084/2003. Commission Regulation (EC) No 1085/2003, as well as the requirements set out in Volume 9 of the Commission's publication of the rules on medicinal products in the European Union.

This annex is divided into four parts:

Part I sets out the format of the application, the summary of product characteristics, the labelling, the package leaflet and the requirements for the submission of standard applications (modules 1 to 5).

Part II sets out the exceptions to be applied to "specific requests", namely: sufficiently proven medical use, essentially similar medicinal products, fixed combination medicinal products, biological medicinal products similar, exceptional circumstances and mixed requests (part of the literature and part of own studies).

Part III addresses the "Specific requirements for marketing authorisation applications" for biological medicinal products (main plasma archive; main archive on vaccine antigens), radiopharmaceuticals, homeopathic medicines, herbal medicines and orphan medicines.

Part IV, dealing with 'advanced therapy medicinal products', addresses the specific requirements of gene therapy medicinal products (by means of an autologous or allogeneic system, or by xenogenic system) and medicinal products of cell therapy, both of human and animal origin, and medicinal products for xenogenic transplants.

PART I. REQUIREMENTS OF THE STANDARD MARKETING AUTHORISATION FILES

1. Module 1: Administrative information

1.1 Index. -An exhaustive index of modules 1 to 5 of the file submitted for requesting marketing authorization should be submitted.

1.2 Application form.-The medicinal product for which the application is submitted must be identified by name and the name of the active substance (s), together with its pharmaceutical form, route of administration, and final presentation, including the package.

The name and address of the applicant must be entered, as well as the name and address of the manufacturers and the places where the various stages of manufacture are carried out (including the manufacturer of the finished product and the manufacturer). manufacturer or manufacturers of the active substances) and, where appropriate, the name and address of the importer.

The requestor must identify the type of request and indicate, where appropriate, the samples it provides.

To be attached with the administrative data copies of the manufacturing authorization as defined in Article 18 of Royal Decree 1564/1992, together with a list of countries in which the authorization has been granted, copies of the summaries of product characteristics approved by the Member States and the list of countries in which the application was submitted.

As indicated in the application form, the applicants must, inter alia, provide detailed information on the medicinal product concerned, the legal basis for the application, the proposed holder of the application, marketing authorisation and the manufacturer or manufacturers, information on the legal status of orphan medicinal products, scientific advice and a paediatric development programme.

1.3 Summary of Product Characteristics, Labelling and Package Leaflet.

1.3.1 Technical document.-The applicant shall propose a technical information sheet or summary of the product characteristics, in accordance with Article 6.

1.3.2 Labelling and package leaflet.-The proposed labelling text for the immediate packaging and outer packaging, as well as the package leaflet, should be provided. They shall all comply with Chapter III and Annexes III, IV and V.

1.3.3 Machinery and samples. The applicant shall provide samples and/or models of the primary packaging and outer packaging, labels and leaflets of the relevant medicinal product.

1.3.4 Technical sheets already approved. -With the administrative data of the application form, copies of all technical data sheets of the product will be attached in accordance with Article 6 and a list of countries in which it has been submitted request.

1.4 Information about the experts. -According to Article 6.5.j), experts will be required to provide detailed reports of their findings on the documents and data constituting the authorization file placing on the market, in particular modules 3, 4 and 5 (chemical, pharmaceutical and biological documentation, non-clinical documentation and clinical documentation, respectively). Experts shall address the key points related to the quality of the medicinal product and the studies carried out on animals and human beings and to report all relevant data for the assessment.

These requirements must be met by providing a comprehensive summary of the quality, an overview of the non-clinical part (data extracted from animal studies) and an overview of the clinical part to be included in the Module 2 of the application dossier for the marketing authorisation. Module 1 will present a statement signed by the experts, along with a synthesis of their academic data, their training and their work experience. Experts shall have the appropriate technical or professional qualifications. The professional relationship between the expert and the applicant shall be declared.

1.5 Special requirements for different types of applications. -Part II of this Annex sets out the specific requirements for different types of applications.

1.6 Assessment of the risk to the environment.-Where appropriate, a general assessment of possible risks to the environment due to the use and/or use of the environment shall be included in the applications for marketing authorisation. the elimination of the medicinal product and proposals for labelling provisions to be made. The risks to the environment related to the release of medicinal products containing or consisting of genetically modified organisms (GMOs) in accordance with Law 9/2003 of 25 April, establishing the scheme, should be addressed. the legal basis for the contained use, voluntary release and placing on the market of genetically modified organisms and Royal Decree 178/2004 of 30 January approving the Regulation for the development and implementation of Law 9/2003.

The risk-related information for the environment shall be listed as an annex to Module 1.

The information shall be submitted in accordance with the provisions of the above provisions, taking into account all guidance documents published by the Commission on the implementation of that Directive.

The information will consist of the following elements:

an introduction;

a copy of all possible written consents to the deliberate release into the environment of GMOs for research and development purposes pursuant to Title II of Law 9/2003 of 25 April;

the information required in Annexes II to IV to Directive 2001 /18/EC, including methods of detection and identification and the unique identifier of GMOs, plus any additional information on GMOs or the product which is relevant for the assessment of the risk to the environment;

an environmental risk assessment report drawn up on the basis of the information specified in Annexes III and IV to Directive 2001 /18/EC and

accordance with Annex II to Directive 2001 /18/EC;

a conclusion in which the above information and the risk assessment for the environment are taken into account and an appropriate risk management strategy is proposed including, as far as GMOs and the product concerned are concerned. a plan to monitor the post-marketing phase and the determination of any special indication to be included in the summary of product characteristics, labelling or package leaflet;

appropriate measures to inform citizens.

The author's signature, the author's academic, training and work experience data and a statement of the relationship between the author and the applicant should be included.

2. Module 2: Summaries

The purpose of this module is to summarize the chemical, pharmaceutical and biological data and the non-clinical and clinical data presented in modules 3, 4 and 5 of the marketing authorisation dossier, and to provide the Reports and synthesis as described in Article 6.5.j.).

The decisive points must be addressed and analyzed. Objective summaries will be offered in which tables will be included. The reports shall be submitted to the tables or to the information contained in the main documentation presented in Module 3 (chemical, pharmaceutical and biological documentation), module 4 (non-clinical documentation) and module 5 (documentation). (clinical).

The information contained in Module 2 shall be submitted in accordance with the format, content and numbering system as defined in Volume 2 of the Explanatory Note for applicants. The summaries and summaries shall comply with the basic principles and requirements set out below:

2.1 General index. -Module 2 must include an index of the scientific documentation presented in modules 2 to 5.

2.2 Introduction.-The pharmacological class, mode of action and proposed clinical use of the medicinal product for which the marketing authorisation is requested should be indicated.

2.3 Overall Quality Summary-A comprehensive summary of quality will be presented, in which information related to chemical, pharmaceutical and biological data will be examined.

The emphasis should be on critical parameters and key issues in relation to quality aspects, as well as on the justification for cases where the relevant guidelines are not followed. This document will set out the general lines of the corresponding detailed data presented in Module 3.

2.4 Overview of the non-clinical part. -An integrated and critical assessment of the non-clinical evaluation of the drug in animals/in vitro should be presented. The discussion and justification of the test strategy and the deviation from the relevant guidelines shall be included.

Except for biological medicinal products, an assessment of impurities and degradation products, as well as their potential pharmacological and toxicological effects, should be included. The impact of any possible difference in chirality, the chemical form and the profile of impurities between the compound used in non-clinical studies and the product to be placed on the market should be discussed.

For biological medicinal products, the comparability of the material used in non-clinical studies, clinical studies and the medicinal product to be marketed will be evaluated.

A specific safety assessment of any new excipient should be performed.

The characteristics of the medicinal product demonstrated in the non-clinical studies will be defined and the impact of the conclusions on the safety of the medicinal product for the clinical use envisaged in the study will be discussed. human.

2.5 Overview of the clinical part. -The general view of the clinical part is to provide a critical analysis of the clinical data included in the clinical summary and module 5. The approach to the clinical development of the drug, including the design of the critical study, the decisions related to the studies and the performance of the studies, will be outlined.

A brief overview of the clinical conclusions will be provided, in which important limitations will be addressed and the risks and benefits will be assessed based on the findings of the clinical studies. The conclusions on efficacy and safety should be interpreted in order to justify the proposed dose and the indications and an assessment of how the product information sheet and others will optimise the benefits and address them. risks.

The issues relating to the effectiveness or security that arise in the development, as well as the outstanding issues of resolution, will be outlined.

2.6 Non-clinical summary.-The results of the pharmacology, pharmacokinetics and toxicology studies performed in animals/in vitro will be presented as written and tabulated objective summaries, which will be presented in the order next:

Introduction.

Written summary of pharmacology.

Tabulated summary of pharmacology.

Written summary of pharmacokinetics.

Tabulated summary of pharmacokinetics.

Written Toxicology Summary.

Toxicology tabulated summary.

2.7 Clinical Summary-A detailed objective summary of the clinical information concerning the medicinal product included in Module 5 will be provided. It will comprise the results of all biopharma studies, clinical pharmacology studies and clinical studies on efficacy and safety. A synopsis of each study should be presented.

The summary clinical information will be presented in the following order:

Summary of biopharmaceutical studies and related analytical methods.

Summary of Clinical Pharmacology Studies.

Clinical efficacy summary.

Clinical Safety Summary.

Synopsis of each study.

3. Module 3: Chemical, pharmaceutical and biological information for medicinal products containing chemical and/or biological active substances

3.1 Format and presentation. The general scheme of Module 3 is as follows:

Index.

Data set:

Active principle:

General information:

Nomenclature.

Structure.

General properties.

Manufacturing:

Manufacturer (s).

Description of the manufacturing process and the controls in progress.

Material control.

Control critical stages and intermediate products.

Validation and/or evaluation of the process.

Developing the manufacturing process.

Characterization:

Elucidation of the structure and other features.

Impurities.

Control of the active principle:

Specifications.

Analytical procedures.

Validation of analytical procedures.

Batch analysis.

Justification for the specifications.

Reference materials or standards.

Container closure system.

Stability:

Summary and conclusions on stability.

Stability protocol after authorization and stability commitment.

Stability data.

Product terminated:

Description and composition of the medication.

Pharmaceutical development:

Drug components:

Active principle.

Excipients.

Drug:

Development of the formulation.

Overdose.

Physical-chemical and biological properties.

Developing the manufacturing process.

Container closure system.

Microbiological attributes.

Compatibility.

Manufacturing:

Manufacturer (s).

Formula of the batch.

Description of the manufacturing process and process control systems.

Control of critical stages and intermediate products.

Validation and/or evaluation of the process.

Control of the excipients:

Specifications.

Analytical procedures.

Validation of analytical procedures.

Justification for the specifications.

Excipients of human or animal origin.

New excipients.

Control of finished product:

Specification (-ons).

Analytical procedures.

Validation of analytical procedures.

Batch analysis.

Characterization of impurities.

Justification for the specification (-ons).

Reference materials or standards.

Container closure system.

Stability:

Summary and conclusions on stability.

Stability protocol after authorization and stability commitment.

Stability data.

Attachments:

Facilities and equipment (only biological medicines).

Evaluation of security against foreign/foreign agents.

Excipients.

Supplementary information for the European Union:

The process validation scheme for the finished product.

Healthcare product.

Certificate (s) of suitability.

Medicines containing or using in the process of making material of animal and/or human origin (procedure for transmissible spongiform encephalopathies, TSEs).

bibliographic references.

3.2 Content-Basic Principles and Requirements.

1. The chemical, pharmaceutical and biological data to be provided shall include, in relation to the active substance (s) and the finished product, all relevant information about the development, the manufacturing process, the characterization and properties, quality control operations and requirements, as well as a description of the composition and presentation of the finished product.

2. Two main sets of data, respectively related to the active principle (s) and to the finished product, shall be submitted.

3. This module shall also provide detailed information on the starting materials and raw materials used during the manufacturing operations of the active substance (s) and the excipients incorporated in the product formulation finished.

4. All the procedures and methods used for the manufacture and control of the active substance and the finished product shall be described in sufficient detail to enable them to be reproduced in the tests carried out at the request of the competent authority. All tests shall be in line with the current state of scientific progress and shall be validated. The results of the validation studies shall be provided. In the case of test procedures included in the European Pharmacopoeia, this description shall be replaced by the reference for the monograph (s) and general chapter (s)

5. The monographs of the Spanish Royal Pharmacopoeia and the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in them.

However, where a material of the European Pharmacopoeia or the pharmacopoeia of a Member State has been prepared by a method capable of leaving impurities not controlled in the monograph of the pharmacopoeia, they must be declare such impurities and their maximum tolerance limits and an appropriate test procedure shall be described. In cases where a specification appearing in a monograph of the European Pharmacopoeia or in the pharmacopoeia of a Member State may be insufficient to ensure the quality of the substance, the competent authorities may request to the marketing authorisation holder more appropriate specifications. The competent authorities shall inform the authorities responsible for the pharmacopoeia concerned. The marketing authorisation holder shall provide the details of the alleged insufficiency and the additional specifications applied to the authorities responsible for that pharmacopoeia.

In the case of the analytical procedures included in the European Pharmacopoeia, this description may be replaced in each relevant paragraph by the detailed reference to the monograph (s) and chapter (s). general (s).

6. If the starting materials, raw materials, active substance (s) or excipient (s) are not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, compliance with the monograph of the pharmacopoeia of the a third country. In such cases, the applicant shall submit a copy of the monograph, accompanied by the validation of the analytical procedures contained in the monograph and by a translation, where appropriate.

7. Where the active substance and/or starting material, raw material or excipients are the subject of a monograph of the European Pharmacopoeia, the applicant may refer to a certificate of suitability, which, when issued by the European Pharmacopoeia European address for the quality of the medicinal product (EDQM) shall be presented in the appropriate paragraph of this Module. These certificates of suitability for the monograph of the European Pharmacopoeia shall be deemed to replace the relevant data in the relevant paragraphs described in this module. The manufacturer shall ensure in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of the Medicines.

8. For a well-defined active substance, the manufacturer or the applicant may provide that:

a) the description of the manufacturing process,

b) quality control during manufacturing, and

(c) validation of the process is provided in a separate document (closed part) addressed directly to the competent authorities by the manufacturer of the active substance, as a master file of the active substance.

In this case, however, the manufacturer must provide the applicant with all the data which may be necessary for the applicant to take responsibility for the medicinal product. The manufacturer shall undertake in writing in front of the applicant to ensure the homogeneity of the lots and not to modify the manufacturing process or specifications without having previously informed him.

Documents shall be submitted to the competent authorities in support of this request for amendment; such documents shall also be provided to the applicant when they relate to the open part of the master file.

9. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies (materials derived from ruminants): at each stage of the manufacturing process, the applicant shall demonstrate compliance with the materials used with the Explanatory Note on the Minimisation of the Risk of Transmission of Animal Spongiform Encephalopathy (s) through Medicines and their updates, published by the Commission in the Official Journal of the European Union.

The demonstration of compliance with the aforementioned Explanatory Note may be carried out by presenting, preferably, a certificate of suitability in relation to the relevant monograph of the European Pharmacopoeia issued by the European Directorate for the Quality of the Drug, or the scientific data to corroborate such compliance.

10. For foreign/foreign agents, information should be provided to assess the risk with regard to potential contamination by such agents, whether viral or non-viral, as set out in the guidelines. and in the relevant monograph and general chapter of the European Pharmacopoeia.

11. All equipment and special equipment that may be used at some stage of the manufacturing process and the control operations of the finished product shall be described with the necessary details.

12. Where appropriate and necessary, the EC mark required by Community legislation on medical devices shall be submitted.

Particular attention should be given to the following selected items.

3.2.1 Active principles or principles.

3.2.1.1 General information and information on starting materials and raw materials.

(a) Information shall be provided on the nomenclature of the active substance including the recommended international common name (INN), the name of the European Pharmacopoeia if applicable and the name (s) chemistry (s).

The structural formula, including relative and absolute stereochemistry, molecular formula and relative molecular mass, will be provided. In the case of biotechnological medicinal products, if appropriate, the schematic amino acid sequence and the relative molecular mass must be reported.

A list of physico-chemical properties and other relevant properties of the active substance, including biological activity in the case of biological drugs, will be presented.

(b) For the purposes of this Annex, starting materials shall mean all materials from which the active substance is manufactured or extracted.

In the case of biological medicinal products, starting materials shall mean any substance of biological origin, such as microorganisms, organs and tissues of plant or animal origin, cells or fluids (including blood and plasma) of human or animal origin and biotechnological cellular designs (cellular substrates, whether or not recombinant, including primary cells).

A biological medicine is a product whose active substance is biological.

A biological substance is one that is produced or extracted from a biological source and that requires, for characterization and determination of its quality, a combination of physico-chemical and biological assays together with the production process and its control.

Biological medicinal products: immunological medicinal products and medicinal products derived from human blood or plasma; medicinal products falling within the scope of paragraph 1 of the Annex to the Regulation (EC) No 726/2004; advanced therapy medicinal products as defined in Part IV of this Annex.

Any other substance used for the manufacture or extraction of the active substance (s), but not directly derived from the active substance, such as reagents, culture media, fetal calf serum, Additives and buffer solutions used for chromatography, etc., are considered as raw materials.

3.2.1.2 Process of manufacturing the active principle or principle.

(a) The description of the manufacturing process of the active substance represents the applicant's commitment to the manufacture of the active substance. In order to adequately describe the manufacturing process and the controls in process, the appropriate information set out in the guidelines published by the European Medicines Agency shall be provided.

(b) A list of all the materials necessary to manufacture the active substance (s) shall be presented, identifying where each material is used. Information on the quality and control of such materials shall be provided. Information shall also be provided to demonstrate that the materials meet the appropriate standards for their intended use.

A relationship of raw materials will be presented and their quality and control procedures will also be documented.

The name, address and responsibility of each manufacturer, including its contractors, and each production site or proposed facility dedicated to manufacturing and control shall be provided.

c) For biological medicinal products the following additional requirements shall apply.

The origin and history of the starting materials will be described and documented.

With regard to specific measures for the prevention of the transmission of animal spongiform encephalopathies, the applicant shall demonstrate that the active substance complies with the provisions of the Explanatory Note on Minimisation. the Risk of Transmission of the Agents of Animal Spongiform Encephalopathy through Medicines and their updates, published by the Commission in the Official Journal of the European Union.

When cell banks are used, it must be demonstrated that the characteristics of the cells have remained unchanged in the steps used for production and subsequently.

Seed materials, cell banks, mixtures of unmanufactured serum or plasma and other materials of biological origin, as well as, where possible, the materials obtained from them, must be subjected to tests to check that they are free from foreign/external agents.

When the presence of potentially pathogenic foreign/external agents is unavoidable, the corresponding material should be used if a subsequent treatment ensures its removal and/or inactivation, and this must be validated.

Whenever possible, the production of vaccines should be based on a system of seed lots and established cell banks. In the case of bacterial and viral vaccines, the characteristics of the infectious agent must be demonstrated in the sowing materials. In addition, for live vaccines, the stability of the attenuation characteristics must be demonstrated in the seed material, if this test is not sufficient, the attenuation characteristics must also be demonstrated at the stage of the production.

In the case of medicinal products derived from human blood or human plasma, the origin and criteria for collection, transport and transport shall be described and documented in accordance with Part III of this Annex. preservation of the starting materials.

The manufacturing facilities and equipment will be described.

(d) the tests and acceptance criteria carried out at each of the critical stages, information on the quality and control of the intermediate products, as well as on the validation of the intermediate products, should be provided, where appropriate. process and/or assessment studies.

e) If the presence of potentially pathogenic foreign/external agents is unavoidable, the corresponding material should be used only if a subsequent treatment ensures its removal and/or inactivation, and this must be validated in the section where the assessment of viral safety is addressed.

f) A description and discussion of the significant changes introduced in the manufacturing process during the development and/or manufacturing site of the active substance shall be provided.

3.2.1.3 Characterisation of the active substance or principle. -Data should be submitted showing the structure and other characteristics of the active principle (s). Confirmation of the structure of the the active substance (s) from some physicochemical and/or immuno-chemical and/or biological method, as well as information on impurities.

3.2.1.4 Control of the active principle (s).-Detailed information on the specifications used for the routine controls of the active principle (s), the justification for the choice of such specifications, methods of analysis and their validation.

The results of the control in batches manufactured during development will be presented.

3.2.1.5 Standards or reference materials. -Standards and reference preparations will be identified and described in detail. Where relevant, chemical and biological reference material of the European Pharmacopoeia shall be used.

3.2.1.6 Envase and system for closing the active substance. -The description of the package and the system or systems of closure and their specifications shall be presented.

3.2.1.7 Stability of the active principle (s).

a) The types of studies performed, the protocols used and the results of the studies should be summarized.

(b) Detailed results of the stability studies, including information on the analytical procedures for obtaining such data, as well as the validation of these data, shall be presented in the appropriate format. procedures.

(c) The stability protocol shall be provided after the authorisation and the stability commitment.

3.2.2 Product terminated.

3.2.2.1 Description and composition of the finished product.-The finished product and its composition should be described. The information shall include the description of the pharmaceutical form and its composition with all the components of the finished product, the quantity of the products per unit and the function:

From the active beginning (s).

Component (s) of the excipients, whatever their nature or the quantity used, including the colorants, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, flavor correctors, flavourings, etc.

The components of the outer cover of the medicinal products (hard capsules, soft capsules, suppositories, coated tablets, film-coated tablets, etc.) to be ingested or administered to the patient otherwise.

These aspects should be completed with any other relevant data relating to the type of packaging and, if appropriate, its closure system, together with details of the devices to be used for the administration of the packaging. medication and will be supplied with it.

The "usual terminology", to be used in the description of the components of the medicine, should be:

In the case of products listed in the European Pharmacopoeia or, failing that, in the national pharmacopoeia of a Member State, the main name collected in the heading of the corresponding monograph with reference the pharmacopoeia in question;

for the other products, the international common name recommended by the World Health Organization or, failing that, the exact scientific name; substances lacking in the international common name or the exact scientific name shall be described by declaring to its origin and method of obtaining, by supplementing this data with any other relevant detail, if necessary;

with regard to colouring matters, the designation by the code 'E' which is attributed to them in Royal Decree 2001/1995 of 7 December 1995 approving the positive list of colouring additives authorised for use in the Manufacture of foodstuffs as well as their conditions of use.

To provide the "quantitative composition" of the active substances of the medicinal product, it is necessary, in the pharmaceutical form, to specify the mass or number of units of biological activity either per dose or per unit. of mass or volume, of each active principle.

Active substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass and, if necessary or relevant, by the mass of the active fractions of the molecule.

In the case of medicinal products containing an active substance the authorisation of which has been requested in any Member State for the first time, the quantitative declaration of an active substance which is a salt or hydrate systematically express in terms of the mass of the active fragments of the molecule. All subsequent authorisations for medicinal products in the Member States shall have their qualitative composition expressed in the same way for the same active substance.

The units of biological activity will be used in substances that cannot be defined in molecular terms. When the World Health Organization has defined a unit of biological activity, it is the one to be used. In cases where an international unit has not been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substance, using, where appropriate, the units of the European Pharmacopoeia.

3.2.2.2 Pharmaceutical development.-This chapter will be devoted to information on development studies to establish that the pharmaceutical form, formulation, manufacturing process, closure system the microbiological attributes and the instructions for use are appropriate for the intended use specified in the marketing authorisation application dossier.

The studies described in this chapter are different from the tests of routine controls performed according to the specifications. The critical parameters of the formulation and the attributes of the process that may influence the reproducibility of the batch, the efficacy of the medicinal product and its quality shall be determined and described. Additional support data shall, where appropriate, refer to the relevant chapters of Module 4 (Reporting of non-clinical studies) and Module 5 (Reporting of clinical studies) of the marketing authorisation application dossier.

(a) The compatibility of the active substance with the excipients should be documented, as well as the key physical-chemical characteristics of the active substance that may influence the efficacy of the finished product or the compatibility of the of the different active substances with each other in the case of the products in which they are combined.

(b) The choice of the excipients shall be documented, in particular in relation to their respective functions and concentration.

c) The development of the finished product shall be described, taking into account the proposed route of administration and use.

d) Any overdosage in the formulation (s) should be justified.

e) As far as physical-chemical and biological properties are concerned, all parameters concerning the performance of the finished product shall be processed and documented.

f) The selection and optimization of the manufacturing process, as well as the differences between the manufacturing process (s) used to produce pivotal clinical batches and the process used for manufacturing the manufacturing process, will be presented. proposed finished product.

g) The suitability of the packaging and the closure system used for the storage, transport and use of the finished product shall be documented. Consideration may be given to the potential interaction between the medicinal product and the package.

(h) The microbiological attributes of the pharmaceutical form in relation to non-sterile and sterile products must comply with the requirements of the European Pharmacopoeia and be documented in accordance with this.

i) In order to provide useful and appropriate information for the labelling, the compatibility of the finished product with reconstitution diluents and administration devices shall be documented.

3.2.2.3 Process of manufacturing the finished product.

(a) The description of the manufacturing method to accompany the application for authorisation shall be drawn up in such a way as to give a clear picture of the nature of the operations carried out.

For this purpose, that description must include at least:

Reference to the different stages of the manufacturing process, including the process control systems and the corresponding acceptance criteria, so that the processes used in the production of the process can be evaluated. Pharmaceutical form may result in an adverse change in the components;

in case of serial manufacturing, complete information on precautions taken to ensure the homogeneity of the finished product;

experimental validation studies of the manufacturing process when using a non-standard manufacturing method or when it is critical to the product;

in the case of sterile drugs, details of the sterilization and/or aseptic processes used;

the detailed formula for the batch.

The name, address and liability of each manufacturer, including its contractors, and each production site or proposed facility dedicated to manufacturing and testing shall be submitted.

(b) Data relating to product control tests which may be carried out at an intermediate stage of the manufacturing process shall be included in order to ensure consistency of production.

These tests are essential to check the conformity of the medicinal product with the formula when, exceptionally, the applicant proposes an analytical method for analysing the finished product which does not include the determination of all active substances (or all components of the excipient subject to the same requirements as the active substances).

The above will also apply when the quality control of the finished product depends on the controls in process, especially in the case that the medicinal product is primarily defined by its preparation process.

c) A description, documentation and results of the validation studies shall be presented for the critical stages or tests used in the manufacturing process.

3.2.2.4 Control of the excipients.

a) A relationship of all the materials necessary to manufacture the excipient (s) will be presented, identifying when each material is employed in the process. Information on the quality and control of such materials shall be provided. Information shall also be provided to demonstrate that the materials meet the appropriate standards for their intended use.

In all cases, the colours must meet the requirements set out in Royal Decree 2001/1995 of 7 December 1995. In addition, the colours must comply with the purity criteria set out in Royal Decree 2107/1996 of 20 September 1996 laying down the rules for the identity and purity of the colours used in foodstuffs.

b) The specifications of each excipient should be detailed, as well as their justification.

The analytical procedures shall be appropriately described and validated.

c) Specific attention shall be given to excipients of human or animal origin.

With regard to specific measures concerning the prevention of the transmission of animal spongiform encephalopathies, the applicant must also demonstrate that the medicinal product is manufactured in accordance with the Explanatory Note on Minimisation of the Risk of Transmission of Animal Spongiform Encephalopathy Agents through Medicines and their updates, published by the Commission in the Official Journal of the European Union.

In order to demonstrate compliance with the aforementioned Explanatory Note, a certificate of suitability with the monograph on Transmissible Spongiform Encephalopathies of the Pharmacopoeia may be presented, preferably European, or the scientific data that corroborates such compliance.

d) New excipients.

For the excipients used for the first time in a medicinal product or for a new route of administration, they shall be submitted in accordance with the format of the active substance previously described in all manufacturing, characterization and controls, cross-referencing safety-related support data, both clinical and non-clinical.

A document will be presented containing detailed information of a chemical, pharmaceutical and biological nature. Such information shall be submitted in the same order as the chapter dedicated to the active substance (s) in module 3.

New excipients information may be presented as a separate document in the format described in the preceding paragraphs. Where the applicant is not the manufacturer of the new excipient, the separate document shall be made available to the applicant for submission to the competent authority.

Additional information on toxicity studies with the novel excipient will be provided in Module 4 of the dossier.

In module 5, clinical studies will be presented.

3.2.2.5 Control of the finished product. For the purposes of control of the finished product, a batch of a medicinal product shall mean an entity comprising all the units of a pharmaceutical form which come from the same quantity. initial material and have undergone the same series of manufacturing and sterilisation operations or, in the case of a continuous production process, all units manufactured within a given time span.

Unless justified, the maximum tolerable deviation of the content of the active substance in the finished product shall not exceed ± 5% at the time of manufacture.

Detailed information on the specifications, the justification (release and validity period) of their choice, the methods of analysis and their validation shall be provided.

3.2.2.6 Standards or reference materials.-The standards and reference materials used to test the finished product shall be determined and described in detail if they have not been submitted previously in the item relative to the active principle.

3.2.2.7 Envase and closure of finished product.-The description of the packaging and the system or systems of closure, including the identity of each primary packaging material and its specifications, shall be delivered. The specifications shall include the description and identification. Methods not collected in the pharmacopoeia (with validation) shall be included, where appropriate.

For non-functional exterior conditioning materials only a brief description will be provided. Additional information will be provided for the functional outer packaging materials.

3.2.2.8 Stability of the finished product.

a) The types of studies performed, the protocols used and the results of the studies should be summarized.

(b) The detailed results of the stability studies, including information on the analysis procedures followed to obtain the data, as well as the validation of the data, shall be presented in the appropriate format. such procedures; for vaccines, information on cumulative stability shall be provided in cases where it is relevant.

(c) The stability protocol shall be provided after the approval and the stability commitment.

4. Module 4: Non-clinical reports

4.1 Format and presentation. The general scheme of module 4 is as follows:

Index.

Studies reports.

Pharmacology:

Primary Pharmacodynamics.

Secondary Pharmacodynamics.

Safety Pharmacology.

Pharmacodynamic interactions.

Pharmacokinetics:

Analytical methods and validation reports.

Absorption.

Distribution.

Metabolism.

Excretion.

pharmacokinetic (non-clinical) interactions.

Other pharmacokinetic studies.

Toxicology:

Toxicity by single dose.

Repeated administration toxicity.

Genotoxicity.

In vitro.

In vivo (including toxicocytic support assessments).

Carcinogenesis:

Long-term studies.

Studies in the short or medium term.

Other studies.

Reproductive and developmental toxicity:

Fertility and initial embryonic development.

Embryonic and fetal development.

prenatal and postnatal development.

Studies in which doses are given to the offspring (young animals) and/or are subsequently evaluated.

Local Tolerance.

Other studies on toxicity:

Antigenicity.

Immunotoxicity.

mechanistic studies.

Dependency.

Metabolites.

Impurities.

Other.

bibliographic references.

4.2 Content: Principles and Basic Requirements. -Special attention should be given to the following selected elements:

1. The toxicological and pharmacological tests shall show the following:

(a) the potential toxicity of the product and the dangerous or undesirable effects that may occur in humans under the proposed conditions of use, assessing these effects according to the pathological process of treat;

b) their pharmacological properties, in relation to the dosage and pharmacological activity with the use indicated in human beings. All results must be reliable and of general application. To the extent that it is appropriate, mathematical and statistical procedures will be used for the elaboration of the experimental methods and the assessment of the results.

In addition, it will be necessary to inform clinicians about the therapeutic and toxicological potential of the product.

2. In the case of biological medicinal products such as immunological medicinal products and medicinal products derived from human blood or plasma, it may be necessary to adapt the requirements of this module for certain products; for this reason, the the applicant shall justify the programme of the tests.

When setting the test schedule, the following points should be taken into account:

All tests requiring repeated administration of the product shall be designed to take into account the possible induction of antibodies and interference by these; a study of the function should be provided. reproductive, foetal and perinatal toxicity, mutagenic potential as well as carcinogenic potential. Where the effects are attributable to components other than the active substance or principle, the study may be replaced by the validation of the removal of those components.

3. The toxicology and pharmacokinetics of an excipient to be used for the first time in the pharmaceutical field should be investigated.

4. When significant degradation is possible during the storage of the medicinal product, the toxicology of the degradation products shall be taken into account.

4.2.1 Pharmacology. The pharmacology study should be carried out following two different approaches:

First, actions related to the proposed therapeutic use should be adequately studied and described. Recognised and validated tests shall be carried out whenever possible, both in vivo and in vitro. Novel experimental techniques shall be described in a sufficiently detailed manner to enable them to reproduce. The results will be expressed in quantitative terms, using, for example, dose-effect and time-effect curves, etc. As far as possible, comparisons shall be made with the data for a substance or substances with a similar therapeutic action.

Secondly, the applicant should investigate the potential unintended pharmacodynamic effects of the substance in the physiological functions. Such research shall be carried out at exposures corresponding to and above the intended therapeutic range. Experimental techniques, unless they are the usual techniques, shall be described in such a way as to enable them to be reproduced, and the investigator must prove their validity. Any indication of modification of the responses resulting from the repeated administration of the substance shall be considered.

With regard to the pharmacodynamic interaction of medicinal products, the testing of combinations of active substances may be justified either by pharmacological needs or by clinical indications. In the first case, the pharmacodynamic study should highlight those interactions that make the combination for clinical use recommended. In the second case, where clinical experimentation is intended to scientifically justify the combination of substances, the investigation shall determine whether the expected effects of the combination can be demonstrated in animals and at least the the importance of adverse reactions.

4.2.2 Pharmacokinetics-The pharmacokinetics of the study of the whole process of the active substance and its metabolites in the body. It comprises the study of absorption, distribution, metabolism (biotransformation) and excretion of substances.

The study of these different phases can be carried out mainly with physical, chemical or biological methods, and by observing the actual pharmacodynamic activity of the substance itself.

The data concerning the distribution and disposal will be necessary in all cases where such data are indispensable for determining the doses administered to human beings, as well as in the chemotherapeutic agents (antibiotics, etc.) and in substances the use of which is based on non-pharmacodynamic effects (e.g. numerous diagnostic agents, etc.).

In vitro studies may also be performed, with the advantage of using human material for comparison with animal material (i.e., protein fixation, metabolism, drug interaction).

The pharmacokinetic study of all pharmacologically active substances is necessary. In the case of new combinations of known substances which have been studied in accordance with the provisions of this royal decree, it will not be necessary to require pharmacokinetic investigations if the toxicity tests and the clinical experimentation justify their omission.

The pharmacokinetic program will be developed in such a way that comparison and extrapolation between animals and human beings are possible.

4.2.3 Toxicology.

(a) Single-dose toxicity-A single dose toxicity test is a qualitative and quantitative study of toxic reactions which may result from a single administration of the active substance or principle contained in the the medicine, in the proportions and in the physical-chemical state in which they are present in the product.

The single dose toxicity test may be performed in accordance with the relevant guidance published by the European Medicines Agency.

(b) Toxicity by continuous administration. -Continuous administration toxicity tests shall be aimed at revealing the functional and/or anatomical-pathological alterations subsequent to repeated administration of the principle. the active substance or combination of active substances in question and to establish how these alterations are related to the dosage.

It is generally advisable to perform two tests: one in the short term, for two to four weeks, and the other for the long term. The duration of the second test will depend on the conditions of the clinical use. Its purpose is to describe the possible harmful effects, to which attention should be paid in clinical studies. The duration is defined in the corresponding guidelines published by the European Medicines Agency.

(c) Genotoxicity. -The object of the study of the mutagenic and clastogenic potential is to reveal the alterations that a substance can cause in the genetic material of people and cells. Mutagenic substances may pose a risk to health, as exposure to mutagenic poses the risk of inducing a germ mutation, with the possibility of hereditary disorders, and the risk of somatic mutations, which may even be may be a cause of cancer. Such a study shall be mandatory for any new substance.

(d) Carcinogenesis.-Testing aimed at revealing carcinogenic effects is usually required:

1. These studies shall be carried out with all medicinal products for which clinical use is provided for a prolonged period of the patient's life, either on an ongoing basis or on a repeated and intermittent basis.

2. Studies on certain medicinal products are recommended if they are thought to represent a carcinogenic potential, for example by reference to a product of the same class or structure, or as a result of tests obtained from studies of continuous administration toxicity.

3. Studies with unequivocally genotoxic components are not necessary as they are assumed to be carcinogenic that affect different species and pose a risk to the human being. If a drug of this type is intended to be administered in a chronic manner to humans, a chronic study may be necessary to detect early tumorigenic effects.

(e) Toxicity in reproduction and development. -Research on possible alterations in the male or female reproductive function, as well as the harmful effects for the offspring, must be carried out by means of relevant evidence.

These include studies on the impact on the male and female reproductive function, on toxic and teratogenic effects at all stages of development from conception to sexual maturity, as well as on latent effects, when the product under investigation has been administered to the woman during pregnancy.

The omission of such tests should be adequately justified.

Depending on the indicated use of the medicinal product, additional studies on the development of the offspring may be justified when the medicinal product is administered.

Embryonic and fetal toxicity studies will normally be conducted with two species of mammals, one of which should not be a rodent. Perinatal and postnatal studies shall be carried out with at least one species. If the metabolism of a drug in a given species is known to be similar to that of man, it is desirable to include this species. It is also desirable that one of the species be the same as that of the toxicity studies by continuous administration.

The conception of the study will be determined taking into account the state of scientific knowledge at the time the application is submitted.

f) Local Tolerance-The goal of local tolerance studies is to determine whether the drugs (both active substances and excipients) are tolerated in the places of the body that may come into contact with the medication as a result of your administration during clinical use. The test procedure should be such that any mechanical effect of the administration, or the purely physico-chemical actions of the product, can be distinguished from toxicological or pharmacodynamic effects.

Tests on local tolerance should be performed with the preparation being developed for human use, using the vehicle and/or the excipients in the treatment of the group or control groups. If necessary, positive checks and reference substances shall be included.

The conception of local tolerance tests (choice of species, duration, frequency and route of administration, dosage) will depend on the problem to be investigated and the proposed conditions of administration in the clinical use.

The reversibility of local injuries should be performed when relevant.

Animal studies may be replaced by validated in vitro tests, provided that the results of the tests are of similar quality and utility for the purposes of the safety assessment.

In the case of chemical substances applied to the skin (e.g., dermal, rectal, vaginal) the awareness potential at least in one of the currently available test systems will be assessed (study with guinea pigs). or local lymph node test.

5. Module 5: Clinical studies reports

5.1 Format and presentation. The general scheme of module 5 is as follows:

Index of clinical studies reports.

List in the form of a table of all clinical studies.

Reports from clinical studies.

Reports of biopharmaceutical studies.

Reports of bioavailability studies.

Reports of comparative bioavailability and bioequivalence studies.

Reports of in vitro-in vivo correlation studies.

Bioanalytical and analytical methods reports.

Reports of studies on pharmacokinetics by human biomaterials.

Reports of plasma protein fixation studies.

Reports of studies on hepatic metabolism and interaction.

Reports of studies using other human biomaterials.

Reports of human pharmacokinetic studies.

Reports of pharmacokinetic studies and initial tolerance in healthy subjects.

Reports of pharmacokinetic studies and initial tolerance in patients.

Intrinsic factor pharmacokinetic studies reports.

Extrinsic factor pharmacokinetic studies reports.

Reports of pharmacokinetic studies in the population.

Reports of studies of human pharmacodynamics.

Reports of pharmacodynamic and pharmacokinetic/pharmacodynamic studies in healthy subjects.

Reports of pharmacodynamic and pharmacokinetic/pharmacodynamic studies in patients.

Reports of studies on efficacy and safety.

Reports of controlled clinical studies regarding the stated indication.

Reports of uncontrolled clinical studies.

Data analysis reports from various studies, including any meta-analysis, bridging analyses, and formal integrated analysis.

Other study reports.

Post-marketing experience reports.

bibliographic references.

5.2 Content: Principles and Basic Requirements. -Particular attention should be paid to the following selected items.

(a) Clinical data to be supplied in compliance with the provisions of Article 6.5.j) must be allowed to form a sufficiently well-founded and scientifically valid opinion as to whether the specialty responds to the criteria for the granting of the marketing authorisation. For this reason, it is mandatory to communicate the results of all clinical trials that have been conducted, both favorable and unfavorable.

(b) Clinical trials shall always be preceded by the necessary pharmacological and toxicological tests on animals carried out in accordance with the provisions of Module 4 of this Annex. The investigator shall be aware of the conclusions of the pharmacological and toxicological tests and therefore the applicant shall provide at least the investigator's manual, which shall consist of all relevant information known before the initiation of a clinical trial, including chemical, pharmaceutical and biological data, toxicological, pharmacokinetic and pharmacodynamic data in animals, as well as the results of previous clinical trials, with useful data to justify the nature, scale and duration of the proposed test; at the request of the investigator must provide complete pharmacological and toxicological reports. In the case of materials of human or animal origin, all means available prior to the start of the test shall be used to ensure that infectious agents are not transmitted.

(c) Marketing Authorisation Holders shall take the necessary steps to ensure that documents from the essential clinical trials (including data collection forms) other than the medical file of the subject to be guarded by data owners:

For a minimum of 15 years after the completion or interruption of the test, or

for a minimum of two years after the granting of the last marketing authorisation in the European Union and in cases where there are no pending or planned marketing applications in the European Union, or

for a minimum of two years following the official interruption of clinical development of the product under investigation.

The medical file of the subject shall be kept in accordance with the applicable regulations and in accordance with the maximum period permitted by the hospital, institution or private consultation.

However, documents may be retained for a longer period, if required by applicable regulatory provisions or the agreement with the sponsor.

It will be up to the promoter to report to the hospital, institution or private consultation about the time when they will not need to continue to keep these documents.

The sponsor or the owner of the data shall retain all remaining documentation relating to the test during the period of validity of the medicinal product.

Such documentation shall include: the protocol, including the justification, the objectives, the statistical design and the methodology of the test, with the conditions under which it is carried out and managed, as well as the details of the research medicinal product, the reference medicine and/or the placebo used; the standard working procedures; all written reports on the protocol and procedures; the investigator's manual; the collection log of each subject's data; the final report; the audit certificate (s), when have the (them). The sponsor or the subsequent owner shall keep the final report until after five years after the expiry of the period of validity of the medicinal product.

In addition to the tests carried out within the European Union, the marketing authorisation holder shall take all additional measures for the documentation file in accordance with the provisions of the Directive. 2001 /20/EC and in Spain Royal Decree 223/2004 of 6 February and in detailed guidelines for implementation.

Any changes to the ownership of the data must be documented.

All data and documents shall be made available to the competent authorities if they so request.

(d) The data on each clinical trial shall be sufficiently detailed to permit an objective judgment, and shall contain in particular:

The protocol, including the justification, the objectives, the statistical design and the methodology of the test, with the conditions under which it is carried out and managed, as well as the details of the medicinal product under consideration employ;

the audit certificate (s), when the (them) are available;

the list of investigators; each investigator shall indicate his name, address, position, degree and clinical obligations, record where the test was conducted and gather the information relating to each of the patients, including the data collection forms for each subject;

the final report, signed by the investigator and for multicenter trials by all researchers or by the investigator responsible for coordination.

e) The above data on clinical trials shall be forwarded to the competent authorities. However, the applicant may omit part of this information with the consent of those authorities. Upon request, you must send the complete documentation without delay.

The investigator shall, in the conclusions of the experiment, decide on the safety of the product under the normal conditions of use, its tolerance and its effectiveness, providing all the necessary details. useful for indications and contraindications, the dosage and the average duration of treatment, as well as, if necessary, particular precautions for use and clinical signs of dosing. When reporting on the results of a multicenter study, the principal investigator shall, in his conclusions, express his opinion on the safety and efficacy of the medicinal product which is the subject of the study on behalf of all centres.

f) Clinical observations of each test shall be summarized, indicating:

1) The number of subjects treated, distributed by sex;

2) the selection and age distribution of the groups of patients who are the subject of research and comparative testing;

3) the number of patients who have been prematurely removed from trials, as well as the reasons for this;

4) in the event that controlled trials have been carried out in accordance with the above, if the control group:

You have not been treated,

received a placebo,

has received another known effect medication,

you have received a non-medication treatment;

5) the frequency of adverse reactions observed;

6) all details on patients who have a special sensitivity (elderly, children, pregnant or menstruating women) or whose physiological or pathological condition requires special consideration;

7) parameters or criteria to evaluate effectiveness, as well as the results regarding these parameters;

8) a statistical evaluation of the results, to the extent required by the design of the trials and the variables involved.

g) In addition, the investigator should in any case point out his observations on:

1) Any indication of habituation, addiction or difficulty in patients who stop taking the medication;

2) interactions observed with other medicinal products to be administered simultaneously;

3) the criteria according to which certain patients were excluded from the trials;

4) any death that occurred during the test or during the monitoring period.

(h) Data relating to a new combination of medicinal substances must be identical to those required for new medicinal products, and must justify the safety and efficacy of the combination.

i) It is mandatory to justify partial or total absence of data. If unexpected results occur during the trials, additional pre-clinical, toxicological and pharmacological tests shall be carried out and documented.

It will be necessary to provide data on any modification of the pharmacological action following repeated administration, as well as on the determination of long-term dosing.

5.2.1 Reports of biopharmaceutical studies. -Reports of bioavailability studies, comparative bioavailability, bioequivalence, in vitro-in vivo correlation and bioanalytical and analytical methods should be reported.

In addition, the bioavailability should be evaluated where necessary to demonstrate the bioequivalence of the medicinal products referred to in Articles 7, 8 and 9.

5.2.2 Reports of studies on pharmacokinetics by human biomaterials. For the purposes of this Annex, human biomaterials shall mean all proteins, cells, tissues and related materials of human origin that are use in vivo or ex vivo to evaluate the pharmacokinetic properties of medicinal substances.

In this respect, reports of plasma protein fixation studies, studies of hepatic metabolism, and interaction of active substances and studies using other human biomaterials will be delivered.

5.2.3 Reports of Human Pharmacokinetic Studies.

a) The following pharmacokinetic characteristics are described:

Absorption (speed and magnitude),

distribution,

metabolism,

excretion.

The significant aspects from the clinical point of view should be described, including the involvement of the kinetic data for the dosing regimen, especially for patients at risk, and the differences between the man and the animal species used in the pre-clinical studies.

In addition to the normal multiple sample pharmacokinetic studies, population pharmacokinetic analyses based on a dispersed sampling during clinical studies may also address the issues related to the contribution of intrinsic and extrinsic factors to the variability of the pharmacokinetic dose-response relationship.

Reports of pharmacokinetic studies and initial tolerance in healthy subjects and in patients, reports of pharmacokinetic studies to assess the impact of intrinsic and extrinsic factors and reports will be delivered Population pharmacokinetic studies.

(b) When the medicinal product is to be administered on a regular basis simultaneously with other medicinal products, data should be provided on the co-administration tests carried out to demonstrate possible modifications of the medicinal product. pharmacological action.

The pharmacokinetic interactions between the active substances and other medicinal products or substances will be investigated.

5.2.4 Reports of Human Pharmacodynamics Studies.

a) The pharmacodynamic action correlated with efficacy should be demonstrated, including:

The dose-response relationship and its temporary course,

the justification for the dosage and the conditions of administration,

when possible, the mode of action.

The pharmacodynamic action not related to efficacy will be described.

The demonstration of pharmacodynamic effects in humans will not be sufficient for itself to establish conclusions as to a possible therapeutic effect.

(b) When the medicinal product is to be administered on a regular basis simultaneously with other medicinal products, data should be provided on the co-administration tests carried out to demonstrate possible modifications of the medicinal product. pharmacological action.

Pharmacodynamic interactions between active substances and other drugs or substances will be investigated.

5.2.5 Reporting on efficacy and safety studies.

5.2.5.1 Reports of controlled clinical studies regarding the stated indication. -In general, clinical trials will be conducted in the form of controlled clinical trials wherever possible, randomized and, as appropriate, in comparison with a placebo and a known medicinal product, the therapeutic value of which is well established; any other design must be justified. The treatment assigned to the control group will vary according to the cases and will also depend on ethical and therapeutic considerations. In this sense, it may sometimes be more convenient to compare the effectiveness of a new drug with the effect of a known drug, whose therapeutic value is well established, and not with the effect of a placebo.

1. As far as possible, and especially in trials where the effect of the product cannot be objectively measured, measures shall be taken to avoid bias, including methods of randomisation and blind (double-blind) methods.

2. The test protocol shall include a detailed description of the statistical methods to be used, the number of patients and the reasons for which (with the calculation of the statistical value of the test), the level of significance to be used and a description of the statistical unit. The measures to be taken to avoid bias, in particular the methods of randomisation, should be documented. The inclusion of a large number of patients in the course of a trial should in no case be considered as the valid substitute for a well-executed controlled trial.

Safety data should be examined taking into account the guidelines published by the Commission, paying particular attention to facts that result in the alteration of the dose or the need for medication. concomitant, serious harmful events, events leading to withdrawal and deaths. All patients or groups that are at greatest risk should be determined and particular attention should be paid to potentially vulnerable patients who may be unnumerous, e.g. children, pregnant women, sensitive elderly people, people with strong metabolism or excretion abnormalities, etc. The impact of the safety assessment for potential jobs of the medicinal product shall be described.

5.2.5.2 Reports of uncontrolled clinical studies, data analysis reports obtained in various studies and other reports from clinical studies. -All these reports should be provided.

5.2.6 Post-marketing experience reports.-If the medicinal product is already authorised in third countries, information on adverse reactions to the medicinal product in question and medicinal products should be provided. contain the same active substances, if possible in relation to the rate of use.

5.2.7 Data collection and patient listings. -When presenting the data collection notebooks and patient lists in accordance with the relevant guidelines published by the European Medicines Agency, they must be provided and presented in the same order as the clinical study reports and be indexed by study.

PART II. MARKETING AUTHORISATION FILES AND SPECIFIC REQUIREMENTS

Some medicinal products have specific characteristics which make it necessary to adapt all the requirements of the application dossier for the marketing authorisation set out in Part I of this Annex. In order to take into account these special situations, applicants shall use an appropriate and appropriate presentation of the dossier.

1. Bibliographic applications. -The specific rules set out below shall apply to medicinal products whose active principle (s) have, as referred to in Article 10, a "clearly established medicinal use" (or sufficiently checked), with a recognized efficacy and an acceptable level of safety.

The applicant shall submit modules 1, 2 and 3 as described in Part I of this Annex.

For modules 4 and 5, clinical and non-clinical features should be addressed through a detailed scientific literature.

The following specific rules will apply to demonstrate the existence of sufficiently proven medical use:

(a) The factors to be taken into account in determining a sufficiently proven medical use of the components of the medicinal product are as follows:

The period during which a substance was used,

the quantitative aspects of employment of the same,

the degree of scientific interest in its use (which is reflected in the published scientific literature),

the consistency of scientific assessments.

Therefore, different time periods may be required in order to establish the sufficiently proven medical use of the different substances. In any event, the period of time necessary to establish that a component of a medicinal product has a sufficiently proven medicinal use may not be less than 10 years from the first systematic and documented use of that substance as a medicinal product within the European Union.

(b) The documentation submitted by the applicant shall cover all aspects of the assessment of safety and/or efficacy and include or refer to a relevant bibliographic study, taking into account the studies prior to and subsequent to the marketing and published scientific literature on experimentation in the form of epidemiological studies, and in particular comparative epidemiological studies. All existing documents, both favourable and unfavourable, must be communicated. With regard to the provisions on "sufficiently proven medical use", it is particularly necessary to clarify that the "bibliographic reference" to other tests (post-marketing studies, epidemiological studies, etc.), and not only Test-related data may serve as a valid test of the safety and efficacy of a medicinal product if an application explains and satisfactorily justifies the use of these sources of information.

(c) Particular attention shall be given to any omitted information and shall be justified because the existence of an acceptable level of safety and/or efficacy may be affirmed, despite the absence of certain studies.

(d) In the general view of non-clinical and/or clinical parts, the relevance of all the data presented in relation to a product other than that to be marketed shall be explained. It should be assessed whether the product examined can be considered to be similar to the product for which the marketing authorisation has been requested despite the differences.

e) The post-marketing experience of other products containing the same components will be of particular importance and the applicants should particularly insist on this aspect.

2. Essentially similar medicines.

(a) Applications based on Article 7 shall contain the data described in modules 1, 2 and 3 of Part I of this Annex, provided that the applicant has obtained the consent of the holder of the authorisation original marketing to cross-reference the contents of your modules 4 and 5.

(b) Applications based on Article 7 shall include the data described in modules 1, 2 and 3 of Part I of this Annex together with data demonstrating bioavailability and bioequivalence with the medicinal product original, provided that it is not a biological medicinal product (see Part II, point 4, similar biological medicinal products).

Non-clinical/clinical overviews of such products will focus especially on the following items:

The reasons why essential similarity is claimed;

a summary of the impurities present in lots of the active substance (s) as well as those of the finished product (and, where appropriate, the decomposition products that are formed during storage) as proposed for be a marketer, accompanied by an assessment of such impurities;

an assessment of bioequivalence studies or a justification for not having carried out the studies following the guidelines on "Research on labiopavailability and bioequivalence";

an update of the published literature on the substance and this application; annotations will be accepted for this purpose of articles from specialized publications;

each statement in the summary of the characteristics of the product not known or deduced from the properties of the medicinal product and/or its therapeutic group should be discussed in the summaries/overviews of the medicinal products. non-clinical/clinical parts and be justified by published literature or supplementary studies;

where appropriate, the applicant shall provide additional data to test the equivalence of the safety and efficacy properties of the different salts, esters or derivatives of an authorised active substance, in the event that they claim the essential similarity.

3. Additional data required in specific situations. -Where the active substance of an essentially similar medicinal product contains the same therapeutic fraction as the original authorised medicinal product, associated with a compound/derivative of salts/esters different, there should be evidence that there is no alteration of the pharmacokinetics of the fraction, pharmacodynamics and/or toxicity that may change their safety/efficacy profile. Otherwise, such an association shall be deemed to constitute a new active principle.

In cases where the medicinal product is intended for a different therapeutic use or is present in a different pharmaceutical form or is to be administered by different or different dosing routes, the the results of appropriate toxicological and pharmacological tests and/or clinical trials.

4. Similar biological medicinal products. -In the case of biological medicinal products, the provisions of Article 9 may not be sufficient. If the information required in the case of generic medicinal products does not permit demonstration of the analogue nature of two biological medicinal products, additional data, in particular the toxicological and clinical profile, shall be provided.

When an independent applicant requests, after the end of the data protection period, a marketing authorisation for a biological medicinal product as defined in point 3.2 of Part I of this Annex, relate to an original medicinal product which has obtained marketing authorisation in the European Union, the approach set out below shall apply.

The information to be provided will not be limited to modules 1, 2 and 3 (pharmaceutical, chemical and biological data), supplemented by data on bioequivalence and bioavailability. The type and amount of additional data (i.e. toxicological data, non-clinical data and relevant clinical data) shall be determined in each case, in accordance with all relevant scientific guidelines.

Due to the diversity of biological medicinal products, the competent authority shall determine whether it is necessary to require the identified studies provided for in modules 4 and 5, taking into account the special characteristics of each medication.

The general principles to be applied are set out in the guidelines published by the European Medicines Agency, in which the characteristics of the biological medicinal products concerned are taken into account. If the medicinal product originally authorised has more than one indication, the efficacy and safety of the medicinal product which is claimed to be similar or, if necessary, must be demonstrated separately for each of the medicinal products. declared indications.

5. Associations of authorised active substances. -Applications based on Article 11 shall refer to new medicinal products consisting of at least two active substances which have not previously been authorised as fixed dose associations.

In the case of these applications, a complete dossier (modules 1 to 5) will be submitted for the fixed dose association. Where appropriate, information concerning the places of manufacture and the assessment of the safety of foreign/external agents shall be provided.

6. Documentation for applications for authorisation under special conditions. -Where, as provided for in Article 26, the applicant can demonstrate that he is unable to provide complete data on the efficacy and safety under normal conditions for use of the product, for any of the following reasons:

The cases for which the products in question are indicated are so rarely presented that the applicant cannot reasonably be required to provide the detailed evidence;

the current state of science development does not allow you to provide complete information;

principles of commonly admitted medical deontology prohibit the collection of this information, the marketing authorisation may be granted on the basis of certain specific obligations.

These obligations may include the following:

The applicant shall conclude, within a period specified by the competent authority, a specific programme of studies, the results of which shall form the basis of a new risk/benefit assessment.

the specialty in question will only be issued with a prescription and, if necessary, only its administration will be authorized if it is carried out under strict medical supervision, if possible in a hospital and, in the case of a radiopharmaceutical by an authorised person;

the package leaflet and any other medical information will highlight that, in relation to certain aspects, there is no reliable data on the medicinal product in question.

7. Mixed applications for marketing authorisation. -For mixed marketing authorisation applications, the application files in which modules 4 and/or 5 consist of a combination of limited study reports shall be understood clinical and/or clinical studies conducted by the applicant and bibliographic references. All other modules shall conform to the structure described in Part I of this Annex. The competent authority shall accept the proposed format presented by the applicant on a case-by-case basis.

PART III. SPECIAL MEDICINES

This part sets out the requirements related to the nature of certain medications.

1. Biological drugs.

1.1 Blood products.-For medicinal products derived from human blood or plasma and by way of derogation from Module 3, the requirements of the dossiers referred to in " information on the starting materials and raw materials " relating to the starting materials derived from human blood or plasma may be replaced by a Main File on Certified Plasma according to the provisions of this Part.

(a) Principles: For the purposes of this Annex:

"Main File on Plasma (PMF)" means the independent and independent documentation of the marketing authorisation dossier containing all the relevant detailed information on the characteristics of all human plasma used as starting material and/or raw material for the manufacture of subfractions or fractions, which are part of the medicinal products or medical devices mentioned in Royal Decree 710/2002, 19 of The Court of the Court of the Court of the European Court of 7 May, in which the Court of medical devices, in respect of which they incorporate stable derivatives of human blood or plasma, such as excipient and active substance (s).

Each human plasma fractionation/processing centre or establishment shall prepare and keep the relevant detailed set of information referred to in the main plasma file per day.

The applicant for a marketing authorisation or the marketing authorisation holder shall submit the main plasma file to the European Medicines Agency or to the competent authority. Where the applicant for a marketing authorisation or the holder of the marketing authorisation is not the holder of the main plasma file, this file shall be made available to the applicant or to the holder of the authorisation of the placing on the market for submission to the competent authority. In any event, the applicant or marketing authorisation holder shall assume responsibility for the medicinal product.

The competent authority evaluating the marketing authorisation shall wait for the European Medicines Agency to issue the certificate before taking a decision on the application.

All marketing authorisation files containing any component derived from human plasma shall be sent to the main plasma file corresponding to the plasma used as a starting material or material. premium.

(b) Content: In accordance with the provisions of Royal Decree 1088/2005 of 16 September 2005 laying down the technical requirements and minimum conditions for blood donation and transfusion centres and services, concerning the requirements to be met by donors and the verification of donations, the main plasma file shall include information on the plasma used as starting material or raw material, in particular:

1. Origin of the plasma.

(a) Information about the establishments or establishments in which the blood or plasma is collected, including inspection and approval, as specified in Article 45 of Royal Decree 1088/2005, and epidemiological data on Blood-borne infections.

b) Centers or information establishments where donations are analyzed, including the category of inspection and approval.

c) Selection/exclusion criteria for blood and plasma donors.

d) An implanted system that allows the traceability of each donation from the collection of blood and plasma to finished products and vice versa.

2. Plasma quality and safety.

a) Compliance with the European Pharmacopoeia monographs.

b) Realization of the analysis of donations in the Transfusion centres to detect infectious agents, including information on methods of analysis and, in the case of plasma banks, validation data on the methods of analysis used.

c) Technical characteristics of blood and plasma collection bags, including data on the anticoagulant solutions used.

d) Plasma storage and transport conditions.

e) Procedures for maintaining inventory and/or quarantine periods.

f) Characterization of the original plasma mixture.

3. System in operation between the manufacturer of medicinal products derived from plasma and/or the entity dealing with the fractionation or treatment of plasma, on the one hand, and blood establishments, on the other, which defines the conditions of their use interaction and specifications agreed between them.

In addition, a list of the drugs for which the file is valid will be offered in the main plasma archive, both the drugs that have obtained a marketing authorization and those on the obtain it, including the medicinal products referred to in Article 2 of Royal Decree 223/2004 of 6 February.

c) Evaluation and certification:

For medicinal products not yet authorised, the applicant for the marketing authorisation shall submit a complete dossier to the competent authority, which shall be accompanied by a separate main plasma file. if it does not already exist.

The main plasma archive will be subject to a scientific and technical evaluation carried out by the European Medicines Agency. The positive assessment shall entail the issue of a certificate of compliance with Community legislation relating to the main plasma file, which shall be accompanied by the assessment report. The certificate to be issued shall be valid throughout the European Union.

The main plasma file will be updated and certified again annually.

The modifications made subsequently in the formulation of the main plasma file must follow the evaluation procedure laid down in Regulation (EC) No 542/95 concerning the examination of the modifications of the the terms of the marketing authorisations falling within the scope of Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and for which the European Agency for Medicines. The conditions for the assessment of those amendments are laid down in Regulation (EC) 1085/2003

In a second step, after the first, second, third and fourth indents, the competent authority which grants or has granted the authorization to place the medicinal product on the market shall take into account certification, recertification or modifications of the main plasma file on the medicinal products concerned.

By way of derogation from the second indent of this point (assessment and certification), where a main plasma file corresponds only to medicinal products derived from blood or plasma, the authorisation of which is the marketing is limited to a single Member State, the scientific and technical evaluation of that main plasma file shall be carried out by the competent national authority of that Member State.

1.2 Vaccines. -With regard to vaccines for human use and notwithstanding the provisions of Module 3 on "active principle (s)", the following requirements shall apply, when based on the use of a file system Vaccine antigen principal.

The application dossier for the marketing authorisation of any vaccine other than that of human influenza shall include a main file on each vaccine antigen that constitutes an active substance in the vaccine.

(a) Principles: For the purposes of this Annex:

"Main file on a vaccine antigen (VaMF)" means an independent part of the application dossier for the marketing authorisation of a vaccine containing all relevant information of a nature biological, pharmaceutical and chemical in relation to each of the active substances that are part of the medicinal product. The independent party may be common to one or more monovalent vaccines and/or combined with the same applicant or marketing authorisation holder.

Each vaccine may contain one or more distinct antigens. Each vaccine contains as many active substances as antigens.

A combined vaccine contains at least two distinct antigens intended for the prevention of one or more infectious diseases.

A monovalent vaccine contains a single antigen intended for the prevention of a single infectious disease.

b) Content: The main file on vaccine antigen shall contain the following information extracted from the relevant part (active substance) of Module 3 on 'data quality' as defined in Part I of the present Annex:

Active principle.

1. General information, including the monitoring of the relevant monographs of the European Pharmacopoeia.

2. Information on the production of the active substance: it should cover the manufacturing process, information on starting materials and raw materials, the specific measures on safety assessment with regard to TSEs and the foreign/external agents and facilities and equipment.

3. Characterization of the active substance.

4. Quality control of the active principle.

5. Standards and reference materials.

6. Container and system for closing the active substance.

7. Stability of the active substance.

c) Evaluation and certification:

In the case of new vaccines containing a new antigen, the applicant shall submit to a competent authority a complete marketing authorisation application dossier including all the main files. for vaccine antigen corresponding to each of the antigens that are part of the new vaccine, in the event that no major file of each antigen already exists.

The European Medicines Agency will carry out the scientific and technical evaluation of the aforementioned main archive on vaccine antigen. The positive assessment of a medicinal product shall entail the issue of a certificate of compliance with Community legislation relating to each main vaccine antigen file, which shall be accompanied by the assessment report. The certificate to be issued shall be valid throughout the European Union.

The first indent shall apply to each vaccine consisting of a new combination of vaccine antigens, irrespective of whether any such antigen may form part of vaccines already authorised in the Union. European.

Changes in the content of a main vaccine antigen file for a vaccine authorised in the European Union will be subject to a scientific and technical assessment by the European Agency of Medicinal products in accordance with the procedure laid down in Regulation (EC) No 1085/2003. In the event of a positive assessment, the European Medicines Agency shall issue a certificate of compliance with the Community legislation of the main archive on the vaccine antigen. The certificate to be issued shall be valid throughout the European Union.

By way of derogation from the first, second and third indents of this paragraph (assessment and certification), where a main vaccine antigen file corresponds solely to a vaccine that has been the subject of a marketing authorisation which has not been granted (or which will not be granted) in accordance with a Community procedure and provided that the authorised vaccine includes vaccine antigens not assessed by a Community procedure, the national authority competent who granted the marketing authorisation shall carry out the assessment scientific and technical of the above main archive on vaccine antigen and its subsequent modifications.

In a second step, after the first, second, third and fourth indents, the competent authority which grants or has granted the marketing authorisation shall take into account the certification, the recertification or amendments to the main file on vaccine antigen relating to the medicinal products concerned.

2. Radiopharmaceuticals and precursors.

2.1. Radiopharmaceuticals. For the purposes of this paragraph, a complete dossier shall be submitted in which the following specific data shall be included:

Module 3.

(a) In the case of radiopharmaceutical reactive equipment which must be radiolabelled after delivery by the manufacturer, the active substance shall be deemed to be that part of the formulation whose purpose is transport or attach to the radionuclide. The description of the method of manufacture of radiopharmaceutical reactive equipment shall include data on the manufacture of the equipment itself and data on the final recommended treatment for the production of the radiopharmaceutical. The necessary specifications of the radionuclide shall be described, if relevant, in accordance with the general monograph or monographs specific to the European Pharmacopoeia. In addition, any compound essential for radioactive marking shall be described. The structure of the radiolabelled composite shall also be described.

As for radionuclides, the nuclear reactions they produce will be discussed.

In a generator, both parent and child radionuclides will be considered active principles.

(b) Data shall be provided on the nature of the radionuclide, the identity of the isotope, the likely impurities, the carrier, the use and the specific activity.

c) The target materials for irradiation are included among the starting materials.

d) Consideration shall be given to chemical/radiochemical purity and its relationship to biodistribution.

e) The radionuclidic purity, the radiochemical purity and the specific activity shall be described.

f) Detailed information on the tests of the parent and child radionuclides is required for the generators. In the case of the eluids of a generator, tests must be carried out on the parent radionuclide and the other components of the generator.

g) The requirement to express the active substance content according to the mass of the active fractions shall only apply to radiopharmaceutical reactive equipment. In the case of radionuclides, the radioactivity shall be expressed as bequerels, setting a date and, if necessary, a given time, with reference to the time zone. The type of radiation emitted shall be indicated.

h) In the case of reactive equipment, the specifications of the finished product shall include proof of the effectiveness of the products after the radioactive marking. Appropriate controls of radiochemical and radionuclide purity of the radiolabelled product shall be included. All essential materials for radioactive marking shall be identified and controlled.

i) Information on stability in the case of radionuclide generators, reactive equipment combined with radionuclides and radiolabelled products shall be provided. The stability in use of radiopharmaceuticals in multidose vials should be documented.

Module 4. -It is estimated that the toxicity may be associated with the radiation dose. When radiopharmaceuticals are used for diagnostic purposes, this is a consequence of the use of the radiopharmaceuticals; when used for therapeutic purposes, it is the desired property. Therefore, the assessment of the safety and efficacy of radiopharmaceuticals will take into account the requirements for medicinal products in general and the dosimetry of radiation. The exposure to organ and tissue radiation shall be documented. Estimates of the absorbed radiation dose shall be calculated according to an internationally recognised specified system for a given route of administration.

Module 5. -Where appropriate, the results of clinical trials shall be provided; if not done, it shall be justified in the expert report of the clinical documentation.

2.2 Radiopharmaceutical precursors for radiolabelling. -In the specific case of a radiopharmaceutical precursor having only the object of radiolabelling, the primary objective shall be to provide information on the possible consequences of a low efficiency of radiolabelling or of the "in vivo" dissociation of the radiolabelled conjugate, i.e. aspects related to the effects of the free radionuclide on the patient. On the other hand, it is also necessary to present all relevant information in relation to occupational risks, such as exposure to radiation from professionally exposed workers and the environment.

In particular, the following information shall be provided as appropriate:

Module 3.-The provisions of Module 3, as defined in points (a) to (i), shall apply, where appropriate, to the registration of the radiopharmaceutical precursors.

Module 4.-With regard to single dose toxicity and continued administration, the results of studies conducted in accordance with the principles of good laboratory practice should be provided. are set out in Royal Decree 1369/2000 of 19 July 2000 amending Royal Decree 822/1993 of 28 May 1993 laying down the principles of good laboratory practice and their application in the conduct of non-clinical studies on chemical substances and products, and Royal Decree 2043/1994 of 14 October 1994 on inspection and verification of good laboratory practice, unless otherwise justified.

Radionuclide Mutagenicity studies are not considered useful in this particular case.

Information related to the chemical toxicity and distribution of the corresponding non-radioactive nuclide should be submitted.

Module 5. -Clinical information obtained from clinical studies using the precursor is not considered appropriate in the specific case of a radiopharmaceutical precursor that is solely for the purpose of marking radioactive.

However, information will be provided to demonstrate the clinical utility of the radiopharmaceutical precursor when linked to appropriate carrier molecules.

3. Homeopathic medicinal products. -This paragraph sets out the specific provisions on the application of modules 3 and 4 to homeopathic medicinal products as defined in Article 2.31.

Module 3.-The provisions of Module 3 shall apply to the documents submitted for applications for the marketing authorization for homeopathic medicinal products as defined in Article 55, with the amendments set out in continuation:

(a) Terminology. The Latin name of the homeopathic stock described in the application dossier for marketing authorization must be in accordance with the Latin name of the European Pharmacopoeia or, in its absence, with the of an official pharmacopoeia of a Member State. The name or traditional names used in each Member State shall be included, where relevant.

(b) Control of the starting materials.-Details and documents on the starting materials, i.e. all the materials used including the raw and intermediate materials until the final dilution to be incorporated the finished product, which are attached to the application, shall be supplemented by additional data on the homeopathic strain.

The general quality requirements shall apply to all starting materials and raw materials, as well as to the intermediate steps of the manufacturing process up to the final dilution to be incorporated in the finished product. If possible, a quantitative determination is required if there is a presence of toxic components and if, due to the high degree of dilution, the quality cannot be controlled in the final dilution to be incorporated. Each step of the manufacturing process shall be carefully described from the starting materials to the final dilution to be incorporated in the finished product.

Dilutions must be performed in accordance with the homeopathic manufacturing methods set out in the relevant monograph of the European Pharmacopoeia or, failing that, in an official pharmacopoeia of a Member State.

(c) Methods of control of the finished product.-The general quality requirements shall apply to the finished homeopathic medicinal products; the applicant shall duly justify any derogation.

The identification and quantitative determination of all relevant components from a toxicological point of view shall be carried out. Where it can be justified that the identification and/or quantification of all relevant components from a toxicological point of view is not possible (e.g. due to dilution in the finished product), the quality shall be be demonstrated by the complete validation of the manufacturing and dilution processes.

(d) Stability tests.-The stability of the finished product must be demonstrated. The stability data of the homeopathic strains are generally transferable to the dilutions/comminities obtained therefrom. If the quantitative identification or determination of the active substance is not possible due to the degree of dilution, the stability data of the pharmaceutical form may be considered.

Module 4. The provisions of this module shall apply to the simplified registration of homeopathic medicinal products referred to in Article 55 (b), with the following specifications.

The absence of any data will be justified; for example, it will be justified why the existence of an acceptable level of safety may be affirmed, despite the absence of certain studies.

4. Herbal medicinal products. -Applications for herbal medicinal products shall be submitted with a complete file containing the following specific details.

Module 3.-The provisions of Module 3, including the monitoring of the relevant monographs of the European Pharmacopoeia, shall apply to the authorisation of herbal medicinal products. The state of scientific knowledge shall be taken into account when submitting the application.

The following specific aspects of herbal medicinal products should be considered.

1. Plant substances and preparations. For the purposes of this Annex, the term 'plant substances and plant preparations' shall be considered equivalent to the term 'herbal drugs and herbal drug preparations' as defined in the Pharmacopoeia. European.

With regard to the nomenclature of plant substances, the binomial scientific name of the plant (genus, species, variety and author), as well as its chemotype (where appropriate), the parts of the plants used, shall be included. definition of the plant substance, the other names (synonyms mentioned in the other pharmacopoeias) and the laboratory code.

With regard to the nomenclature of the plant preparation, the binomial scientific name of the plant (genus, species, variety and author), as well as its chemotype (where applicable), the parts of the plants used, shall be included. definition of the plant preparation, the proportion between the plant substance and the plant preparation, the solvent (s) for extraction, other names (synonyms mentioned in other pharmacopoeias) and the laboratory code.

To document the section of the structure of the plant substance (s) and the vegetable preparation (s) where appropriate, the physical form, the description of the components with known therapeutic activity or the markers (molecular formula, relative molecular mass, structural formula, including relative and absolute stereochemistry, molecular formula and relative molecular mass), as well as those of other constituents.

In order to document the paragraph on the manufacturer of the plant substance, the name, address and liability of each supplier, including contractors, and each location or installation shall be included, where appropriate. proposed for the production/collection and control of the plant substance.

In order to document the paragraph on the manufacturer of the plant preparation, the name, address and liability of each manufacturer, including contractors, and each manufacturing site or manufacturing site shall be included, where appropriate. proposed installation for the manufacture and testing of the plant preparation.

In relation to the description of the manufacturing process and the controls of the process of the plant substance, information shall be provided to adequately describe the production and collection of plants, including provenance the geographical location of the medicinal plant and its conditions of cultivation, harvesting, drying and storage.

In relation to the description of the manufacturing process and the process controls of the plant preparation, information shall be provided to adequately describe the manufacturing process of the plant preparation, including the description of the treatment, solvents and reagents, purification phases and standardization.

With regard to the development of the manufacturing process, it shall be submitted where appropriate a short summary describing the development of the plant substance (s) and the plant preparation (s), taking into account the route of administration and use proposed. Where appropriate, the results in which the phytochemical composition of plant substances and plant preparations (s) are compared, as the case may be, shall be discussed in the supporting literature and plant substances and preparations. plants, as the case may be, containing as active substances the herbal medicinal product for which authorisation is sought.

With regard to the elucidation of the structure and other characteristics of the plant substance (s), information on the botanical, macroscopic, microscopic and phytochemical characterization, as well as its activity, will be provided. biological if necessary.

With regard to the elucidation of the structure and other characteristics of the plant preparations, information on the phytochemical and physicochemical characterization, as well as on its biological activity, shall be provided. required.

The specifications of the plant substance (s) and the plant preparation (s) shall be submitted as appropriate.

It will also be reported if appropriate about the analytical procedures used to control the plant substance (s) and the plant preparation (s).

With regard to the validation of analytical procedures, where appropriate, information on analytical validation shall be provided, including the experimental data of the analytical procedures used to control the plant substance (s) and the plant preparation (s).

In relation to the analysis of the lots, the lots and the results of the lots shall be described in relation to the plant substance (s) and the plant preparation (s), including those of the pharmacopoeia substances.

The specifications of the plant substance (s) and the plant preparation (s) shall be justified, where appropriate.

The reference standards and materials used to test the plant substance (s) and the plant preparation (s) shall also be reported as appropriate.

Where the plant substance or plant preparation is the subject of a monograph, the applicant may apply for a certificate of suitability issued by the European Medicines Quality Directorate.

2. Herbal medicinal products. -With regard to the development of the formulation, a succinct summary will be presented in which the development of the herbal medicinal product will be described, taking into account the proposed route of administration and use. Where appropriate, the results in which the phytochemical composition of the products referred to in the supporting bibliographic data and the herbal medicinal product for which authorisation is sought shall be discussed, where appropriate.

5. Orphan medicinal products. -In the case of an orphan medicinal product to be governed by Regulation (EC) No 726//2004 of 31 March, as well as Regulation (EC) No 141/2000, the general provisions set out in point 6 of the Part II (special conditions). The applicant shall provide reasons in the non-clinical and clinical summaries for the reasons which prevent it from providing the complete information, as well as the risk/benefit balance of the orphan medicinal product concerned.

PART IV. ADVANCED THERAPY MEDICINAL PRODUCTS

Advanced therapy drugs are based on manufacturing processes that are based on various biological molecules produced by genetic transfer and/or biologically advanced modified therapeutic cells such as active substances or part thereof.

The submission of the application for marketing authorisation for such medicinal products shall satisfy the format requirements set out in Part I of this Annex.

Modules 1 to 5 will apply. As regards genetically modified organisms intentionally released into the environment, attention should be paid to the persistence of the GMOs in the recipient and the possible duplication and/or modification of the GMOs when they are released into the environment. environment. The risk information for the environment shall be listed in the Annex to Module 1

1. Gene therapy medicinal products (of human and xenogenic origin). For the purposes of this Annex, a product obtained by a set of manufacturing processes intended to be transferred shall be understood as a gene therapy medicinal product, either "in vivo" either 'ex vivo', a prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic acid) to human/animal cells and their subsequent expression 'in vivo'. Genetic transfer involves a system of expression contained in a distribution system known as vector, which may be of viral or non-viral origin. The vector may also be included in a human or animal cell.

1.1 Diversity of gene therapy drugs.

a) Gene therapy drugs based on allogeneic or xenogenic cells.

The vector is prepared for use and stored before transferring it to the host cells.

Cells have been previously obtained and can be treated as a cell bank (bank or bank collection established by obtaining primary cells) with limited viability.

Genetically modified cells by the vector represent an active principle.

Additional steps can be taken to obtain the finished product. Essentially, the object of such a drug is its administration to a certain number of patients.

b) Gene therapy drugs in which autologous human cells are used.

The active substance is a vector batch prepared for use that is stored before transferring it to autologous cells.

Additional steps can be taken to obtain the finished product.

These products are prepared from cells obtained from a single patient. The cells are then genetically modified by a vector prepared for use which contains the appropriate gene which has been prepared in advance and is the active substance. The preparation, intended by definition for a single patient, is reinjected to the patient. The entire manufacturing process, from the collection of the patient's cells to the reinjection to the patient, will be considered as a single intervention.

c) Management of vectors prepared for use with inserted genetic material (prophylactic, diagnostic or therapeutic).

The active substance is a vector batch that is ready for use.

Additional steps can be taken to obtain the finished product. This type of medication is intended for administration to several patients.

The transfer of genetic material may be performed by direct injection of the vector prepared for use to its recipients.

1.2 Specific requirements for module 3. -Among the gene therapy drugs are the following:

Naked nucleic acid.

Complexed nucleic acid or non-viral vectors.

Viral vectors.

Genetically modified cells.

As for other medicines, the three main elements of the manufacturing process can be established, namely:

The starting materials: the materials from which the active substance is manufactured, such as the gene in question, expression plasmids, cell banks and virus or non-viral vector stocks;

active substance: recombinant vector, virus, naked or complex plasmids, cell-producing viruses, genetically modified cells in vitro;

finished product: active substance formulated in your final primary container for intended medical use. Depending on the type of gene therapy medicinal product, the route of administration and the conditions of use may require the 'ex vivo' treatment of the patient's cells (see 1.1.b).

Particular attention should be given to the following elements:

(a) Information on the relevant characteristics of the gene therapy medicinal product, including its expression in the target cell population, shall be provided. Information on the source, construction, characterization and verification of the coding genetic sequence, including its integrity and stability, shall be provided. The complete sequence of other genes, the regulatory elements and the skeleton of the vector shall be provided.

b) Information about the characterization of the vector used to transfer and transport the gene will be provided. This shall include its physico-chemical and/or biological/immunological characterization.

For medicinal products using a micro-organism, such as bacteria or viruses, to facilitate genetic transfer (biological genetic transfer), data on the pathogenesis of the parent strain and on its tropism specific types of tissues and cells, as well as the dependence of interaction on the cell cycle.

For medicinal products that use non-biological means to facilitate gene transfer, the physico-chemical properties of the components must be reported individually and in combination.

(c) The principles of establishment and characterization of cell banks or seed lots shall apply, where appropriate, to medicinal products produced by gene transfer.

d) The source of the cells that host the recombinant vector should be reported.

The characteristics of the human source, such as age, gender, results of microbiological and viral tests, exclusion criteria, and country of origin will be documented.

For cells of animal origin, detailed data concerning the following elements shall be provided:

Origin of animals.

Breeding and caring for animals.

transgenic animals (methods of creation, characterization of transgenic cells, nature of the inserted gene).

Measures to prevent and control infections in source/donor animals.

Testing relative to infectious agents.

Installations.

Control of starting materials and raw materials.

The methodology of cell collection should be documented, including the place, type of tissue, operational process, clustering, storage and traceability, as well as controls performed during the collection.

e) The assessment of viral safety and traceability of products from the donor to the finished product are essential parts of the documentation to be presented. For example, the presence of viruses competent for replication in stocks of non-replicating viral vectors will be excluded.

2. Somatic cell therapy medicinal products (of human and xenogenic origin). For the purposes of this Annex, somatic cell therapy medicinal products shall be understood to be the use in humans of live somatic cells, both anthology and of the patient himself), as allogeneic (from another human being) or xenogenic (from animals), whose biological characteristics have been substantially altered as a result of their manipulation to obtain a therapeutic, diagnostic or preventive effect by metabolic, pharmacological and immunological means. Such manipulation includes the expansion or activation of autologous "ex vivo" cell populations (p. e.g., adoptive immunotherapy), the use of allogeneic and xenogenic cells associated with "ex vivo" or "in vivo" (p. E.g., microcapsules, arrays, and intrinsic, biodegradable or non-biodegradable scaffolds.

Special requirements for cell therapy medicinal products in relation to Module 3. Somatic cell therapy drugs include the following:

Manipulated cells to modify their immune, metabolic or other functional properties in qualitative or quantitative aspects.

Cells classified, selected and manipulated, which are subsequently subjected to a manufacturing process in order to obtain the finished product.

Cells handled and combined with non-cellular components (e.g., matrices or biological or inert medical devices) that exert the intended action in principle in the finished product.

Autologous cell derivatives expressed in vitro under specific culture conditions.

Genetically modified cells or cells subjected to other types of manipulation to express previously unexpressed or otherwise unapproved functional properties.

The entire manufacturing process, from the collection of the patient's cells (autologous situation) to reinjection to the patient, will be considered as a single intervention.

As for the other medicines, the three elements of the manufacturing process can be established, namely:

Starting materials: the materials from which the active substance is manufactured, i.e. organs, tissues, body fluids or cells;

active substances: cells, cell lysates, cell lysates, proliferating cells and cells used together with inert matrices and sanitary products;

finished products: active substance formulated in your final primary container for intended medical use.

(a) General information on the active substance (s): The active substances of the cell therapy medicinal products consist of cells which, as a result of "in vitro" treatment, have prophylactic properties, diagnosis or treatment other than their original physiological and biological properties.

This section will describe the type of cells and culture concerned. The tissues, organs or biological fluids from which the cells derive are documented, as well as the autologous, allogeneic or xenogenic nature of the donation and its geographical origin. The collection of cells, sampling and storage prior to subsequent transformations shall be detailed. In the case of allogeneic cells, special attention will be given to the first phase of the process, which includes the selection of donors.

You should be informed about the type of manipulation performed and the physiological function of the cells that are used as the active substance.

b) Information related to the starting materials of the active principle (s).

1. Human somatic cells. -Human somatic cell therapy medicinal products are formed by a defined number (pool) of viable cells that derive from a manufacturing process that begins either at the level of the organs or tissues. recovered from a human being, either at the level of a very defined cell bank system, in which the cell pool is based on continuous cell lines. For the purposes of this Chapter, the active substance, the pool of seed of human cells, and the finished product, the pool of human cell seeds formulated for the intended medical use, shall be understood.

The starting materials and each stage of the manufacturing process, including the viral safety aspects, will be thoroughly documented.

1. Organs, tissues, cells and body fluids of human origin: The characteristics of the human source, such as age, sex, microbiological status, exclusion criteria and country of origin, shall be documented.

The description of the sampling, including the place, type, operational process, grouping, storage and traceability, as well as the checks carried out should be documented.

2. Cell Banking Systems: The relevant requirements described in Part I shall apply for the preparation and quality control of cell banking systems. This refers basically to allogeneic or xenogenic cells.

3. Ancillary materials or medical devices: Information on the use of any raw material (p. (e.g., cytokines, growth factors, culture media) or potential auxiliary medical devices (p. e.g. cell classification products, matrix of biocompatible polymers, fibers, accounts), as regards their biocompatibility, functionality and the risk of infectious agents.

2. Somatic animal (xenogenic) cells.-Detailed information on the following elements shall be provided:

Origin of animals.

Breeding and caring for animals.

Genetically modified animals (methods of creation, characterization of transgenic cells, nature of the gene inserted or removed).

Measures to prevent and control infections in source/donor animals.

Tests for infectious agents, including vertically transmitted microorganisms (also endogenous retroviruses).

Installations.

Cell bank systems.

Control of starting materials and raw materials.

(a) Information on the manufacturing process of the active principle (s) and the finished product: The different steps of the manufacturing process, such as organ/tissue dissociation, the selection of the population, should be documented. Cell culture of interest, cell culture "in vitro", and transformation of the cell, either by physical-chemical agents or by gene transfer.

b) Characterisation of the active principle (s): All relevant information on the characterization of the cell population in question will be provided from the point of view of the identity (species of origin, cytogenetics of bandeo, morphological analysis), purity (foreign/external microbial agents and cellular contaminants), potency (defined biological activity) and adequacy (cariology and tumorigenicity tests) for the intended medical use.

c) Pharmaceutical development of finished product: In addition to the specific method of administration used (intravenous infusion, injection at the site of injury, transplant surgery), information on the use of possible auxiliary medical devices (biocompatible polymers, matrix, fibres, beads), with regard to their compatibility and durability.

d) Traceability: A detailed diagram will be presented to ensure traceability of products from the donor to the finished product.

3. Specific requirements for gene therapy medicinal products and somatic cell therapy (human and xenogenic origin) in relation to modules 4 and 5

3.1 Module 4. -For gene therapy and somatic drugs, it is recognized that the conventional requirements set out in Module 4 for non-clinical drug testing are not always adequate, due to the structural and biological properties, unique and diverse, of such products, which cover a high degree of specificity according to species and subject, immunological barriers and differences in pleiotropic responses.

The reasons for non-clinical development and the criteria for choosing relevant species and models should be adequately illustrated in Module 2.

It may be necessary to identify or develop new animal models in order to contribute to the extrapolation of specific conclusions on functional parameters and toxicity for the "in vivo" activity of products in human beings. The use of such animal models of disease should be scientifically justified in order to support safety and proof of the concept for the sake of effectiveness.

3.2 Module 5.-The efficacy of advanced therapy medicinal products should be demonstrated and described in Module 5. However, in the case of certain therapeutic products and indications, it may not be possible to conduct conventional clinical trials. Module 2 shall justify any deviation from the current guidelines.

The clinical development of advanced therapy drugs will have some special traits due to the complexity and lability of the active substances. It requires additional considerations, due to issues related to the viability, proliferation, migration and differentiation of cells (somatic cell therapy) and their ability to grow and differentiate (cell therapy), and special clinical circumstances in which the products are used or the special mode of action by means of gene expression (somatic gene therapy).

In the application for authorisation of advanced therapy medicinal products the special risks related to such products, derived from potential contamination with infectious agents, should be addressed. Particular emphasis should be placed on early stages of development, including the choice of donors in the case of cell therapy medicinal products, and therapeutic intervention as a whole, including management and administration. appropriate for the product.

Furthermore, module 5 of the application should include, if appropriate, data on the inspection and control measures of the functions and the development of the living cells in the recipient, in order to prevent the transmission of infectious agents to the latter and minimise any potential risks to public health.

3.2.1 Studies of human pharmacology and efficacy. -Studies of human pharmacology should provide information on the mode of action and the effectiveness that are foreseen according to justified parameters, the biodistribution, the dosage appropriate, the timing and methods of administration or mode of use desirable for efficacy studies.

Conventional pharmacokinetic studies may not be relevant for certain advanced therapy products. At times, studies in healthy volunteers are not feasible and the setting of dosing and kinetics will be difficult to determine in clinical trials. However, it is necessary to study the "in vivo" distribution and behavior of the product, including cell proliferation and long-term function, as well as the scope and distribution of the gene product and the duration of the expression. Desired gene. Appropriate tests shall be used and, if necessary, developed to trace the cell product or cell that expresses the desired gene in the human body and to control the function of the cells that were administered or transfected.

The assessment of the efficacy and safety of an advanced therapy medicinal product should include the thorough description and evaluation of the therapeutic procedure as a whole, including special routes of administration (e.g. "ex vivo" cell transfection, "in vitro" manipulation or the use of intervention techniques) and the detection of possible associated regimens (including immunosuppressive, antiviral and cytotoxic).

The procedure in its integrity in clinical trials should be tested and described in the product information.

3.2.2 Safety. -Safety issues arising from the immune response to medicinal products or proteins expressed, immune rejection, immunosuppression and failure of the devices should be considered. immunoisolation.

Certain advanced gene therapy and somatic cell therapy drugs (e.g., xenogenic cell therapy products and some gene transfer) may contain particles and infectious agents suitable for use in the the duplication. Patient monitoring may be carried out as regards the development of possible infections and their pathological sequelae during the prior and/or post-authorisation phases; such surveillance may be extended to persons in contact with the patient, including health personnel.

By using certain somatic cell therapy and gene transfer drugs, the risk of contamination with potentially transmissible agents cannot be completely eliminated. However, the risk may be reduced to a minimum by the measures described in Module 3.

The measures included in the production process shall be supplemented by accompanying test methods, quality control processes and appropriate monitoring methods to be described in Module 5.

The use of certain advanced somatic cell therapy medicinal products may be limited, temporarily or permanently, to establishments which have documented specialised skills and facilities to ensure a specific monitoring of the safety of patients. The same approach may be relevant for certain gene therapy medicinal products which are associated with a potential risk of containing infectious agents suitable for duplication.

In the application will also be considered and will address aspects of long-term follow-up in relation to late complications.

Where appropriate, the applicant shall present the detailed risk management plan covering the clinical and laboratory data of the patient, the epidemiological data arising and, where appropriate, data from the sample files. tissue from the donor and the recipient. Such a system is necessary to ensure the traceability of the drug and the rapid response to suspected adverse event models.

4. Specific statement on xenotransplantation medicinal products. For the purposes of this Annex, xenotransplantation shall mean any procedure involving the transplantation, implantation or infusion into a human recipient of living tissues or organs. from animals, or fluids, cells, tissues or organs that have experienced 'ex vivo' contact with live cells, tissues or organs.

There will be very special attention paid to the starting materials.

In this respect, detailed information shall be provided in relation to the following elements according to specific guidelines:

Origin of animals.

Breeding and caring for animals.

Genetically modified animals (methods of creation, characterization of transgenic cells, nature of the gene inserted or removed [knocked out]).

Measures to prevent and control infections in source/donor animals.

Testing relative to infectious agents.

Installations.

Control of starting materials and raw materials.

Traceability.

ANNEX II

Contents of the Product Characteristics or Summary of Product Characteristics

The Product Characteristics or Summary of Product Characteristics will contain the following data in this order:

1. Name of the medicinal product.

2. Qualitative and quantitative composition.

3. Pharmaceutical form.

4. Clinical data.

4.1 Therapeutic indications.

4.2 Posology and method of administration.

4.3 Contraindications.

4.4 Special warnings and precautions for use.

4.5 Interactions with other medications and other forms of interaction.

4.6 Pregnancy and breast-feeding.

4.7 Effects on ability to drive and use machines.

4.8 Adverse reactions.

4.9 Overdose.

5. Pharmacological properties:

5.1 Pharmacodynamic properties.

5.2 Pharmacokinetic properties.

5.3 Preclinical data on security.

6. Pharmaceutical data:

6.1 List of excipients.

6.2 Incompatibilities.

6.3 Period of validity.

6.4 Special precautions for storage.

6.5 Nature and contents of container.

6.6 Special precautions for disposal, and "other manipulations", where appropriate.

7. Holder of the marketing authorisation.

8. Number of the marketing authorization.

9. Date of the first authorization/renewal of the authorization.

10. Date of revision of the text. -In addition, in case of radiopharmaceutical medicinal products:

11. Dosimetry for radiopharmaceuticals, with a full detailed explanation of the internal radiation dosimetry.

12. Instructions for the preparation of radiopharmaceuticals, additional detailed instructions for the extemporaneous preparation and the quality control of this preparation and, where appropriate, maximum storage time during which any preparation intermediate, as an eluid, or the radiopharmaceutical ready for use meets the intended specifications.

ANNEX III

Labeling content of products that are manufactured industrially

Part One. Information to be included in the outer packaging

1. Name of the medicinal product, consisting of the name of the medicinal product, followed by the dosage and pharmaceutical form and, where appropriate, the indication of the target infants, children or adults; when the product contains up to three active principles shall include the Spanish Official Denomination (DOE), in its absence, the International Denomination (INN) or, failing that, its common name.

As a general rule, the names of the medicinal products will not contain abbreviations or acronyms. However, the Spanish Agency for Medicinal Products and Sanitary Products may, for reasons of public health and at the request of the applicant, authorise its inclusion.

2. The name of the medicinal product must also be indicated in the Braille alphabet in the outer packaging or, in its absence, in the immediate packaging, taking into account the particularities of each medicinal product.

3. Qualitative and quantitative composition, in active principles per unit of administration or, in the form of administration for a given volume or weight, using the Official Spanish Denominations or the Common Denominations International, or, failing that, their common or scientific names.

4. List of excipients which have a known action or effect and which are binding declarations. In addition, all excipients should be indicated in the case of a product for injection, topical preparation or eye drops.

5. Pharmaceutical form and content by weight, volume or units of administration.

6. Method of administration and route of administration.

7. Warning: "Keep out of reach and sight of children."

8. Special warnings, when required by the medicinal product.

9. In the case of medicinal products containing radionuclides, transport conditions of dangerous goods.

10. In the case of medicinal gases, the technical specifications to be met, the conditions of supply and transport, and, where appropriate, the corresponding symbols, shall be included.

11. The expiry date stated clearly (month and year). In addition, medicinal products with reduced stability after reconstitution, dilution or opening, shall indicate the time of validity of the reconstituted preparation, diluted or after opening and shall include a box for entry by the medicinal products. users. For medicinal products containing radionuclides, it shall be expressed day/month/year, and in case of time: minutes and country of the time reference.

12. Special precautions for storage, where appropriate.

13. Special precautions for disposal of unused medicinal products and waste materials derived from their use, where appropriate, and, where appropriate, the symbols authorised by the Spanish Agency for Medicinal Products and Medical Products, the effects of facilitating the application and development of systems for the collection of medicinal products and promoting the protection of the environment.

14. Name and address of the marketing authorisation holder of the medicinal product and, where appropriate, the name of the local representative designated by the holder.

15. National Drug Code.

16. Batch of manufacture.

17. For medicinal products not subject to medical prescription, the indication of use.

18. Prescription and dispensing conditions.

19. Symbols, acronyms and legends described in Annex IV.

20. Box or blank space to indicate the prescribed dosage, duration of treatment and frequency of use or takes, except in cases where the Spanish Agency for Medicinal Products and Health Products determines, taking into account particularities of each medicinal product.

21. Seal of the National Health System, where applicable.

Part 2: Information to be included in the primary packaging

1. The primary packaging or, where appropriate, the shielding of protection of medicinal products containing radionuclides, which are presented without outer packaging, shall include the information collected in the first part.

2. The primary packaging or, where appropriate, the protective shield of medicinal products containing radionuclides, other than the small packages and blisters referred to in paragraphs 3 and 4, shall include the information collected. in the first part, except those corresponding to paragraphs 18, 20 and 21, and the legends of paragraph 19.

3. Where the primary packaging or, as the case may be, the shielding of the protection of medicinal products containing radionuclides, contained in an outer packaging, is so small that it does not permit the inclusion of the data provided for in the first part, take at least the following information:

(a) Name of the medicinal product as referred to in paragraph 1 of the first part and, if necessary, the route of administration,

b) expiration date,

c) manufacturing batch number,

d) form of administration, if necessary,

e) content by weight, by volume or in units of administration and in the case of medicinal products containing radionuclides,

f) any other information necessary for the safe and safe use of the medicinal product.

g) international symbol of radioactivity, in the case of medicinal products containing radionuclides.

h) name of the manufacturer, in the case of medicinal products containing radionuclides.

4. The primary packaging of medicinal products presented in the form of blisters and strips when contained in an outer packaging shall bear at least the following information:

(a) Name of the medicinal product, as referred to in paragraph 1 of the first part,

b) expiration date,

c) manufacturing batch number,

(d) name of the marketing authorisation holder of the medicinal product,

e) any other information necessary for the safe and safe use of the medicinal product.

In case the primary conditioning is ready to be cut into units, the integrity of the product identification, the expiration date, and the batch number, must be guaranteed in each unit.

5. Information in the ampoules of the solvent:

a) Identification of content;

b) volume content;

(c) name of the marketing authorisation holder of the medicinal product;

d) manufacturing batch number;

e) expiration date;

f) any other information necessary for the safe and safe use of the medicinal product.

ANNEX IV

Symbols, acronyms, and legends

The symbols, acronyms, and legends that should appear on the drug labeling will be as follows:

1. Symbols:

a) Dispensing subject to medical prescription:

b) Official prescription for narcotic drugs in list I annexed to the 1961 Single Convention:

(c) Medicinal products containing psychotropic substances included in Annex I to Royal Decree 2829/1977 of 6 October:

(d) Medicines containing psychotropic substances included in Annex II to Royal Decree 2829/1977 of 6 October:

e) How to store in a refrigerator:

f) Medicines that can reduce the ability to drive or operate dangerous machinery:

Driving: see package leaflet

On white background, a red equilateral triangle, with the apex up, and with a black car inside on white background. Its size shall be adapted to that of the package; in any case, the side of the triangle shall not be less than 10 mm.

g) Medicines that can produce photosensitivity:

Photosensitivity: see package leaflet

On white background, a red equilateral triangle, with the apex up. Inside and on white background, a white cloud with the black edge covering part of the sun. Its size shall be adapted to that of the package; in any case, the side of the triangle shall not be less than 10 mm.

The legend will be printed on the same white background, bold and black. It will be placed below or, if necessary, next to the triangle.

(h) International symbol of radioactivity in the 1991 UNE-73302 standard on flags for ionising radiation signalling:

Radioactive material

On white background, a black equilateral triangle, with the apex up. Inside and on a yellow background, the symbol established by the standard UNE-73302 indicative of radioactivity in black. Its size shall be adapted to that of the package; in any case, the side of the triangle shall not be less than 10 mm.

The legend will be printed on the same white background, bold and black. It will be placed below or, if necessary, next to the triangle.

i) Combative medicinal gas symbol:

On white background, a black diamond. Inside and on orange-yellow background, a flame of fire on a circle printed in black (symbol established for the combing substances of Annex II to Royal Decree 363/1995, of 10 March for which the Regulation on notification of new substances and classification, packaging and labelling of dangerous substances). Its size shall be adapted to that of the package; in any case, the side shall not be less than 10 mm.

j) Symbol of flammable medicinal gas:

On white background, a black diamond. Inside and on red background, a flame of fire printed in black. Its size shall be adapted to that of the package; in any case, the side shall not be less than 10 mm.

2. Acronym:

a) Advertising medication: EFP.

b) Drug for hospital use: H.

c) Drug diagnosis or prescription by certain medical specialists: DH.

d) Medication of special medical control: ECM.

e) Renewable dispensing drugs: TLD.

f) Traditional plant-based medicines: MTP.

The symbols between (a) and (e) inclusive, and the acronyms must be located in the upper right corner of the two main faces of the outer packaging on the right side or below the National Code and in the upper right angle of the primary packaging, where appropriate, under the same conditions. The other symbols shall be placed in another well visible place of the outer packaging in order to ensure their maximum readability.

3. Legends: The symbols and acronyms provided for in paragraphs 1 and 2 shall be accompanied by the following legends on the outer packaging:

a) "Medication not subject to medical prescription"

(b) "MEDICINAL PRODUCT SUBJECT TO MEDICAL PRESCRIPTION"

The legend 'MEDICINAL PRODUCT SUBJECT TO MEDICAL PRESCRIPTION' shall be placed in the outer packaging in a visible place and, in order to ensure its maximum readability, shall be printed in capital letters of a size not less than 2 mm in height, in bold and in black or in other colour which is clearly highlighted in relation to the background.

In addition, if the prescription and dispensing conditions require it, the legends will also be included:

c) "Hospital use".

d) "Hospital diagnostics".

e) "Special Medical Control".

In homeopathic medicinal products with therapeutic indication the legend will be included:

f) "homeopathic medicine".

In traditional herbal medicinal products, the following legend shall be included in the paragraph corresponding to the indication, labelling and package leaflet:

g) "Based exclusively on its traditional use".

ANNEX V

Minimum contents of the package leaflet for industrial products

The package leaflet shall be drawn up in accordance with the technical information sheet and shall include the following information in this order:

1. For the identification of the medicinal product:

(a) Denomination of the medicinal product, followed by dosage and pharmaceutical form and, where appropriate, the indication of the target infants, children or adults; where the product contains only one active substance and its denomination is a name of fantasy, shall include the Spanish Official Denomination (DOE), in its absence, the International Common Name (INN) or, failing that, its common or scientific name.

b) Pharmacotherapeutic group, or type of activity, in terms easily understandable to the consumer or user

2. Therapeutic indications.

3. Enumeration of the necessary information prior to the taking of the medicinal product:

a) Contraindications,

b) appropriate employment precautions,

c) drug interactions and other interactions (e.g., alcohol, tobacco, food) that may affect the drug's action,

d) special warnings that must:

1. Take into account the particular situation of certain categories of users (children, pregnant women or during the breastfeeding period, elderly, sportsmen, people with certain specific pathologies).

2. to mention the possible effects of treatment on the ability to drive a vehicle or to manipulate certain machines;

3. to include warnings concerning excipients whose knowledge is important for the safe and effective use of the medicinal product.

4. Required and customary instructions for good use, in particular:

a) Posology;

(b) form and, if necessary, route of administration, as well as instructions for the extemporaneous preparation of the medicinal product for the purpose of correct administration;

(c) frequency of administration, specifying, if necessary, the time when the medicinal product is or may be administered;

d) in the case of radiopharmaceutical medicinal products, all precautions to be taken by the user and the patient during the preparation and administration of the medicinal product, and if necessary, when the nature of the medicinal product is requires;

e) duration of treatment, when it has to be limited;

f) measures to be taken in the event of overdose (e.g. symptoms, emergency treatment);

g) attitude to be taken in the event that the administration of one or more doses has been omitted;

h) indication of the risk of withdrawal syndrome, if appropriate;

(i) specific recommendation to consult the doctor or pharmacist, as appropriate, for any clarification on the use of the product;

5. Description of the adverse effects which may be observed during the normal use of the medicinal product and, where appropriate, measures to be taken. The user should be expressly instructed to tell his doctor or pharmacist any side effects that were not described in the package leaflet.

6. Reference to the expiry date shown on the package, with:

(a) A warning not to exceed this date and, where appropriate, another warning to indicate the maximum validity period for those prepared with reduced stability after dilution, reconstitution or after open the container;

(b) where appropriate, special precautions for storage and, where appropriate, storage conditions for preparations after dilution, reconstitution, or after opening of the package;

c) where appropriate, a warning regarding certain visible signs of deterioration;

(d) precautions to be taken for the disposal of the unused medicinal product and any materials that have been in contact with it;

7. Full qualitative composition (in active substances and excipients), as well as the quantitative composition in active substances, for each presentation of the medicinal product, using the Official Spanish Denominations or, failing that, the International Common Names, or in their absence, common or scientific denominations.

8. Pharmaceutical form and content by weight, by volume, or in units of administration, for each presentation of the medicinal product.

9. Name and address of the marketing authorisation holder and, where applicable, his local representative.

10. Name and address of the manufacturer, if different from the holder.

11. Where the medicinal product is authorised by means of mutual recognition and decentralised procedure with different names in the Member States concerned, a list of the names authorised in each Member State.

12. Date of last revision of the package leaflet.