Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices is the legal framework in which all the provisions relating to the authorisation and manufacture of medicinal products are covered. possible guarantees of safety, quality and effectiveness of these guarantees.

Quality is one of the characteristics of drugs that is of greater importance in terms of public health. This is why there is a worldwide tradition of internationally agreed standards and recommendations on the requirements to be required for the manufacture and control of medicinal products for human and veterinary use.

In our legal order these aspects were collected in Royal Decree 1564/1992, of 18 December, for which the regime of authorization of pharmaceutical laboratories and importers of medicines and the quality assurance of their industrial manufacturing and Royal Decree 109/1995 of 27 January on veterinary medicinal products. In these rules it is consolidated, as a basic tool to guarantee the quality of medicinal products, the system of prior authorization to the operation of pharmaceutical laboratories manufacturers or importers of medicinal products, which ensures that all the authorised medicinal products are manufactured by authorised entities and subject to periodic inspections to verify compliance with the standards of correct manufacture of the medicinal products.

The holder of an authorisation as a manufacturer or importer of medicinal products should exercise these activities in such a way as to ensure that the medicinal products which it manufactures or amount are in conformity with the intended use and comply with the requirements of the marketing authorisations, without posing a risk to patients for having inadequate safety, quality or efficacy. The quality of the medicinal product is a requirement of capital importance, prior to and necessary for the fulfilment of the other legal requirements, since without quality medicinal products, obtained through controlled and reproducible manufacturing processes, it is possible to ensure safety for patients, animal health or the efficacy of a pharmacological treatment.

The quality standards contained in the principles and guidelines of the European Union's correct manufacturing standards are in line with internationally recognised standards of quality, in an area where the EU Harmonisation at global level is growing and is perceived as a necessity by all stakeholders. Therefore, compliance with these common standards also allows the Spanish pharmaceutical industry to compete in an increasingly global market.

In the light of the technical progress and experience gained, the European Union considered it necessary to update the existing provisions in this field concerning medicinal products for human use by Directive 2003 /94/EC of the European Parliament and of the Council Commission of 8 October 2003 laying down the principles and guidelines of good manufacturing practice for medicinal products for human use and for medicinal products for human use research.

For transposition into national law, Royal Decree 2183/2004 was published, of 12 November, amending Royal Decree 1564/1992 of 18 December 1992 on the development and regulation of the system of authorisation of pharmaceutical laboratories and importers of medicinal products and quality assurance in their industrial manufacture.

On the other hand, the basic aspects relating to the manufacture and import of medicinal products were included in 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, as amended inter alia by Directive 2004 /27/EC of the European Parliament and of the Council of 31 March and in Directive 2001 /82/EC of the European Parliament and of the Council of 6 November 2001, establishing a Community code on veterinary medicinal products Amended, inter alia, by Directive 2004 /28/EC of the European Parliament and of the Council of 31 March and were incorporated into our legal order by Law 29/2006 of 26 July.

The authorisation of manufacturers and importers of medicinal products is of great importance in relation to the quality assurance of medicinal products, as has already been mentioned, and therefore the European legislation lays down requirements. (a) specific measures to be verified by the authorities of the Member States and also establishes a system for the exchange of information on authorisations granted. It is therefore essential that the regulation of authorisations, which is at national level called pharmaceutical laboratories, corresponds to the figures and requirements of European legislation.

In the elaboration of this standard, the detailed guide to the correct manufacturing standards, published by the Commission and whose version in Spanish, permanently updated according to the advances, have been taken into account. technicians, publishes the Ministry of Health and Social Policy.

In addition, the abovementioned Law 29/2006 of 26 July introduces a basic aspect, contained in those Directives, in relation to the quality requirements which are required for the active substances used in the manufacture of medicines. This is an extremely important issue in relation to the quality of medicinal products which, until a few years ago, did not have specific requirements for quality assurance. The implementation of these requirements is posing an important challenge for the pharmaceutical industry and in this royal decree the aspects of the Law are developed.

Likewise, the law establishes the bases of the public register of pharmaceutical laboratories that this royal decree develops for its implementation. The publication of these data reinforces the guarantees of the pharmaceutical chain as well as the transparency policies of the Ministry of Health and Social Policy.

On the other hand, the foreign trade in medicinal products has suffered a significant increase, so that these activities have multiplied in quantity and complexity, which is why we need to modify these aspects, such as were in the previous regulations, in order to adapt them to the current situation of a global market, in which these requirements allow the quality of the products to be guaranteed in all cases.

By means of this royal decree, the requirements laid down in the aforementioned directives, relating to the manufacture and import of medicinal products for human and veterinary use and active substances, are integrated into a single provision. (a) the use of pharmaceutical products, thus supplementing the transposition of Community legislation in this field.

It is also necessary to mean that, in order to complete the incorporation into our national law of the provisions of the mentioned directives, related to the matters of authorization, registration, conditions of (a) Dispensing and pharmacovigilance, both for medicinal products for human use and for veterinary medicinal products, were adopted by the Royal Decrees: 1345/2007 of 11 October, which regulates the procedure for authorisation, registration and dispensing of medicinal products for human use manufactured industrially; 1344/2007 of 11 October 2007 on the pharmacovigilance of medicinal products for human use; and 1246/2008 of 18 July 2008 regulating the procedure for the authorisation, registration and pharmacovigilance of veterinary medicinal products industrially manufactured.

It should also be pointed out that, by means of this royal decree, Royal Decree 1564/1992 of 18 December 1992, for which the system of authorization of pharmaceutical laboratories is developed and regulated, is completely repealed. importers of medicinal products and the quality assurance of their industrial manufacture, as well as Titles IV and V of Royal Decree 109/1995 of 27 January 1995 on veterinary medicinal products relating to the manufacture and health guarantees of trade The Community and third countries of veterinary medicinal products.

On the other hand, in the framework of the Plan for the Reduction of Administrative Burdens and the Improvement of Regulation, it is necessary to reduce administrative burdens for applicants and to take advantage of the advantages of the the information and the communication, therefore, it is possible to present the requests referred to in this provision, as well as the monitoring of their processing, through electronic means, and some administrative interventions are suppressed. In this respect, the procedure for the appointment of the technical directors has been abandoned, in favour of a system of simple notification of the technical director appointed by the laboratory. This is not to be achieved, in order to comply with the provisions of Directive 2001 /83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use and the Directive 2001 /82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products, the Spanish Agency for Medicinal Products and Sanitary Products, as one of the necessary requirements to grant authorization to the lab, you can make the precise findings to ensure that the technical director designated by the laboratory meets the precise requirements to perform such a function.

In this regard, it should be noted that Article 63.1 of Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices provides that natural or legal persons who are engaged in the Manufacture of medicinal products or any of the processes which the latter may understand, including fractionation, conditioning and presentation for sale, must be authorized in advance by the Spanish Agency for Medicinal Products and Products Sanitary. Such authorisation shall also be necessary for the importation and placing on the market of medicinal products, and even for the assumption that the medicinal product is manufactured exclusively for export. For its part, 63.2.c) comprises as one of the requirements for obtaining the authorization to have a responsible technical director.

Finally, in relation to the requirements to show the responsibility of the technical director of a pharmaceutical laboratory, the requirements of qualification and qualification are modified in this royal in order to reflect scrupulously provided for in the above mentioned directives.

In its virtue, on the proposal of the Ministries of Health and Social Policy, and Environment, and Rural and Marine Environment, with the prior approval of the First Vice President of the Government and Minister of the Presidency, according to the Council of State and prior deliberation of the Council of Ministers at its meeting on 25 June 2010,

DISPONGO:

CHAPTER I

General provisions

Article 1. Object and scope of application.

1. This royal decree is intended to regulate:

(a) The manufacture and import of medicinal products for human use, veterinary medicinal products, and investigational medicinal products.

b) Making active principles.

c) The correct manufacturing rules.

d) The authorization of pharmaceutical laboratories.

e) The authorisation of the laboratories holding the marketing authorisation for medicinal products.

f) Registration of pharmaceutical laboratories.

g) Inspection, sampling, and quality issues.

(h) Foreign trade in medicinal products and the dispatch of medicinal products authorised in Spain to other Member States, without prejudice to the applicable customs legislation.

2. This royal decree will apply to:

(a) Natural or legal persons who manufacture medicinal products for human use, medicinal products for veterinary use, or investigational medicinal products.

(b) Natural or legal persons carrying out the qualitative and quantitative analyses required for the importation of investigational medicinal products or medicinal products.

(c) Manufacturers of active substances used as raw materials in the manufacture of medicinal products, the activity of which consists in the complete or partial manufacture or the importation of an active substance used as material premium, as well as the processes of fractionation, conditioning and presentation prior to incorporation into a medicinal product, including reconditioning and relabelling.

(d) The natural or legal persons who hold the authorization to place medicinal products on the market and who have facilities for their storage in Spain.

3. By way of derogation from the above, no authorisation shall be required as a manufacturer of medicinal products, in the case of the preparation of official formulae and official preparations carried out solely for the purpose of dispensing pharmacists in a pharmacy or approved pharmaceutical service, or for preparations, fractionation and changes in the preparation or presentation of medicinal products to be carried out by the pharmacy or the services of pharmacy in the field of its functions, although compliance with the requirements laid down by the with regard to Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices. In addition, authorisation shall not be required as a manufacturer of medicinal products for the production of self-vaccines for veterinary use.

4. Without prejudice to the requirement of specific quality standards, the centres referred to in Article 3.2 (a) of Royal Decree 1345/2007 of 11 October 2007 governing the procedure for the authorisation, registration and conditions of Dispensing of industrially manufactured human medicinal products do not require authorisation as a manufacturer of medicinal products.

Article 2. Definitions.

For the purposes of this provision:

1. Packaging: all operations, including packaging and labelling, to which a bulk product must be submitted in order to become a finished product.

2. Technical director: in the European regulations qualified person, is the maximum health guarantee of the quality of the medicinal products, which must meet the conditions of qualification and will have the responsibilities and obligations established in this rule.

3. Export: the removal of medicinal products, active substances or investigational medicinal products from third countries, without prejudice to the specific rules for medicinal products whose intra-Community trade is subject to authorisation export.

4. Manufacture: all operations involving the acquisition of materials and products, production, quality control, release, storage, distribution of medicinal products and the controls relating to such operations.

5. Pharmaceutical quality assurance: a set of measures taken to ensure that medicines and medicines in research are of the quality required for the use to which they are intended.

6. Import: entry of any medicinal product, active substance or investigational medicinal product from third countries, without prejudice to the specific rules for medicinal products whose intra-Community trade is subject to authorisation of import.

7. Pharmaceutical laboratory manufacturer: named in the European legislation manufacturer or, holder of the manufacturing authorization, is the natural or legal person engaged in the manufacture of medicinal products or investigational medicinal products.

8. Pharmaceutical laboratory importer: in the European legislation importer, or holder of the import authorization, is the natural or legal person engaged in the performance of the qualitative and quantitative analyses required for the importation of medicinal products from third countries.

9. Laboratory holder of the marketing authorisation: is the natural or legal person responsible for placing the medicinal product on the market, for which it has obtained the required marketing authorisation, and which it has in Spain facilities, own or contracted, to store and distribute their medicines.

10. Good manufacturing standards: the part of the quality assurance that ensures that the drugs are manufactured and controlled in accordance with the appropriate quality standards for the intended use.

11. Manufacturing plant: each of the facilities where a pharmaceutical laboratory manufacturer or importer develops its manufacturing and/or control activities.

Article 3. Incompatibilities.

1. Without prejudice to the incompatibilities established for the exercise of public activities, the provision of services in pharmaceutical laboratories, or the existence of any kind of direct economic interest in the manufacture, preparation, distribution and marketing of medicinal products, shall be incompatible with the clinical practice of medical, dental, veterinary and other health professions with the right to prescribe or indicate the supply of medicinal products; medicines.

2. Without prejudice to the incompatibilities established for the exercise of public activities, the professional practice of the pharmacist in the office of pharmacy or in a service of hospital pharmacy and other care structures shall be incompatible with any class of direct economic interests of the pharmaceutical laboratories.

Article 4. Telematics presentation of requests.

The applications referred to in this royal decree will be submitted by means or means of telematics to the Spanish Agency for Medicines and Health Products, as provided for in Article 27.6 of Law 11/2007, 22 of June, the electronic access of citizens to public services, unless it is justified that the access and availability of the precise technological means are not guaranteed.

CHAPTER II

Manufacture and importation of investigational drugs and drugs

Section 1. Authorization Procedure

Article 5. Authorization.

1. Natural or legal persons engaged in the manufacture of investigational medicinal products or medicinal products or any of the processes which the latter may understand, including those of fractionation, packaging and presentation for sale, They will have the consideration of pharmaceutical laboratories, and must be authorized in advance by the Spanish Agency for Medicines and Health Products. Such authorisation shall also be necessary even if the medicinal product is manufactured exclusively for export.

2. By way of derogation from the above paragraph, this manufacturing authorisation shall not be required for the re-labelling of the price of medicinal products, performed exceptionally, by the marketing authorisation holder.

3. The authorization referred to in paragraph 1 shall also be required for the pharmaceutical laboratories importing, carrying out the necessary analyses for the importation of medicinal products or investigational medicinal products from third countries. To this end, the provisions included in this royal decree will apply to this import activity in the same way as it is made to the manufacture of medicines.

4. The authorization for the manufacture and/or import activities shall be preceded by an assessment, including an inspection carried out by the Spanish Agency for Medicinal Products and Sanitary Products, the subject of which shall be the verification of the information provided pursuant to Article 6 is accurate.

Article 6. Requirements of the applicant for a pharmaceutical laboratory authorisation manufacturer and/or importer.

To obtain the manufacturer or importer pharmaceutical laboratory authorization, the applicant must meet the following requirements:

(a) Specify the medicinal products and pharmaceutical forms to be manufactured or imported, as well as the place, establishment or laboratory of their manufacture or control.

(b) To provide adequate and sufficient local, technical and control equipment for the activity it intends to carry out, in order to meet the legal requirements, both from the manufacturing and control point of view, and of the preservation of the medicinal products.

c) Dispose of a responsible technical director, a manufacturing officer and a quality control officer, with sufficient qualifications. However, in laboratories manufacturing small quantities or simple products, the quality control function may be attributed to the technical director, but the manufacturing responsibility must correspond to a different person.

Article 7. Request for authorization.

1. Applications for authorisation as a pharmaceutical laboratory manufacturer and/or importer of medicinal products shall be submitted in accordance with the terms of Article 4, by means of the computerised application established for that purpose by the Spanish Agency of Medicines and Healthcare products.

2. 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.

3. The application for approval of a pharmaceutical manufacturer or importer shall be accompanied by the following information and documentation:

(a) Name or social reason of the applicant and registered office or registered office, NIF or CIF, and, in the case of a legal person, certification of registration in the Commercial Registry, and must be collected in the social object the activity to be performed.

b) Name of the legal representative and accreditation of such representation.

(c) Technical memory justifying compliance with the requirements of Article 6, in accordance with the guidance published by the Spanish Agency for Medicines and Health Products, in accordance with the international consensus documents on the content of such memory.

d) Proposal for a Director/s/s, accompanied by the documents listed in Article 19.1.

(e) Justifying the payment of the corresponding fees, as set out in Article 111 of Law 29/2006, of 26 July.

Article 8. Admission to processing.

1. The Spanish Agency for Medicinal Products and Health Products, after receipt of the documentation and within a maximum period of ten days, shall verify that the application meets the intended requirements and shall notify the applicant of its admission to the process.

2. Where the application does not meet the requirements laid down, the person concerned shall be required to submit the application within 10 days, with the indication that, if he does not do so, he shall be given the withdrawal of his request in accordance with the provisions of the provided for in Article 71.1 of Law No 30/1992 of 26 November 1992 on the Legal Regime of Public Administrations and of the Common Administrative Procedure, subject to a decision declaring that circumstance, with an indication of the facts produced and the applicable rules.

Article 9. Assessment of the file, hearing and resolution procedure.

1. The application shall be admissible, the assessment of the dossier shall be carried out. To this end, the Spanish Agency for Medicinal Products and Sanitary Products may require additional documentation or clarifications from the applicant on any extreme object of the application, setting a period of one month for the submission of the additional information, the time limit for notifying the resolution is suspended until the required data is received or the time limit is given.

2. The Spanish Agency for Medicinal Products and Sanitary Products shall carry out the necessary inspection at the appropriate facilities to verify compliance with the provisions of Articles 6 and 6 of the application. 7.

3. If the result of the assessment is unfavourable, the Spanish Agency for Medicinal Products and Sanitary Products shall notify the applicant of the reasons for which the requested authorisation is not applicable, so that, within 15 months of the days, you can make the allegations and present the documentation that you consider appropriate.

4. When the results of the evaluation are favorable, the Spanish Agency for Medicines and Health Products will issue the authorization resolution, which will be communicated immediately to the autonomous communities by any of the media. accepted in law, including electronic ones.

5. After the procedure has been completed, a reasoned decision shall be made to notify the person concerned, with the expression of the resources provided for in accordance with the rules in force.

6. The maximum period for notification of the decision of the approval procedure of a pharmaceutical laboratory manufacturer and/or importer shall be 90 days from the date of receipt of the application by the Spanish Agency of Medicines and Healthcare products.

Article 10. Content of the authorization.

1. The authorisation shall contain data on facilities, activities, pharmaceutical forms and technical directors.

2. The manufacturer or importer pharmaceutical laboratory authorisation shall be granted in accordance with the state of scientific and technical knowledge generally accepted at the time of the decision.

3. The manufacturer or importer pharmaceutical laboratory authorisation document shall be in conformity with the harmonised format in accordance with Community procedures.

Section 2. Authorization Amendments

Article 11. Procedure for the modification of the authorizations.

1. The amendment of the requirements laid down in Article 6, which are included in the authorisation as a pharmaceutical laboratory manufacturer and/or importer, shall be subject to prior authorisation by the Spanish Agency for Medicinal Products and Products Health care, which must be presented in accordance with the terms of Article 4, through the application of information technology established by the Spanish Agency for Medicines and Health Products.

However, administrative changes concerning laboratory data, such as, among other possible, changes in the name or social reason of the applicant and the home or home, shall not be subject to authorisation. The European Commission will be able to provide information to the Spanish Agency for Medicinal Products and Health Products, in order to issue new updated authorisation.

2. Where the application does not meet the requirements laid down, the person concerned shall be required to submit the application within 10 days, with the indication that, if he does not do so, he shall be given the withdrawal of his request in accordance with the provisions of the provided for in Article 71.1 of Law No 30/1992 of 26 November of 26 November, after a decision has been taken to declare that circumstance, with an indication of the facts produced and the applicable rules.

3. When the application is processed, the evaluation of the dossier will be carried out, to this end, the Spanish Agency for Medicinal Products and Sanitary Products may require additional documentation or clarifications to the applicant on any the purpose of the application, by setting a one-month time limit for the submission of the additional information, by suspending the time limit for notifying the decision until the required data are received or the time limit has elapsed.

4. The amendment of the authorisation shall be preceded by an assessment, which may include an inspection carried out by the Spanish Agency for Medicinal Products and Sanitary Products, the purpose of which shall be to verify that the applicant has the means appropriate and appropriate personal and material to ensure the pharmaceutical quality in each of the operations which are the subject of the application.

5. Where the result of the assessment is unfavourable, the Spanish Agency for Medicinal Products and Sanitary Products shall notify the applicant of the reasons for which the authorisation of the requested amendment does not proceed, in order to ensure that 15 days ' time limit, be able to make the allegations and present the documentation that you consider appropriate.

6. When the results of the evaluation are favourable, the Spanish Agency for Medicines and Health Products will issue the appropriate authorization resolution, which will be communicated immediately to the Autonomous Communities by any of the the means admitted in law, including electronic means.

7. After the procedure has been completed, a reasoned decision shall be made to notify the person concerned, with the expression of the resources provided for in accordance with the rules in force.

8. The time limit for notification of the decision of the procedures for the modification of the authorisation shall be 30 days from the date of receipt of the application by the Spanish Agency for Medicinal Products and Health Products, which may be extended for up to 90 days.

9. Amendments to the position of technical director shall follow the procedure laid down in Article 19.

Section 3. First Procedure for the suspension and revocation of the authorization, and precautionary measures

Article 12. Suspension and revocation of the authorisation.

The Spanish Agency for Medicinal Products and Sanitary Products may agree to suspend or revoke, in whole or in part, the authorization of a pharmaceutical laboratory manufacturer and/or importer when it no longer meets the requirements established in this royal decree that they were taken into account to grant such authorization.

Article 13. Procedure for suspending or revoking the authorisation.

1. The Spanish Agency for Medicinal Products and Sanitary Products may suspend or revoke, ex officio or at the request of a party, the authorization of a pharmaceutical and/or importer laboratory.

2. Where the procedure is initiated on its own initiative, an initiation agreement shall be issued giving the person concerned a hearing.

3. Where the procedure is initiated at the request of the person concerned, and where the application does not meet the requirements laid down, the person concerned shall be required to submit the application within 10 days, indicating that, if he does not do so, shall be given the withdrawal of its request in accordance with the provisions of Article 71.1 of Law No 30/1992 of 26 November, after a decision has been taken to declare that circumstance, indicating the facts produced and the applicable rules. If the application does not present deficiencies or have been remedied, it shall be admitted to the proceedings and notified to the person concerned. After the procedure has been completed, the person concerned shall be heard.

4. In both cases, the maximum period for the notification of the decision of the procedure for the suspension or revocation of the pharmaceutical laboratory approval manufacturer and/or importer shall be six months from the date of the agreement of the initiation or submission of the application. Should the suspension or revocation of the authorisation be agreed, the laboratory concerned shall cease in the performance of its activities from the date on which the decision is notified to it. The Agency shall immediately inform the Autonomous Communities of these suspensions and revocations by any of the eligible media, including electronic means.

Article 14. Precautionary measures.

1. In the event that there is or is reasonably suspected imminent and serious health risk, the health authorities may adopt the following precautionary measures, in accordance with the provisions of Article 99 of the Law. 29/2006, July 26:

a) The quarantine and withdrawal of the drug market.

b) The suspension of activities.

2. The health authority which adopts any precautionary measure must immediately inform the Spanish Agency for Medicines and Health Products, in order to make it known to the health services, responsible entities or General public the adoption of these measures.

3. The duration of the precautionary measures, without prejudice to successive extensions agreed by reasoned resolutions, shall not exceed what is required by the situation of imminent and serious risk.

4. The Spanish Agency for Medicinal Products and Sanitary Products, within the period of validity of the precautionary measures, shall agree to the initiation of the suspension procedure or the procedure for revocation, provided for in Article 13, by pronouncing on the confirmation, modification or lifting of the same.

Section 4. Obligations of the holder of the pharmaceutical laboratory authorization manufacturer or importer

Article 15. General obligations.

1. The holder of the pharmaceutical laboratory authorisation manufacturer or importer shall be obliged, at least:

(a) Dispose of sufficient staff and the technical qualification necessary to ensure the quality of the medicinal products manufactured or imported and the execution of the controls from the source.

b) Provide medicines according to current legislation.

c) Get the required authorization to make any modification you want from the manufacturing or import authorization, as set out in Article 11 of this royal decree.

d) Allow, at all times, the competent authorities access to carry out inspections of premises, files and documents.

e) Allow the technical director to be able to perform his duties, making all necessary means available to him.

(f) To respond to the obligations that are due to them during the time of their activity, including in the event of suspension of the activity, and during the five years after its closure.

g) Meet the principles and guidelines of the correct manufacturing standards and use as raw materials only active principles, manufactured in accordance with the detailed guidelines of the correct manufacturing standards active substances.

(h) Dispose of an updated technical memory, the content of which will be adjusted to the guide to this effect by the Spanish Agency for Medicines and Health Products, which reflects both the policy of the quality system and the quality assurance activities of the company, such as the manufacturing and/or control operations performed on the plants.

i) Velar because all drug processing operations, subject to a marketing authorization, are carried out in accordance with the same.

j) For investigational medicinal products, ensure that manufacturing operations are carried out in accordance with the protocol authorised by the Spanish Agency for Medicines and Health Products, and in accordance with the established in Royal Decree 223/2004 of 6 February on the regulation of clinical trials with medicinal products, and Royal Decree 109/1995 of 27 January 1995 on veterinary medicinal products.

k) In the event of distribution tasks, they must comply with the regulations that apply to them.

l) Communicate the suspension or cessation of your activities.

2. Holders of authorisations for the manufacture of veterinary medicinal products, in addition to the obligations laid down in the preceding paragraph, shall keep detailed records of all the veterinary medicinal products they have supplied, including samples.

These records, which must be available to the competent authorities for at least three years, shall include at least the following data for each transaction, whether or not it is paid: date, name of the veterinary medicinal product, quantity supplied, name and address of the consignee and lot number.

Section 5

Article 16. Technical director.

1. Each manufacturing plant must have a technical director.

2. In the case of pharmaceutical laboratories which have several manufacturing plants, the holder of the authorization of a pharmaceutical laboratory shall designate one of the technical directors of the plants for the purposes of interlocution with the health authorities.

3. Where the laboratory has facilities for the storage of medicinal products at locations other than those of the manufacturing plants, the technical director shall be assisted by a responsible technician in each of the warehouses, which shall be responsible for shall have the qualification set out in Article 17.1 and 2.

4. The holder of the manufacturing authorisation shall have a permanent and continuous technical director at each manufacturing site.

5. The laboratory shall have at least one alternate technical director for each head technical director, who shall replace him in the event of a temporary absence, and to which the same qualification and obligations requirements as the director shall apply. technical operator.

Article 17. Qualification of the technical director.

1. The technical director must be in possession of a diploma, certificate or other evidence of a course of university training-or an equivalent training course-with a minimum duration of four years of theoretical and practical training in the one of the following scientific specialties: pharmacy, medicine, veterinary medicine, chemistry, chemistry and pharmaceutical technology, biology.

However, the minimum duration of the university training cycle may be three and a half years when that cycle is followed by a period of theoretical and practical training of a minimum duration of one year, and which includes a period of practice of at least six months in a pharmacy open to the public, and sanctioned by a university-level examination.

2. The training cycle shall contain a theoretical and practical teaching which may cover at least the following basic subjects:

-experimental physics,

-general and inorganic chemistry,

-organic chemistry,

-analytical chemistry,

-pharmaceutical chemistry, including drug analysis,

-general and applied biochemistry (medical),

-physiology,

-microbiology,

-pharmacology,

-pharmaceutical technology,

-toxicology,

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

To the extent that certain diplomas, certificates or other evidence of formal qualifications listed in the first subparagraph do not comply with the criteria laid down in this paragraph, the Spanish Agency for Medicinal Products and Medicinal Products ensure that the person concerned has provided evidence of satisfactory knowledge in the field of the subjects in question.

3. The technical director must have, for at least two years, and in one or more undertakings which have obtained a manufacturing authorization, from activities of qualitative analysis of medicinal products, from quantitative analysis of active substances, as well as tests and verifications necessary to ensure the quality of the medicinal products.

The duration of practical experience may be reduced by one year when the university training cycle lasts for at least five years, and in one and a half years when the course of training has a minimum duration of six years.

4. Where radioactive installations are available, the technical director shall also have a supervisory licence for such installations.

Article 18. Responsibilities of the technical director.

1. The technical director shall be responsible for:

(a) In the case of medicinal products manufactured in Spain, each batch of medicinal products has been manufactured and controlled in accordance with the legislation in force and in compliance with the requirements required for the authorization of marketing.

(b) In the case of medicinal products from third countries, even if they have been manufactured in the European Union, each batch of imported manufacture has, in a Member State, been the subject of a full qualitative analysis, a quantitative analysis of at least all the active substances and all other tests or verifications necessary to ensure the quality of the medicinal products, in compliance with the requirements required for the authorization of the medicinal products. marketing.

Lots of medicinal products controlled in a Member State, referred to in points (a) and (b), shall be exempt from those controls when they are placed on the market in Spain, although they must be accompanied by the control signed by the technical director.

(c) In the case of medicinal products imported from third countries with which the European Union has adopted appropriate provisions ensuring that the manufacturer of the medicinal product applies standards of correct manufacturing, at least equivalent to those laid down by the European Union, the technical director of the importer shall ensure that the checks referred to in point (b) have been carried out in the exporting country, and shall be exempt from the checks.

2. In all cases, and in particular before the release to the market of medicinal products, the technical director shall certify that each batch of manufacture complies with the provisions of this Article in a register or equivalent document. provided for in this respect; such registration or equivalent document shall be kept up to date, as the operations are carried out, and be at the disposal of the competent health authority for a period of at least five years.

3. The technical director shall assist the inspection authorities in the performance of their duties and shall be the interlocutor, on the part of the laboratory, before the competent health authorities for the aspects listed in this royal decree.

Article 19. Appointment of the technical director.

1. The designation of technical director shall be notified to the Spanish Agency for Medicinal Products and Sanitary Products, signed by the legal representative of the laboratory and the proposed technical director, accompanied by the following documents:

(a) Academic certifications that demonstrate that the proposed technical director meets the conditions set out in Article 17.

(b) Supporting documentation that the proposed technical director has the experience acquired, in accordance with the provisions of Article 17.3 (3).

c) Statement, from the proposed technical director, not to incur the legally established incompatibilities.

d) Accreditation of the employment relationship between the laboratory and the proposed technical director.

2. Once the appointment of a technical director has been notified and where the appointment of a technical director does not meet the requirements laid down, the person concerned shall be required to provide the person concerned with the documents required within a period of 10 days, indicating the which, if it does not do so, shall be given the withdrawal of its request in accordance with the provisions of Article 71.1 of Law No 30/1992 of 26 November 1992, after a decision has been taken to declare that circumstance, with an indication of the facts produced and the applicable rules.

3. If, after the evaluation of the documentation submitted, it is found that the notified designation does not comply with the provisions applicable to it, the Spanish Agency for Medicinal Products and Health Products shall notify the person concerned of the a resolution indicating the reasons for which the proposed appointment of a technical director is not appropriate, so that, within a period of 15 days, he may make the allegations and present the documents which he or she consider appropriate.

4. Where the result of the said assessment is favourable, the Spanish Agency for Medicinal Products and Sanitary Products shall include the appointment in the content of the authorisation of the laboratory, issued in accordance with Article 10. This appointment shall be brought to the attention of the autonomous communities, immediately and by any of the means admitted to the law, including electronic means.

5. For the notification of the appointment of the alternate technical director, the procedure laid down in this Article shall be followed.

Article 20. Vacancy and replacement of technical director.

1. Where the position of technical director is vacant, the Spanish Agency for Medicinal Products and Sanitary Products shall be informed immediately of the cessation and temporary replacement by an alternate technical director. The Agency shall immediately inform the competent authority of the autonomous community where the laboratory is located by any of the means admitted in law, including electronic means.

2. The temporary replacement of the head technical director may not exceed the maximum period of four months from the date on which the vacancy occurs and the appointment of a final holder shall be dealt with in accordance with the provisions of the Article 19.

Section 6. Third Party Manufacturing

Article 21. Authorization.

1. The implementation, in justified cases, of certain stages of manufacture or certain controls by third parties will require authorization from the Spanish Agency for Medicines and Health Products, which will verify compliance with the the requirements laid down in Article 67 of Law 29/2006 of 26 July and the ability of third parties to comply with the specifications authorised in each case for the medicinal product.

2. The authorisation referred to in the previous paragraph, where the third party is permanently involved in a manufacturing or control phase, shall be granted in conjunction with the authorisation of the medicinal product. Any modification in the approved conditions affecting the intervention of third parties in the manufacture or control of medicinal products shall be governed by the provisions of Chapter VI of Royal Decree 1345/2007 of 11 October 2007 on the the procedure for the authorisation, registration and conditions for the supply of medicinal products for human use manufactured industrially, and Chapter VI of Royal Decree 1246/2008 of 18 July 2008 governing the authorisation procedure, registration and pharmacovigilance of industrially manufactured veterinary medicinal products.

3. It shall not be necessary to request the modification of the marketing authorisations for medicinal products for the intervention of a third party, on a transitional basis, in manufacturing or control operations on an exceptional basis and for a maximum period six months, at the reasoned request of the holder of the marketing authorisation for the medicinal product, although the prior authorisation of the Spanish Agency for Medicinal Products and Sanitary Products shall be required. Such authorisation may be renewable on a reasoned request from the marketing authorisation holder of the medicinal product.

Article 22. Authorization procedure.

1. In the case described in Article 21.3, the application for authorization of manufacture or control by third parties shall be submitted in accordance with the telematic procedure established by the Spanish Agency for Medicinal Products and Sanitary Products, and in The medicinal products, pharmaceutical forms and operations to be carried out shall be specified, designating the laboratories to be involved in those operations.

2. The application shall accompany the contract and the documentation necessary to prove that both parties have the relevant authorisations for the exercise of their activities. The contract must be:

a) Precise the agreed manufacturing or analysis phases, as well as any technical agreement related to the subject matter of the contract, delimiting the tasks of each party.

b) Be signed by the technical directors of the parties, in the technical aspects of the contract.

c) Constar the way in which the technical director of the pharmaceutical laboratory manufacturer and/or importer will carry out their responsibilities in the release of each batch.

3. Where the application does not meet the requirements laid down, the person concerned shall be required to submit the application within 10 days, with the indication that, if he does not do so, he shall be given the withdrawal of his request in accordance with the provisions of the provided for in Article 71.1 of Law No 30/1992 of 26 November of 26 November, after a decision has been taken to declare that circumstance, with an indication of the facts produced and the applicable rules.

4. When the application is accepted, if the result of the assessment is unfavourable, the Spanish Agency for Medicinal Products and Sanitary Products shall notify the applicant of the reasons for which the requested authorisation is not applicable, (a) the purpose of which, within a period of 15 days, may make the allegations and present the documentation which it considers appropriate.

5. After the procedure has been completed, a reasoned decision shall be given, which shall be notified to the person concerned, with the expression of the appeals against the person concerned, within the maximum period of 30 days from the date of receipt of the request. by the Spanish Agency for Medicines and Health Products.

6. The third party may not subcontract any part of the work entrusted to it under the contract, without the written authorization of the other contracting party and shall be subject to the inspection regime governed by Chapter VII.

7. The parties shall ensure that the rules of correct manufacturing are applied.

CHAPTER III

Making active principles

Article 23. General principles.

1. Manufacture, in whole or in part, as well as the importation of active substances used as raw materials for medicinal products must be carried out in accordance with the rules of correct manufacture, published by the Ministry of Health and Social.

2. The manufacturers of active substances do not require authorisation as a pharmaceutical laboratory manufacturer and/or importer, and therefore do not therefore apply the routine monitoring inspections of good manufacturing standards, with the exception of the manufacturing or import activities of sterile or biological active substances for which the relevant authorisation must be available as a pharmaceutical laboratory.

Article 24. Obligations of the pharmaceutical laboratories in relation to the active substances.

1. Pharmaceutical laboratories manufacturers or importers have an obligation to:

(a) Ensure compliance with the correct manufacturing standards by manufacturers of the active substances they use in the manufacture of medicinal products. To this end, the manufacturers of active ingredients used as starting materials shall be audited at regular intervals, at most every three years, to confirm that they comply with the requirements of the correct manufacturing of materials. premiums. The audits shall take into account the principles of the risk management system.

b) Document the supply chain of each starting material.

(c) The technical director shall, for each active principle, issue a declaration that the latter is manufactured in accordance with the principles of the rules of correct manufacturing of raw materials, in accordance with the knowledge acquired by performing audits.

2. In the case of the importing pharmaceutical laboratories, the audit provided for in paragraph 1 (a) may be delegated to the manufacturer of the medicinal product located in a third country, provided that the responsibilities of each party are established. in a contract, as set out in Article 22.2.

Article 25. Annual declaration of the activities and registration of manufacturers or importers of active substances.

1. Manufacturers or importers of active substances and excipients are obliged to make an annual declaration of their activities to the Spanish Agency for Medicines and Health Products. Such a declaration shall be made by means of telematics, by completing the questionnaire set out for that purpose.

2. A Register of undertakings or importers of active principles and excipients shall be maintained, in which the undertakings referred to in the annual activity declaration shall be entered. This register shall be accessible to the competent authorities of the Autonomous Communities.

3. Manufacturers or importers of sterile or biological active substances shall be exempted from making this annual declaration, as this activity is collected in their laboratory authorisation.

CHAPTER IV

Good Manufacturing Rules

Article 26. Compliance with the correct manufacturing standards.

1. The pharmaceutical laboratories manufacturers and/or importers shall ensure that all manufacturing operations and/or control of medicinal products are carried out in accordance with the rules of correct manufacture, as well as with the conditions of marketing authorisations. These obligations shall also apply to the manufacture and/or import of medicinal products intended exclusively for export.

2. For medicinal products and medicinal products for imported human use, the pharmaceutical laboratories importing shall ensure that the products have been manufactured:

(a) In accordance with rules that are at least equivalent to the correct manufacturing standards established by the European Union.

b) By duly authorized manufacturers.

3. The interpretation of the principles and guidelines of the rules of correct manufacture must be carried out in accordance with the detailed guide of standards of correct manufacture published by the European Commission, translated and published the Ministry of Health and Social Policy.

4. Manufacturers of active substances used as raw materials for medicinal products, as well as manufacturers of the excipients to be established by the European Commission, are required to comply with the guidelines for raw materials collected in the Part II of the detailed guide to the correct manufacturing standards, as well as the Annexes that apply to them.

Article 27. Update of the authorized specifications.

1. Pharmaceutical laboratories manufacturers and/or importers of medicinal products, as well as medicinal products for human use research, shall periodically review their manufacturing methods in order to adapt them to scientific, technical and scientific progress. development of the investigational medicinal product.

2. Where, as a result of the provisions of the preceding paragraph, it is necessary to amend the marketing authorisation for a medicinal product or to amend the authorisation of a clinical trial, the said medicinal products must be requested. modifications to the Spanish Agency for Medicines and Health Products, in accordance with applicable regulations.

Article 28. Quality assurance system.

1. Pharmaceutical laboratories manufacturers and/or importers of medicinal products shall establish, and apply, an effective pharmaceutical quality assurance system, in which the management and personnel of the various departments shall be actively involved. involved, according to the contents of the detailed rules guide for correct manufacturing.

2. The volume of activity and the type of operations carried out by the laboratory shall be taken into account in order to develop or modify the quality assurance system. To this end, the most appropriate principles of analysis and risk management should be applied, according to generally accepted scientific and technical standards. Work should be carried out in accordance with the objectives of continuous improvement of the quality assurance system, based on procedures for monitoring and analysing the effectiveness of the system. The pharmaceutical quality assurance system of a laboratory shall also include the activities contracted to third parties.

3. The quality assurance policy will be picked up in a quality manual, or similar document.

Article 29. Staff.

1. Manufacturers and/or importers shall have sufficient, competent and appropriate staff at all their manufacturing facilities to achieve the objective of the pharmaceutical quality assurance.

2. The tasks of the management and supervisory staff, including qualified personnel, responsible for the application of the correct manufacturing standards shall be defined in the description of duties. Hierarchical relationships must be defined in an organization chart. The establishment plans and descriptions of functions shall be approved in accordance with the internal procedures of the manufacturer and/or importer.

3. The staff referred to in paragraph 2 shall have sufficient powers to perform their duties properly.

4. The staff shall receive initial and permanent training of proven effectiveness, in particular concerning the theory and application of the concepts of quality assurance and standards of good manufacturing and, where appropriate, the specific requirements of development of investigational medicinal products.

5. Hygiene programmes adapted to the activities to be carried out shall be established and implemented. These programmes shall include, in particular, procedures relating to health, hygiene practices and the changing room of staff.

Article 30. Installations and equipment.

1. Manufacturing facilities and equipment shall be located, designed, constructed, adapted and maintained for the intended operations.

2. The layout, design and use of the manufacturing plant and equipment must make it possible to minimise the risk of error and to carry out an efficient cleaning and maintenance in order to avoid contamination, cross and, in general, any negative effects on the quality of the product.

3. Installations and equipment, to be used in operations essential for the quality of the products, shall be subject to appropriate qualification and validation.

Article 31. Documentation.

1. Manufacturers and/or importers shall establish, and maintain, a documentation system based on specifications, manufacturing formulae, preparation and conditioning instructions, procedures and protocols relating to the different processing operations to be carried out. The documents must be clear, error-free and up-to-date.

Procedures, previously established, should be available for general processing operations and conditions, as well as specific documents for the manufacture of each batch. This set of documents shall allow to reconstitute the manufacturing process for each batch and to trace the modifications made during the development of an investigational medicinal product.

2. In the case of medicinal products, the batch documentation shall be kept for at least one year after the expiry date of the same or up to five years after the certification referred to in Article 18.2 of this Regulation. royal decree, depending on which period is longer.

3. In the case of investigational medicinal products, the batch documentation shall be kept for a period of five years following the official conclusion or interruption of the last clinical trial in which the batch was used.

The sponsor of the clinical trial or the holder of a marketing authorisation, if they are different persons, shall be responsible for the keeping of records as established for the marketing authorisation. compliance with the analytical, pharmacotoxicological and clinical standards and protocols relating to the testing of medicinal products, where these are necessary for a future marketing authorisation.

4. Where an electronic, photographic or other data processing system is used, instead of the written documentation, manufacturers and/or importers shall first obtain the validation of the system, demonstrating that the data shall be properly stored during the forecast period. The data stored by these systems shall be readily accessible, in legible form and shall be made available to the competent authorities upon request. Data stored in electronic support shall be protected by means of methods, such as the carrying out of backups and the transfer to another storage system, so that they do not suffer loss or damage, for which they shall be carried out checks and shall be accessible to the inspecting authorities.

Article 32. Production.

1. The different production operations shall be carried out in accordance with prior established instructions and procedures and in accordance with the rules of correct manufacturing. Adequate and sufficient resources should be available for carrying out checks during the manufacturing process. Deviations from the process and product defects will be documented and will be the subject of an in-depth investigation.

2. Appropriate technical or organisational measures shall be taken to avoid cross-contamination and product mixtures. In the case of investigational medicinal products, special attention shall be given to the handling of the products during and after the masking operations, with the understanding of the deliberate concealment of the identity of a investigational medicinal product, in accordance with the instructions of the sponsor.

3. In the case of medicinal products, any new manufacturing or modification relevant to a manufacturing process must be validated. Critical phases of manufacturing processes will be revalidated periodically.

In the case of investigational medicinal products, manufacturing processes must be validated in their entirety as appropriate, taking into account the product development phase. At least the crucial stages of the process, such as sterilisation, will be validated. All stages of design and development of the manufacturing process shall be documented in full.

Article 33. Quality control.

1. Manufacturers and/or importers shall establish, and maintain, a quality control system, which shall be under the responsibility of a person who has the necessary qualifications and is independent of the production process.

2. The laboratories shall adopt the control systems in accordance with the approved specifications, which shall at least include:

a) The final and in-process manufacturing control, which will be set to your key points.

(b) Quality analytical control, which shall ensure that all copies of a medicinal product are identical in composition and meet the requirements of the legal provisions.

3. The quality control unit shall have one or more control laboratories, with the appropriate personnel and equipment to carry out the necessary tests and tests in relation to the raw materials and conditioning materials, as well as as the controls of the intermediate and finished products.

4. In the case of medicinal products, including those imported from third countries, contract laboratories authorised in accordance with Articles 21 and 34 of this provision may be used.

In the case of investigational medicinal products, the sponsor shall ensure that the contracted laboratory complies with the content of the authorisation of the Spanish Agency for Medicinal Products and Sanitary Products, as referred to in Chapter IV of Royal Decree 223/2004 of 6 February on the regulation of clinical trials with medicinal products. In the case of importation of such medicinal products from third countries, analytical control shall not be compulsory if it is established that requirements at least equivalent to the correct manufacturing standards required in the European Union have been met.

5. During the definitive control of the finished medicinal products, prior to their sale or distribution, or to their use in clinical trials, the quality control unit, in addition to the analytical results, shall take into account the other elements essential, such as the conditions of production, the results of the checks during the process, the examination of the manufacturing documents and the conformity of the products with their specifications, including the final packaging.

6. Samples from each batch of the finished medicinal products shall be kept for at least one year from the expiry date and the raw materials (other than solvents, gases or water) for at least two years after the release of the product. finished product, and must be available to the inspecting authorities.

Such periods may be abbreviated if their stability, as mentioned in the relevant specification, is less than the stated period.

The reference samples shall be of sufficient size to allow at least two full analyses to be repeated and their preservation shall be done in the conditions necessary to maintain their stability.

7. For certain medicinal products manufactured individually or in small quantities, or where storage may pose special problems, the Spanish Agency for Medicinal Products and Sanitary Products may authorise other sampling conditions and the preservation of the samples.

In the case of investigational medicinal products, sufficient samples shall be kept for each batch of the bulk-formulated medicinal products and the main components of the packaging used for each finished medicinal product. for at least two years from the date of conclusion or suspension of the last clinical trial in which the lot was used. From both dates, the one that determines the longest period will be chosen.

8. Each quality control unit shall maintain protocols for the samples analysed, where they shall, in addition to the detailed and precise individualisation of the samples, indicate the following:

a) The results of the executed analyses, including observations and data for each test performed.

b) The reference to the applied control pattern.

c) Name and signature of people who have performed the analysis.

d) Final report, dated and signed by the technician responsible for the external laboratory or department, as appropriate.

Article 34. Manufacturing and analysis by contract.

Any manufacturing operation or related operation shall be carried out under a written contract and shall meet the conditions described in Section 6 of Chapter II.

Article 35. Claims, product recall and unmasking in case of emergency.

1. The pharmaceutical laboratories manufacturers will implement a system of registration and examination of complaints, as well as an effective system of rapid and permanent withdrawal of medicines from the distribution network.

2. Each manufacturer and/or importer shall record and investigate any complaint relating to deficiencies, as well as any decision and measure taken as a result of the complaint.

3. Holders of marketing authorisations, or manufacturers and/or importers for medicinal products not marketed in Spain, shall immediately inform the Spanish Agency for Medicinal Products and Sanitary Products of any deficiency which may lead to the withdrawal from the market of a medicinal product in accordance with Article 51, indicating the countries of destination of the medicinal products. The marketing authorisation holder shall inform, in addition, the abnormal supply restrictions of any medicinal product.

4. In the case of investigational medicinal products, manufacturers, in collaboration with the trial promoter, shall establish a system of registration and examination of complaints, as well as an effective system for the rapid and permanent withdrawal of medicinal products in research that has entered into the distribution network, with the identification of all test centres and, where possible, the country of destination.

5. In the case of investigational medicinal products which have a marketing authorisation, the manufacturer of the investigational medicinal product, in collaboration with the sponsor, shall notify the marketing authorisation holder of any a deficiency that may be related to the authorised medicinal product.

6. The sponsor of the clinical trial shall establish a procedure for the rapid identification of the masked products when necessary for a rapid withdrawal. The sponsor shall ensure that the identity of the masked product is disclosed only if necessary.

Article 36. Self-inspection.

The manufacturers and/or importers will carry out repeated self-inspections, which will form part of the quality assurance system, for the control of the application and the respect of the standards of correct manufacturing and to propose any necessary corrective measures. A record of self-inspections and any corrective measures to be taken shall be carried out as a result of them.

CHAPTER V

Marketing authorization holders

Article 37. Laboratory holder of the marketing authorisation.

1. Without prejudice to the obligations laid down in Royal Decree 1345/2007 of 11 October 2007 and Royal Decree 1246/2008 of 18 July 2008, the holders of marketing authorisations which have their own facilities, or Contracted, to store their medicines in Spain, they must have the authorisation as a laboratory holder of the marketing authorisation.

2. Where a pharmaceutical laboratory manufacturer or importer is also the holder of the marketing authorisation for one or more medicinal products, the authorisation as a laboratory holder of the marketing authorisation shall be included in the authorisation as a pharmaceutical manufacturer or importer.

Article 38. Requirements for the laboratory authorisation holder of the marketing authorisation.

In order to obtain the laboratory authorisation holder of the marketing authorisation, the applicant shall at least provide proof of the following requirements:

a) Specify the medicines that you are the holder of and which you are storing.

b) Dispose of premises, technical and control equipment and appropriate and sufficient means for proper storage and distribution, which meet the legal requirements for the preservation of medicinal products.

(c) To permanently and continuously dispose of a responsible technician, in accordance with the requirements of Article 17.1 and 2, who shall carry out the duties entrusted to the marketing authorization holder in the regulations in force; in the field of the storage and distribution of medicinal products, in accordance with the applicable aspects of good distribution practices.

Article 39. Authorisation procedure and documentary requirements.

1. The application for the authorisation of a holding laboratory shall be submitted, in accordance with the terms of Article 4, by means of the computerised application established for that purpose by the Spanish Agency for Medicinal Products and Sanitary Products, and accompanied by the following information and documentation:

(a) Name or social reason of the applicant and registered office or registered office, NIF or CIF, and, in the case of a legal person, certification of registration in the Commercial Registry, and must be collected in the social object the activity to be performed.

b) Name of the legal representative and accreditation of such representation.

(c) Technical memory justifying compliance with the requirements of Article 38, in accordance with the guidance published by the Spanish Agency for Medicines and Health Products on the content of the memory.

(d) Accreditation, by the competent health authority, of compliance with good distribution practices for facilities where the medicinal products are stored.

(e) Proposal for a responsible technician, accompanied by the supporting documentation of compliance with the requirements set out in Article 38.

(f) Justifying the payment of fees, as set out in Article 111 of Law 29/2006, of 26 July.

2. The processing of these authorisations, as well as their modifications, shall be carried out in accordance with Chapter II.

Article 40. Local representative of the marketing authorisation holder for the storage of medicinal products in Spain.

1. The marketing authorisation holder may designate his local representative in Spain for the performance of the functions related to the storage and distribution of his medicinal products.

2. Where the local representative carries out this activity in facilities which are not authorised to manufacture, import or store by the Spanish Agency for Medicines and Health Products, he shall have the express authorisation of that Agency.

3. In such cases, the requirements and procedures laid down in Articles 38 and 39 shall apply.

4. The designation of this representative shall not exonerate the marketing authorisation holder of his responsibilities in this area.

Article 41. Suspension and revocation of the authorisation of the titular Laboratory.

1. The Spanish Agency for Medicinal Products and Sanitary Products may agree to suspend and revoke the authorisation of a holding laboratory where:

(a) The authorisations of the medicinal products for which the holder is a holder are suspended or revoked.

b) Stop gathering the requirements set out in Article 38.

2. The procedures for the suspension and revocation of the authorisation of the titular laboratory shall be in accordance with those laid down in Article 13.

CHAPTER VI

Registration of pharmaceutical laboratories

Article 42. Registration of pharmaceutical laboratories.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall maintain a register of pharmaceutical laboratories as provided for in Article 66 of Law 29/2006 of 26 July.

2. The purpose of the registration of pharmaceutical laboratories shall be to register the authorisations of:

a) Pharmaceutical laboratories manufacturers and/or importers.

(b) The laboratories holding the marketing authorisation.

The authorizations resulting from any transmission, modification or extinction that occur shall also be entered in this registry.

3. The enrollment in this record will be performed according to the laboratory authorization resolution data.

4. This register will be published and your access will be made through the website of the Spanish Agency for Medicines and Health Products.

CHAPTER VII

Inspection, sampling, and quality issues

Article 43. General aspects of the inspections.

1. The Spanish Agency for Medicinal Products and Sanitary Products and the health authorities of the autonomous communities, within the scope of their respective competences, will carry out inspections to the pharmaceutical laboratories in order to verify the compliance with the standards of correct manufacturing. These inspections shall be periodic, at most every three years, and may be planned and communicated in advance or without prior notice, and shall be carried out in accordance with the current competence framework. It shall take into account the collection of the Community procedures published by the European Commission in the field of inspections and exchange of information.

2. The Spanish Agency for Medicines and Health Products and the health authorities of the autonomous communities, in accordance with the current competition framework, may also carry out inspections of manufacturers, importers and distributors of active principles, in order to verify compliance with Part II of the guide to the rules of correct manufacturing, under the premises of risk management. Such inspections may be planned and communicated or carried out without prior notice.

3. At the end of each inspection, a regulatory inspection report shall be drawn up, to be signed by the acting inspector or inspectors and by the technical director of the plant or the technician responsible or, where appropriate, by the person concerned. responsible for the manufacturer, importer or distributor of active substances. It shall contain the most relevant facts and findings that have resulted from the inspection actions.

4. After each inspection, the inspectors shall, where appropriate, draw up a report on compliance with the correct manufacturing standards, published by the Ministry of Health and Social Policy. The content of this report shall be communicated to the inspected. Where sampling is necessary in an inspection, samples shall be taken in accordance with Article 48.

5. An annual inspection plan based on risk management criteria shall be drawn up annually, with the participation of all competent authorities, based on risk management criteria.

6. The competent authorities shall assist each other for inspection purposes.

7. The authorities of the Autonomous Communities and the Spanish Agency for Medicines and Health Products shall exchange the relevant information on the inspections carried out pursuant to the provisions of the preceding paragraphs.

Article 44. Inspections for the authorisation of pharmaceutical laboratories and inspections in third countries.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall carry out appropriate inspections, prior to the authorization of the new installations or to the modifications thereof, to verify that they comply with the legal requirements that are applicable.

2. Without prejudice to any agreements concluded between the European Union and a third country, the Spanish Agency for Medicinal Products and Sanitary Products may request a manufacturer of medicinal products established in a third country to submit to the relevant inspections in order to verify compliance with the correct manufacturing standards.

Article 45. Issuing certificates of compliance with the correct manufacturing standards.

Once the inspection visit has been carried out and compliance with the correct manufacturing standards has been verified, in the 90 days following the inspection, the health authorities shall issue the inspection to the laboratory. a certificate of compliance with those standards, without prejudice to the issue, if any, of the corresponding authorisation by the Spanish Agency for Medicines and Health Products. The validity of the certificate shall be at most three years from the inspection visit.

Article 46. Inspections of manufacturers of active substances.

1. Inspections of active ingredient manufacturers may be carried out in accordance with the processes involved in the manufacture of active substances, both in the production facilities and in the production, storage or distribution facilities in where handling, fractionation, packaging or relabelling activities are carried out.

2. The Spanish Agency for Medicinal Products and Sanitary Products may carry out inspections at the request of the manufacturer, and in accordance with the instructions issued in this respect, on the premises, located both in the national territory and in a third country, in order to review the manufacturing process of one or more active substances related to a record of a medicinal product. The assessment of the opportunity of the inspection shall be carried out by the competent authorities, in accordance with risk management criteria.

3. Once the inspection visit has been carried out and compliance with the correct manufacturing standards has been established, the health authorities acting in the following 90 days shall issue the manufacturer with a certificate of compliance with those rules. The validity of this certificate shall be at most 3 years from the inspection visit.

4. However, that certificate, or other certificate issued by another competent health authority of the European Union or a country with a Mutual Recognition Agreement, shall not exempt the holders of the manufacture of medicinal products from the the obligation to ensure compliance with the standards of correct manufacturing by the manufacturers of active substances.

Article 47. Cooperation with the health authorities of the Member States of the European Union.

1. Where a health authority of a Member State of the European Union requests information relating to a reasoned written inspection, the Spanish Agency for Medicinal Products and Health Products shall transmit the relevant report.

2. If the inspection has been carried out by the autonomous communities, in the exercise of the functions laid down in Article 98 of Law 29/2006 of 26 July, they shall send the information corresponding to the Spanish Agency for Medicinal Products and Medical devices for the purpose of their transfer to the Member State.

3. Where it is necessary to request information on a manufacturer or importer from another Member State, the Spanish Agency for Medicinal Products and Sanitary Products shall be addressed to the competent body of that State, by means of a reasoned letter, and shall be required. the relevant information.

4. In the case provided for in the previous paragraph, if the Spanish Agency for Medicines and Health Products considers that the data provided by another Member State cannot be accepted, before taking a decision, and after attempting to arrive at an agreement with the Member State concerned, shall refer the matter to the European Commission.

5. The Spanish Agency for Medicinal Products and Sanitary Products shall send to the European Medicines Agency the information contained in the authorisation referred to in Article 10 for the recording of this information in a Community database. In addition, the Spanish Agency for Medicinal Products and Sanitary Products shall enter the certificates of good manufacturing standards issued on its territory in this database, administered by the European Medicines Agency on behalf of the European Union.

6. If, following an inspection of a pharmaceutical laboratory, or a manufacturer of active substances, the manufacturer does not comply with the principles and guidelines of the correct manufacturing standards, this information shall be entered in the also in the Community database referred to in the previous paragraph.

Article 48. Sampling.

1. The sampling shall be carried out by means of a document in triplicate before the technical or technical director responsible for the establishment where the inspection visit is carried out. The minutes shall contain in full all the data and circumstances necessary for the identification and characterization of the samples. Together with the samples, the inspector may collect copies of any documentation relevant to the purpose of the inspection.

2. Each sampling shall be carried out in triplicate and each sample shall allow at least a complete analysis. The samples shall be conditioned, sealed and labelled in such a way that, with these formalities and with the signatures of the interveners, stamped on each extraction, the identity of the samples with their content during the time of the procedure is guaranteed. conservation of the same.

3. Of the samples taken, one of the samples shall be held by the laboratory, together with a copy of the minutes, in order to enable it to be used in a contradictory test if necessary. The other two copies shall be withdrawn by the inspector, who shall forward them to the official laboratory for the control of medicinal products.

Article 49. Analysis of the samples.

1. The inspection authorities shall be responsible for the official control laboratory of the Spanish Agency for Medicinal Products and Sanitary Products, or another accredited body, for carrying out the relevant analytical tests.

2. The laboratory to be carried out shall receive a copy of the sample and the relevant documentation for the sample. Once the latter has been completed, it shall, as soon as possible, issue the results obtained and, if requested, a technical report, giving a clear and precise statement on the rating of the sample analysed.

3. Where the result of the initial analysis shows that the samples do not meet the intended quality requirements and the pharmaceutical laboratory does not accept these results, without prejudice to the proof of the right of any of the samples Test means, may request from the instructor of the case the performance of the contradictory analysis.

4. The contradictory analysis shall be carried out in the official laboratory for the control of medicinal products or in the laboratory which has carried out the initial analysis, following the instructions of the expert on the part that the laboratory designates and in the presence of I certify these analyses. To this end, the instructor of the dossier or the laboratory itself shall inform the interested date and time of the conduct of the contradictory analysis.

5. If the data subject expressly or tacitly gives up the contradictory analysis or does not provide the working sample in his or her power, the report shall be drawn up and the results of the first analysis shall be recorded.

6. If there is disagreement between the opinions of the initial analyses and the contradictory analysis, another official or officially accredited laboratory shall be appointed by the competent authority, having in view the background of the previous analyses. analysis and using the third sample, will carry out an urgent third analysis, which will be final and final.

Article 50. Annual plan of sampling of drugs on the market.

1. An annual sampling plan shall be drawn up by the Spanish Agency for Medicinal Products and Health Products and with the participation of all the competent health authorities, in order to ensure the quality of the medicinal products. existing on the market.

2. The samples, collected in the distribution or dispensing establishments, shall be replaced, at no cost to these establishments, by the marketing authorisation holder.

Article 51. Removed due to quality problems.

1. The marketing authorisation holder or the manufacturer and/or importer, in the case of medicinal products not marketed in Spain, shall immediately notify the Spanish Agency for Medicinal Products and Sanitary Products through the system. electronic system, any quality problem that could lead to the withdrawal of the product from the market, supplying all available information and in particular the information concerning the distribution of the batch or lots concerned.

2. The Spanish Agency for Medicinal Products and Sanitary Products will order the withdrawal of the medicinal product and inform the competent authorities of the autonomous communities and the health authorities of all the countries where the batch or batches affected could be distributed, and indicate the reason for this withdrawal.

3. The marketing authorisation holder of the medicinal product concerned shall collaborate with the Spanish Agency for Medicinal Products and Sanitary Products, which shall coordinate with the autonomous communities the monitoring of the effectiveness of the withdrawal.

4. The Spanish Agency for Medicinal Products and Sanitary Products and the competent health authorities of the Autonomous Communities shall carry out appropriate inspections to investigate the quality problems which have led to the withdrawal of the market for the medicinal product, in their respective areas of competence.

CHAPTER VIII

Foreign trade in medicinal products and shipment of authorised medicinal products in Spain to other Member States

Article 52. Import of authorised medicinal products.

1. The importation of medicinal products authorised in Spain and manufactured in third countries shall be carried out by the importing pharmaceutical laboratory or by the marketing authorisation holder, in accordance with the marketing authorisation This medicinal product.

2. Each batch of imported manufacture shall, in a Member State of the European Union, be the subject of a full qualitative analysis of a quantitative analysis of at least all the active substances and of all other tests or verifications necessary to ensure the quality of the medicinal products in compliance with the requirements for the marketing authorisation and shall apply all the provisions of Article 18 to that effect.

3. Where the importing pharmaceutical laboratory, responsible for this control, is located in another country of the European Union, but the import is carried out by the marketing authorisation holder through Spain, the corresponding sampling of each lot must be carried out in Spain, unless an alternative form of sampling has been validated.

Article 53. Import of unauthorized medicinal products.

1. The importation of medicinal products not authorised in Spain and manufactured in third countries which are to suffer in Spain at some stage of their manufacture for subsequent marketing in a Member State of the European Union or in a third country, shall be carried out by an importing pharmaceutical laboratory and shall be authorised in advance by the Spanish Agency for Medicinal Products and Sanitary Products.

2. The Spanish Agency for Medicinal Products and Sanitary Products, following a report by the Ministry of the Environment, and the Rural and Marine Environment, may authorise the entry of medicinal products for animal health, for prevention or for treatment of certain diseases. In the case of the entry of veterinary medicinal products for the exclusive use in one or more livestock holdings or in pet animals, subject to specific veterinary prescription, and therefore without placing on the market of the medicinal product, it shall not be necessary the analysis provided for in Article 52.2 and no prior authorisation shall be required as an importing laboratory.

3. Furthermore, the entry into Spain of unauthorised veterinary medicinal products, with the exception of immunological medicinal products, is permitted in the case of small quantities intended for transit animals in attendance at exhibitions or competitions. farmers or companionship in tourist visits.

Article 54. Export and dispatch to other Member States of authorised medicinal products.

1. The export of medicinal products authorised in Spain may be carried out by the laboratory holder of the marketing authorization, by the manufacturers and/or importers as well as by the wholesale warehouses, in accordance with the provisions of the Article 73 of Law 29/2006 of 26 July.

2. The export of medicinal products for human use, authorised and registered in the Register of medicinal products, shall be notified to the Spanish Agency for Medicinal Products and Sanitary Products by the person concerned to carry out the export. The notification shall include the medicinal products intended to be exported to each of the countries of destination.

3. The medicinal product to be exported shall not be required to comply with the conditions authorised by the Spanish Agency for Medicinal Products and Sanitary Products, in respect of the format, presentation, texts, labelling or characteristics of the packaging, and when the principles of Law 29/2006 of 26 July on guarantees of information to professionals and users are respected.

4. The export of investigational medicinal products, upon accreditation of the approval of the test by the health authorities of the country of destination, may be carried out by the pharmaceutical laboratories manufacturers.

5. The dispatch of medicinal products for human use authorised in Spain to other Member States shall require prior notification to the Spanish Agency for Medicinal Products and Sanitary Products, in accordance with the instructions issued in this respect.

6. In the case of export or dispatch to other Member States of medicinal products for veterinary use, authorised and registered in the Register of medicinal products, notification of such activities may be required where the Spanish Medicines Agency and Healthcare products consider it necessary.

Article 55. Export of unauthorized medicinal products.

1. Pharmaceutical laboratories which wish to manufacture medicinal products which are not authorised in Spain for export must ask the Spanish Agency for Medicinal Products and Sanitary Products for the express authorisation to carry This manufacturing process. In order to obtain such authorization, the pharmaceutical form and the full qualitative and quantitative composition must be communicated, as well as the manufacturing authorization corresponding to the pharmaceutical form and type of medicinal product to which it is treat.

2. The manufacturing authorisations referred to in the previous paragraph shall be renewed periodically in accordance with the determination of the Spanish Agency for Medicinal Products and Sanitary Products. If these authorisations are not renewed, the laboratory must cease in the manufacture of the unregistered medicinal product.

3. The issuance of the manufacturing authorization shall imply the issuance of a certificate for export to the country of destination. The export may also be carried out by other laboratories with which this activity has been contracted.

Article 56. Certifications for foreign trade.

1. At the request of an exporter or of the authorities of an importing third country, the Spanish Agency for Medicinal Products and Sanitary Products shall issue certificates attesting that the manufacturer of the medicinal product is duly authorised and complies with the correct manufacturing rules.

2. The Spanish Agency for Medicinal Products and Health Products shall also issue any other certificate concerning the characteristics of the product, which may be required for the export of medicinal products.

Additional disposition first. Amendment of Article 33 of Royal Decree 223/2004 of 6 February on the regulation of clinical trials with medicinal products.

Article 33 of Royal Decree 223/2004 of 6 February, which regulates clinical trials with medicinal products, is worded as follows:

" 1. The labelling of investigational medicinal products shall be at least in Spanish and shall be in accordance with Annex 13 to the rules for the correct manufacture of medicinal products in the European Union.

2. The labelling of investigational medicinal products shall ensure the protection of the subject and traceability, permit the identification of the product and the test, and facilitate the correct use of the investigational medicinal product. '

Additional provision second. Manufacture of self-vaccines for veterinary use.

The manufacture of self-vaccines for veterinary use, regulated by its specific rules, shall follow principles equivalent to the rules of correct manufacturing for the purpose of ensuring the quality of such medicinal products.

Additional provision third. Actions of the inspection of medicinal genera.

The actions described in Chapter VIII, relating to the external trade of medicinal products, are without prejudice to those which are attributed to the inspection of medicinal genera in the current regulations.

First transient disposition. Adequacy of the current authorisations to the new authorisation regime.

Within six months of the entry into force of this royal decree, the requests that are necessary to adapt the existing authorizations to the provisions of this deadline must be submitted, after this deadline, (a) the authorisations for which the holders have not requested their suitability for the new scheme shall be revoked. The fee payable in this case will be that provided for in Article 109.4 of Law 29/2006 of 26 July on guarantees and rational use of medicines and medical devices

Second transient disposition. Submission of applications by means or non-telematics means.

The submission of the applications provided for in this royal decree may be made, for a period of six months from the date of its entry into force, as laid down in Article 38.4 of Law No 30/1992 of 26 November 1992, Legal status of public administrations and the common administrative procedure.

Transitional provision third. Continuity of technical directors.

The existing appointments of technical directors that would have been made under the regulations in force prior to the entry into force of this royal decree will continue to be valid for all purposes.

Single repeal provision. Regulatory repeal.

As many provisions of equal or lower rank are repealed, they oppose the provisions of this royal decree, and in particular:

(a) Royal Decree 1564/1992 of 18 December 1992 on the development and regulation of the system of authorization of pharmaceutical laboratories and importers of medicinal products and the quality assurance of their industrial manufacture.

(b) Title IV and V of Royal Decree 109/1995 of 27 January 1995 on veterinary 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 exclusive competence to the State in the field of legislation on pharmaceutical products.

Final disposition second. Regulatory development.

The head of the Ministry of Health and Social Policy is hereby authorized to make any provisions necessary for the implementation and development of this royal decree.

Final disposition third. Entry into force.

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

Given in Madrid, on June 25, 2010.

JOHN CARLOS R.

The First Vice President of the Government and Minister of the Presidency,

MARIA TERESA FERNANDEZ DE LA VEGA SANZ