Production of medicinal products

Applicants who wish to pursue this activity must register the business activity, and have the appropriate legal status.

A business entity can produce medicinal products only on the basis and in accordance with the authorisation for manufacturing medicinal products. The authorisation includes the manufacture of medicinal products and their sale to wholesalers of medicinal products and must be acquired for:

•  individual manufacturing sites,
• individual manufacturing activities,
• individual pharmaceutical forms
• and the import of medicinal products from third parties.

The provisions under the previous paragraph apply also for the manufacture of medicinal products that are intended for removal, export or clinical tests of medicinal products.

The manufacturer of the medicine must fulfil the following conditions:

• considering the scope and complexity of medicine manufacture, the manufacturer employs a suitable number of experts with the required education;
• has a concluded contract with a responsible person who is qualified for launching an individual lot of medicine into the market and is constantly available;
• disposes of appropriate premises, devices and the equipment for the manufacture, control, storage and dispatch of medicinal products in accordance with guidelines and principles of good manufacturing practice for medicinal products;
• manufactures medicinal products in accordance with guidelines and good manufacturing practice for medicinal products and uses active substances manufactured in accordance with good manufacturing practice for active substances that were traded in accordance with good distribution practice for active substances;
• and enables the responsible person under item 2 independent performance of tasks with all necessary available means.

The procedure for the acquisition of the authorisation for the manufacture of medicinal products starts on the basis of the application of a legal or natural entity encompassing the general and expert part.

The application for the acquisition of the authorisation for manufacturing medicinal products is submitted by the application to the agency in printed and electronic form.

The general part of the application encompasses the following data and documents:

•  Letter indicating:

- the full and shortened name and head office of the applicant, stating all locations where medicinal products are manufactured;

- activities of the applicant subject to the procedure for the issue of the authorisation for manufacturing medicinal products;

- name and surname of the responsible person and signature of the responsible person;

•  Documentation:

- the list of persons who work as manufacturing and control managers or other persons who take over responsibilities determined in the second chapter of good manufacturing practice;

- evidence on the availability of the person responsible for launching an individual lot of medicine and who is constantly accessible and fulfils the prescribed conditions, evidence on their professional education and appropriate work experience;

- written statement of the applicant to enable the responsible person under the previous item independent performance of duties and that it has all required means;

- written statement of the applicant that they will manufacture medicinal products in accordance with the guidelines and principles of good manufacturing practice;

- written statement of the applicant that they will use only active substances manufactured in accordance with good manufacturing practice;

- written statement of the applicant that only medicinal products manufactured within the activities under the manufacture authorisation will be ensured in accordance with regulations.

The expert part of the application contains information on the applicant on fulfilling expert requirements. The applicant states information in the scope that applies to the scope of their work processes for the manufacture of medicinal products.

The expert part of the application can be replaced by an appropriate internal document of the applicant which contains the prescribed data.

The applicant states data and documents in the expert part which are determined in the Annex to the Rules on conditions for completing activities of making medicinals and determining of conditions and procedure of publishing or revocation of execution of good production practices.

Details

The holder of the authorisation for the manufacture of medicinal products can require a confirmation or certificate on good manufacturing practice (GMP certificate) from the authority competent for medicinal products. The certificate on the implementation of good manufacturing practice can be issued based on the performed special fact-finding procedure within the scope of the authorisation issue or performed control of the fulfilment of conditions for the manufacture of medicinal products at the holder of authorisation.

The certificate on good manufacturing practice is issued by the pharmaceutical inspector to the inspected business entity ex officio within 90 days from the date of inspection, if it is found that the business entity manufactures medicinal products or active substances in accordance with the good manufacturing practices principles and guidelines or within 15 days from the issue of modification of the authorisation for manufacturing medicinal products or the entry or the modification of the entry in the register of manufacturers of active substances.

The certificate on good manufacturing practice is issued on a form in Slovenian and English languages as stipulated in the Compilation of Community Procedures.

The certified application lodged by the holder of the authorisation contains:

• full and short name and address of the applicant;
• the number of the authorisation for manufacturing medicinal products;
• location and activity from the authorisation for which the applicant requests a certificate;
• the number of existing certificates for such activities.

The certificate contains only the information on the conformity of the applicant's activities in the scope of the supervision which is the basis for the issue of the certificate.

The validity of the certificate is usually three years. The validity can be shortened based on the opinion of the pharmaceuticals supervisor.

Details

The activities of manufacturing medicinal products and pharmaceutical forms are determined in the Compilation of Community Procedures on Inspection and exchange of Information (hereinafter: Compilation of Community Procedures) which is published on the website of the European Commission in its respective and valid text.

Legal basis

• Medicinal Products Act (ZZdr-2)

The manufacturer of medicinal products:

•  is enabled to and can place on the market only medicinal products produced as per the marketing authorisation for medicinal products and the manufacturing authorisation for medicinal products;
• verifies the compliance of producers and suppliers of substances with good manufacturing practice for substances or good distribution practice for substances, or both, by conducting assessments;
• ensures that excipients are suitable for use in medicinal products on the basis of the documented risk assessment in accordance with the guidelines of the European Commission which determine good manufacturing practice for excipients;
• verifies and ensures that producers, importers or suppliers from which they obtain substances are entered in registers at the authority responsible for medicinal products in the EU member states in which they have their head offices;
• if they obtain information that medicinal products which are included in the framework of their manufacturing authorisation for medicinal products are falsified or there is suspicion that they are falsified, they immediately inform the competent authority thereof and the holder of the marketing authorisation for medicinal products irrespective of whether the falsified products were on sale through an illegal or legal supply chain;
• ensures authenticity and the quality of substances and excipients used;
• ensures that medicinal products intended for placement on the market in the European Union contain the prescribed protective elements which are attached to the external packaging and
• if they partly or completely remove these protective elements from the product, they must ensure that these activities are implemented in accordance with the regulated procedure.

 The manufacturer of medicinal products ensures appropriate labelling and instructions for the use of medicinal products in compliance with:

• the Rules on the labelling and instructions for medicinal products for human use;
• the Rules on the identification and use instructions of veterinary medicinal products and
• the Rules on radiopharmacological products.

Legal basis

• Medicinal Products Act (ZZdr-2)
• Rules on radiopharmacological products
• Rules on the labelling and instructions for medicinal products for human use
• Rules on the identification and use instructions of veterinary medicinal products

Pharmacovigilance denotes the monitoring of the safety of medicinal products after the acquisition of marketing authorisation, and includes all activities related to the detection, assessment, understanding and prevention of the adverse effects of medicinal products and other medicinal product-related complications.

Activities in the field of pharmacovigilance:

•  collection and assessment of reports on the adverse effects of medicinal products and reporting in the pharmacovigilance system;
• assessment of periodic safety update reports (PSUR);
• assessment of other data related to the safety of medicinal products;
• risk assessment, adoption and implementation of measures for the safe use of medicinal products;
• assessment of plans for risk management and detailed descriptions of the pharmacovigilance system;
• informing of the expert and broader public;
• activities in the international system of pharmacovigilance;
• implementation of pharmacovigilance control at holders of marketing authorisations and
• encouraging health-care workers to report the adverse effects of medicinal products.

 The holder of the marketing authorisation for medicinal products for human use:

•  establishes, maintains and manages the pharmacovigilance system, which ensures the collection and keeping of documentation about all the assumed adverse effects of medicinal products in the European Union and third countries, scientifically assesses all information, studies options for the reduction and prevention of risk, adopts necessary measures and exchanges data with authorities responsible for medicinal products in the EU member states;
• regularly assesses its own pharmacovigilance system and keeps a main dossier on the pharmacovigilance system, which it submits to the competent authority on request;
• manages a risk management system for all medicinal products and updates it proportionately with the established risks and monitors data on pharmacovigilance;
• informs the authority competent for medicinal products in the Republic of Slovenia of newly established or changed risks, on changes in the relationship between the benefits and risks of medicinal products and, in advance or simultaneously, informs the authority competent for medicinal products in the Republic of Slovenia, the European Commission and the European Medicines Agency (EMA) on the content of every publication of information relating to questions about pharmacovigilance;
• immediately submits all data proving that the relationship between benefit and risk remains beneficial at the request of the competent authority;
• meets the requirements and obligations relating to the supervision of non-interventional studies on the safety or efficiency of medicinal products after the acquisition of a marketing authorisation as per this act;
• submits data on all the assumed adverse effects of medicinal products into the EudraVigilance database with the exception of reports on medicinal products with substances from the list of publications monitored by the EMA;
• fulfils obligations relating to periodic safety update reports on medicinal products as per the first and third paragraphs of Article 107.b and the first, second, third and sixth paragraphs of Article 107.c of Directive 2001/83/EC;
• observes procedures during the implementation of pharmacovigilance which are described in detail in implementing measures of the European Commission as per Article 108 of Directive 2001/83/EC, the guidelines on good practices in the field of pharmacovigilance as per Article 108.a of Directive 2001/83/EC and scientific guidelines on efficiency studies after the acquisition of a marketing authorisation as per Article 108.a of Directive 2001/83/EC.

The holder of the marketing authorisation for medicinal products for human use must employ a person responsible for the pharmacovigilance system.

If the marketing authorisation holder does not have its head office in the Republic of Slovenia, it may also appoint, in addition to the person responsible for the pharmacovigilance system, a contact person for pharmacovigilance in the Republic of Slovenia who has a secondary level of education in medicine, veterinary medicine or pharmacy or another compliant level of education as per the law and who is suitably qualified. The contact person for pharmacovigilance must also be appointed if this is requested by the competent authority which issues a decision in this regard. The contact person may be a business entity with its head office in the Republic of Slovenia or an individual with permanent or temporary residence in the Republic of Slovenia who performs pharmacovigilance activities for the needs of one or several business entities.

The provision of pharmacovigilance services is defined in more detail in the Rules on the pharmacovigilance of medicinal products for human use.

Legal basis

• Medicinal Products Act (ZZdr-2)
• Rules on pharmacovigilance of medicinal products for human use
• Rules on the pharmacovigilance of veterinary medicinal products

The holder of the marketing authorisation must have a permanently available person responsible for the pharmacovigilance system who is responsible for the establishment and maintenance of the pharmacovigilance system. The person responsible for pharmacovigilance system: 

is responsible for the establishment and maintenance of the pharmacovigilance system to ensure the collection and comparison of data on all suspected adverse reactions of the medicinal product; has ensured access to the main dossier on the pharmacovigilance system and sufficient jurisdiction for ensuring that the content of the main dossier on the pharmacovigilance system is accurate and regularly updated to reflect the needs of the pharmacovigilance system; has sufficient jurisdiction to impact the implementation of the quality system and pharmacovigilance activities; has an overview of the safety profiles of medicinal products and safety issues and considers as well as monitors the conditions of launching medicinal products and other obligations that affect the safety of medicinal products and the measures for reducing risks; has sufficient jurisdiction with regard to the content of risk management plans, cooperates at the review and approval of protocols of clinical trials after acquiring the marketing authorisation; ensures appropriate quality, accuracy and completion of data on the pharmacovigilance of the medicinal product that are submitted to the competent authority and to all requirements of the competent authority to submit additional data required for assessing benefits and risks connected with the medicinal product, replies in entirety and immediately and submits data on sales; submits all other information relevant for the assessment of benefits and risks connected to the medicinal product to the competent authority, including appropriate data from clinical trials after obtaining the marketing authorisation; guarantees 24-hour availability; has appropriate education, knowledge and skills.

Details

The scales used for measuring in the following fields:

• protection of human and animal health,
• environmental protection and general technical safety,
• goods and services traffic,
• procedures before administrative and judicial authorities

must fulfil metrology requirements confirmed with the first and regular certification during the whole period of application.

The first certification of the metering device is the examination of the new metering device and confirmation of its conformity with the approved type and/or prescribed metrology requirements for the respective type of metering device. The first certification is provided by the producer of the metering device or his authorised representative.

Regular certification of the metering device must be provided by its owner.

The extraordinary certification is mandatory for metering devices which were excluded from application due to re-modelling, fault or other technical deficiencies. The compliance of metering devices with the metrology requirements is determined by applying the extraordinary certification. The extraordinary certification is provided by the holder of the metering device.

Regular and extraordinary certifications are conducted by the Metrology Institute or the appointed legal entity or sole trader.

Evidence

Certification designation on the metering device.

Legal basis

• Metrology Act (ZMer-1)
• Rules on metrological requirements for non-automatic weighing instruments