Part II MODULE II – PHARMACOVIGILANCE SYSTEM MASTER FILE

II.A. Introduction

The legislative requirement for maintaining a PSMF and providing it upon request by applicants (registration certificate holders) was introduced by Directive 2010/84/EU [3], which amended Directive 2001/83/EU [1] with regard to pharmacovigilance (see recitals (7) and (35), Article 23(4), Article 104(3)(b) of Directive 2010/84/EU), and by Regulation (EU) No. 1235/2010 [4], which amended Regulation (EU) No. 726/2004 [5] with regard to pharmacovigilance of medicinal products for human use (see recitals (22) and (25), Article 16(3a) of Regulation (EU) No. 1235/2010), in order to harmonize and strengthen pharmacovigilance activities in the EU and in Ukraine in accordance with the provisions of the Procedure [2] ^N.

The definition of the PSMF is given in Article 1(28e) of Directive 2001/83/EC [1] and in the Procedure [2] ^N, and the minimum requirements for its content and maintenance are set out in Commission Implementing Regulation (EU) No. 520/2012 (hereinafter – IR 520/2012) [6] on the performance of pharmacovigilance activities provided for in Regulation (EU) No. 726/2004 [5] and Directive 2001/83/EC [1] and in Annex No. 11 to the Procedure [2]^N. The detailed requirements set out in the Commission Implementing Regulation and in Annex No. 11 to the Procedure [2]^N are further supported by the guidance in this GVP module.

The PSMF must be located on premises at the site where the main pharmacovigilance activities of the applicant (registration certificate holder) are carried out, or where the QPPV/QPPV of Ukraine operates^N (Article 7(1) IP 520/2012 [6], provisions of the Procedure [2]^N).

Submission of summary data on the pharmacovigilance system to the competent authority is a requirement for an application for state registration (Art. 8(3)(ia) of Directive 2001/83/EC and the provisions of the Procedure for Expert Evaluation of Registration Materials [7]^N). The said summary data on the pharmacovigilance system must contain information on the location of the PSMF (see section II.B.2.1).

This module contains a detailed description of the requirements for the PSMF, including its maintenance, content, and submission to the competent authority.

II.B. Structures and processes

The existence of a PSMF is a legal requirement of the EU and of Ukraine ^N. This module sets out the PSMF requirements that apply to any medicinal product authorized in the EU and in Ukraine^N, regardless of the registration procedure. The requirements for the content and maintenance of the PSMF apply regardless of the organizational structure of the applicant (registration certificate holder), including any subcontracted or delegated activities, or the location where they are carried out. Regardless of where other activities (other than pharmacovigilance) ^N are carried out, the place of residence of the QPPV/local QPPV^N and the location from which they perform their duties must be within the EU and Ukraine^N. If the QPPV does not reside in Ukraine, a single local QPPV who resides and works in Ukraine and is accountable to the QPPV is appointed in the territory of Ukraine. The local QPPV must have an appropriate document confirming their authority. The PSMF must be located or accessible ^N within Ukraine. ^N

The content of the PSMF should reflect the global availability of safety information on medicinal products authorized for medical use in the EU and Ukraine ^N, presenting information on the pharmacovigilance system applied at the global, local and regional levels.

II.B.1. Objectives

The PSMF must describe the pharmacovigilance system and confirm/document its compliance with the requirements of Ukrainian legislation. In addition to meeting the PSMF requirements set out in the provisions of the Procedure[2]^N and the Guideline on Pharmacovigilance, the PSMF must also facilitate the proper planning and conduct of audits by the applicant (registration certificate holder), the performance of the oversight functions of the QPPV/local QPPV^N, and the conduct of audits of the pharmacovigilance system by the authorized institution^N or other compliance control. The PSMF contains an overview of the pharmacovigilance system, which may be requested and assessed by the authorized body during the registration procedure or in the post-registration period.

By creating and maintaining the PSMF, the applicant (registration certificate holder) and the QPPV will be able to:

• ensure that the pharmacovigilance system has been implemented in accordance with legislative requirements;
• confirm the compliance of the pharmacovigilance system with the requirements of legislation;
• obtain information on deficiencies of the pharmacovigilance system or non-compliance with legislative requirements;
• obtain information on risks or current deficiencies in the implementation of individual areas of pharmacovigilance.

Use of this information should contribute to proper management and improvement of the pharmacovigilance system.

The requirements for submission by the applicant (marketing authorization holder) to the competent authority of summary data on the pharmacovigilance system, provision of the PSMF and the history of changes made must ensure planning and effective conduct by the competent authority of an inspection in the EU and an audit of the pharmacovigilance system by the authorized institution^N in Ukraine on the basis of a risk-based approach.

The obligations regarding the PSMF on the part of applicants (registration certificate holders), competent authorities and the European Medicines Agency (EMA) are described in detail in section C (see II.C.1.) and in Ukraine in accordance with the provisions of the Procedure [2] ^N.

II.B.2. Registration and maintenance

II.B.2.1. Summary of the applicant's (marketing authorization holder's) pharmacovigilance system

In accordance with Article 8(3) (ia) of Directive 2001/83/EC [1] and the provisions of the Procedure for Expert Evaluation of Registration Materials [7] ^N, module 1.8.1 of the application for state registration of a medicinal product must contain a summary of the applicant's (marketing authorization holder's) pharmacovigilance system, including the following information:

confirmation that the applicant (registration certificate holder)

• has at its disposal the QPPV/ local PV contact person^N, if different from the QPPV ^N;
• contact details of the QPPV/LCPPV^N, if different from the QPPV ^N;

guarantee letter from the applicant (registration certificate holder)

• on ensuring the functioning of an appropriate system for monitoring the safety of medicinal products during their medical use, including in Ukraine ^N;
• place of main pharmacovigilance activities;
• location of the PSMF for the medicinal product.

Applicants (registration certificate holders) for the registration of traditional herbal medicinal products are not required to submit summary data on their pharmacovigilance systems; however, they are obliged to have a functioning pharmacovigilance system and to create, maintain and make available upon request the PSMF (Article 16g (1) of Directive 2001/83/EC [1], in Ukraine in accordance with the provisions of the Procedure for conducting expert evaluation [7] ^N).

For other herbal medicinal products that are not subject to the registration procedure as traditional medicinal products, it is required to have an operating pharmacovigilance system, to establish, maintain and provide upon request a PSMF (pharmacovigilance system master file), and to submit summary data on the pharmacovigilance system.

For homeopathic medicinal products registered under the simplified procedure in Ukraine, in accordance with the requirements of Annex 7 to the Procedure for Conducting Expert Evaluation [7] ^N, it is not required to have a pharmacovigilance system, to maintain and provide access on request to the PSMF, or to provide summarized data on the pharmacovigilance system (Article 16(3) of Directive 2001/83/EC [1]; in Ukraine, in accordance with the provisions of the Procedure for Conducting Expert Evaluation [7] ^N).

For other homeopathic medicinal products that do not fall under the simplified registration procedure, in Ukraine, in accordance with the requirements of Annex 7 to the Procedure for Expert Evaluation [7] ^N, it is required to have a functioning pharmacovigilance system, to create and maintain the PSMF and provide access to it upon request, and to provide summary data on the pharmacovigilance system (Article 16(3) of Directive 2001/83/EU [1]; in Ukraine, in accordance with the requirements of Annex 7 to the Procedure for Expert Evaluation [7] ^N) .

II.B.2.2. Location, registration and storage of the pharmacovigilance system master file

The PSMF, regardless of format (paper or electronic), must be kept at the site where the main pharmacovigilance activities of the applicant (registration certificate holder) are carried out, or at the site where the QPPV/QPPV of Ukraine operates^N (Article 7(1) IP 520/2012 [6]).

If the MAH is located outside Ukraine and is represented in Ukraine by a / QPPV, the PSMF must be accessible, and it must include information on the pharmacovigilance of medicinal products in Ukraine^N.

When submitting a registration application, the applicant (registration certificate holder) must provide information on the location of the PSMF using the agreed format (Article 26 1(a) IR 520/2012 [6]) and consistently include in the application the PSMF reference number, which is a unique code assigned by the EudraVigilance system to the master file when processing the EudraVigilance medicinal product report message (XEVPRM) (see^[1]). After the registration certificate is issued, the PSMF will be linked by the applicant (registration certificate holder) to the medicinal product code from the EudraVigilance medicinal product dictionary (EVMPD). All PSMFs must be registered in the database under Article 57 of Regulation (EC) No. 726/2004 [5]. In Ukraine, when submitting a registration application, the applicant (registration certificate holder) must specify data on the PSMF: its existence, number and location, in accordance with the provisions of the Procedure for conducting expert evaluation [7]. The legislation does not provide for registration of the PSMF in EudraVigilance ^N .

Applicants (registration certificate holders) must continue to ensure that the data they have entered into the database under Article 57 of Regulation (EC) No. 726/2004 [5] for medicinal products for human use are up to date, including the QPPV, name and contact details (telephone and fax number, postal address and e-mail) and information on the location of the PSMF (Art. 4 (4) of the Implementing Regulation 520/2012 [6]). After a change in information about the QPPV or the location of the PSMF, the database under Article 57 of Regulation (EC) No. 726/2004 [5] must be updated by the applicant (registration certificate holder) immediately, and no later than within 30 days, in order to update the information in the database under Article 57 of Regulation (EC) No. 726/2004 [5] and on the European medicines web portal, as specified in Article 26(1) of Regulation (EC) No. 726/2004 [5] and for continuous oversight by the competent authorities (Article 4 (4) of the Implementing Regulation 520/2012 [6], Article 57 (2)(c) of Regulation (EC) No. 726/2004 [5] (see^[2]). In Ukraine, the applicant (registration certificate holder) must ensure that the information provided by them in the summary description of the pharmacovigilance system is up to date, including the QPPV/local PV contact person: name, contact details (telephone, fax, postal address and e-mail) and information on the location of the PSMF. After a change in information about the QPPV/local PV contact person or the location of the PSMF, the applicant (registration certificate holder) must report such changes in the manner established by legislation (provisions of the Procedure for conducting expert evaluation [7]) ^N .

The required information on the location of the PSMF is data on the location of the premises of the applicant (registration certificate holder) or of a third-party contractor. If the PSMF is kept in electronic format, the location must be the place where these data are directly accessible, and this is sufficient in terms of the actual electronic location (Article 7(3) of IP 520/2012 [6]).

When determining the main place of pharmacovigilance activities, the applicant (registration certificate holder) should consider the location most appropriate for the pharmacovigilance system, since the relative importance of particular activities may vary depending on the medicinal products and in the short term. The registration certificate holder must justify the choice of the PSMF location accordingly. Where the main activities are conducted outside the EU, Ukraine ^N, or where the place where the main pharmacovigilance activities are conducted cannot be determined, the PSMF must be located at the premises where the QPPV/local QPPV^N works.

II.B.2.3. Transfer of responsibility for the pharmacovigilance system master file

The pharmacovigilance system may change over time. The transfer or delegation of duties and activities related to the PSMF must be appropriately documented (see subsections II.B.4.2. and II.B.4.8. of the GVP guideline) and organized so as to ensure that the applicant (registration certificate holder) fulfills its obligations. Since the job responsibilities of the QPPV/LPPV^N state responsibility for the pharmacovigilance system, the QPPV must also be informed of any changes to the PSMF in order to maintain their authority to improve the pharmacovigilance system. Changes that the QPPV/LPPV^N must be informed of regularly and in a timely manner include:

• updates to the PSMF or changes to its location, which are brought to the attention of the competent authority;
• introduction of corrective and/or preventive actions to the PSMF (for example, after audits, inspections, and audits of the pharmacovigilance system by an authorized institution^N in accordance with the provisions of the Procedure [2]) ^N). The QPPV/ deputy QPPV^N must also have access to information on deviations from the processes defined in the pharmacovigilance quality management system;
• changes to the content of the PSMF that meet the criteria for proper oversight of the pharmacovigilance system (in terms of resources, functioning and compliance);
• changes to the conditions for submitting MFSF to the competent authorities;
• transfer of a significant part of pharmacovigilance activities to a third party (for example, preparation of a periodic safety update report by a third party);
• inclusion of medicinal products in the pharmacovigilance system for which the QPPV/LPPV^N is responsible;
• changes to medicinal products covered by the pharmacovigilance system that may require changes or an increased pharmacovigilance workload, for example, new indications for use, studies.

Any QPPV/ local pharmacovigilance contact person^N must officially receive information in writing about the following changes:

• transfer of responsibility for the pharmacovigilance system by the QPPV/LCPPV^N.

The QPPV/ LQPPV^N must be able to verify and ensure that the information in the PSMF is an accurate and up-to-date reflection of the pharmacovigilance system for which they are responsible (see GVP Module I).

II.B.3. Representation of the pharmacovigilance system

According to Article 1(28e) of Directive 2001/83/EC [1] and the Procedure [2] ^N, the PSMF must describe the pharmacovigilance system for one or more medicinal products of the applicant (registration certificate holder). Separate pharmacovigilance systems may, where appropriate, apply to different categories of medicinal products of the applicant (registration certificate holder). Each such system must be described in a separate PSMF. These PSMFs must together cover all medicinal products of the applicant (registration certificate holder) that were registered in accordance with the provisions of Directive 2001/83/EC or Regulation (EC) No. 726/2004 [5] and the provisions of the Procedure for Conducting Expert Evaluation of Registration Materials [7] ^N:

• It is recognized that in some cases an applicant (registration certificate holder) may implement more than one pharmacovigilance system, for example, dedicated systems for certain groups of medicinal products (e.g., vaccines, over-the-counter medicinal products, etc.), or that pharmacovigilance systems may cover the medicinal products of more than one applicant (registration certificate holder). In any case, each system must be described by a separate PSMF.
• In accordance with Articles 8 and 104 of Directive 2001/83/EC [1] and the provisions of the Procedure [2] ^N, a single QPPV/local PV contact person^N must be appointed, who will be responsible for establishing and maintaining the pharmacovigilance system described in the PSMF. Each pharmacovigilance system of the applicant (marketing authorization holder) may have only one QPPV. If the QPPV does not reside in Ukraine, a single local PV contact person who resides and works in Ukraine and reports to the QPPV is appointed in the territory of Ukraine (provisions of the Procedure [2] ^N).
• If the pharmacovigilance system is shared by several applicants (registration certificate holders), each applicant (registration certificate holder) is responsible for ensuring that a PSMF is available to describe the pharmacovigilance system applicable to its medicinal products. The applicant (registration certificate holder) may delegate (for example, to a partner or contractor) by means of a written agreement part or all of the pharmacovigilance activities for an individual product(s) for which the applicant (registration certificate holder) is responsible. In this case, the PSMF of the applicant (registration certificate holder) may refer to the whole PSMF or to individual sections of the PSMF governed by the system of the party to which the activities were delegated, in accordance with an agreement on access to the information of such system for the applicant (registration certificate holder) and the competent authority. The applicant (registration certificate holder) must ensure that the content of the documentation relating to the pharmacovigilance system to which it refers applies to its medicinal products. The activities of keeping the PSMF up to date and accessible may be delegated.
• Where appropriate, a list of all PSMFs owned by the applicant (registration certificate holder) should be provided in an annex (see subsection II.B.4.8. NNPF) (Article 3(7) IR 520/2012 [6], provisions of the Procedure[2]^N), including data on their location, information on the QPPV/LCP^N, and the relevant medicinal product(s).
• The summary data (brief description of the PV system ^N ) submitted to the authorized body must not contain several locations for one PSMF. The PSMF location address required under Article 8(3) of Directive 2001/83/EC [1] (and within the database under Article 57 of Regulation (EC) No. 726/2004 [5]) and the provisions of the Procedure for Expert Evaluation of Registration Materials [7] ^N, must be the address of the location where the main pharmacovigilance activities of the applicant (registration certificate holder) are conducted, or of the premises where the QPPV/LCPPV works^N. This address may differ from the address of the applicant (registration certificate holder), for example, if the applicant (registration certificate holder) is located elsewhere or when a third party conducts the main pharmacovigilance activities.
• Similarly, the QPPV/LPPV^N data for a particular medicinal product in the database under Article 57 of Regulation (EU) No. 726/2004 [5], in accordance with the provisions of the Procedure for Conducting Expert Evaluation [7] ^N may be the QPPV/LPPV^N data of the contractor responsible for the pharmacovigilance system of this product, and not necessarily of the QPPV/LPPV^N directly hired by the applicant (the registration certificate holder).
• When delegating any activity related to the pharmacovigilance system and the PSMF, the applicant (registration certificate holder) bears full ultimate responsibility for the pharmacovigilance system, for providing information on the location of the PSMF, for maintaining it, and for providing it on request to the authorized body (Article 6 of IR 520/2012 [6] and the provisions of the Procedure ^N [2] and the Procedure for Conducting Expert Evaluation [7] ^N). Written agreements must exist that describe in detail the functions and responsibilities regarding the content of the PSMF, its submission and maintenance, as well as the regulation of pharmacovigilance activities in accordance with legislative requirements (based on Article 6 of IR 520/2012 [6] and the provisions of the Procedure [2]) ^N.
• In the case of a shared pharmacovigilance system, it is recommended that the partners agree on how to jointly maintain the relevant sections of their PSMFs. Access to the PSMF for all relevant applicants (marketing authorization holders), as well as its submission to the competent authority, must be defined in written agreements. It is critically important that the applicant (marketing authorization holder) be able to obtain confirmation that the pharmacovigilance system used for its medicinal products is adequate and appropriate.

II.B.4. Information to be included in the pharmacovigilance system master file

The PSMF must contain at least all the documents listed in Article 2 of IR 520/2012 [6] and in the provisions of the Procedure [2] ^N.

The PSMF must contain documents describing the pharmacovigilance system. The content of the PSMF must reflect the global availability of safety information on medicinal products registered in the EU and Ukraine. The PSMF content must be numbered to ensure effective searching within the document, be organized according to the modular system described in the following sections, and have the annex headings described in subsection II.B.6.1. NNPF. The basic principle of the PSMF content structure is that the main sections contain the information necessary to describe the pharmacovigilance system. Detailed information is required for a complete description of the system, and since it may change frequently, it must be included in the form of references and contained in annexes. The control related to changes in the PSMF content is described in subsection II.B.5.NNPF.

It is acceptable that if a registration certificate has not previously been issued (and no PSMF existed), some information in the PSMF cannot be provided at the initial stage, for example, compliance information; however, information on what will be implemented should be provided instead.

II.B.4.1. Section of the pharmacovigilance system master file on the qualified person responsible for pharmacovigilance

Contact information of the QPPV/local pharmacovigilance contact person^N in Ukraine, if different from the QPPV ^N, must be specified in the registration application (Article 8(3)(ia) of Directive 2001/83/EC [1] and the provisions of the Procedure for Expert Evaluation of Registration Materials [7]) ^N and/or in the database under Article 57 of Regulation (EC) No. 726/2004 [5].

Information on the UOVF contained in the ASMF (Article 2(1) IP 520/2012 [6] and provisions of the Procedure [2]) ^N, must include:

• list of responsibilities to ensure that the QPPV/ deputy QPPV^N has sufficient authority to establish a pharmacovigilance system, support and improve its functioning, including in Ukraine ^N;
• summary with key information on the role of the QPPV, including confirmation of registration in the EudraVigilance database; In Ukraine, registration of the local person responsible for pharmacovigilance (LPPV) in the EudraVigilance database is not provided for by law ^N ;
• contact details;
• information on backup mechanisms that will be activated if the QPPV is absent;
• information on the duties of the CPPV, including in Ukraine, if different from the QPPV ^N, including her contact information.

The annexes (see subsection II.B.4.8. of the PSMF guideline) must include a list of tasks delegated to the QPPV. The activities that have been delegated must be listed, indicating to whom exactly, and access to a person with medical education must be specified where necessary (see module I of the PSMF guideline), Article 10(1) of the IP 520/2012 [6] and the provisions of the Procedure [2]^N). This list may be presented as a copy of a procedural document, provided that it contains all the necessary information.

The information provided regarding the QPPV must also include data on qualifications, work experience and pharmacovigilance registrations (including registration in EudraVigilance; in Ukraine, registration of the QPPV/LCPPV in the EudraVigilance database is not provided for by law ^N). Contact details must include surname, first name, patronymic, postal address, telephone, fax and e-mail address, which are the working contact details of the QPPV/LCPPV^N and may not coincide with the address of the applicant (registration certificate holder). If the QPPV was hired by a third party, even if their work address is the address of the applicant's (registration certificate holder's) location, this must be stated, and the name of the company where the QPPV works must be given.

II.B.4.2. Section of the pharmacovigilance system master file on the organizational structure of the applicant (registration certificate holder) certificate

This section must describe the organizational structure of the applicant (marketing authorization holder) with respect to the pharmacovigilance system. This section must contain a description of the companies involved, the main pharmacovigilance units, and the relationships between the organizations and units relevant to the performance of pharmacovigilance obligations. The description must include third parties involved in activities related to the conduct of pharmacovigilance. In particular, the PSMF must describe:

• the organizational structure of the applicant(s) (marketing authorization holder(s)) indicating the position of the QPPV within the organization;
• the site(s) where pharmacovigilance activities are carried out, including collection of reports of adverse reactions, their assessment, entry into the safety database, generation of periodic safety update reports, signal detection and analysis, management of the risk management plan, as well as pre- and post-authorization studies, management of safety variations, summary of product characteristics of the medicinal product(s)/package leaflet (Article 2(2) of IP 520/2012 [6], provisions of the Procedure [2], provisions of the Procedure for Expert Evaluation of Registration Materials [7]) ^N.

The information in this section can be presented visually as diagrams indicating the name of the unit or the third party.

Delegated activities

The PSMF must contain a description of the activities and/or services for fulfilling pharmacovigilance obligations delegated by the applicant (marketing authorization holder), if any (Article 2(6) of IR 520/2012 [6], provisions of the Procedure [2]) ^N. Delegated activities include arrangements with other parties in any country of the world and at the global level concerning the pharmacovigilance system applicable to medicinal products authorized in the EU and Ukraine ^N.

This section should provide information on relationships with other organizations, in particular joint marketing agreements or pharmacovigilance service contracts. Information should be provided on the location and substance of contracts and agreements relating to the fulfillment of pharmacovigilance obligations. Such information may be presented as a list/table indicating the parties involved, their responsibilities and the relevant medicinal products and countries. The list should be organized by: service providers (e.g., medical information, auditors, organizers of patient support programs, study data management, etc.), commercial agreements (distributors, partners, joint marketing, etc.) and other technical services (hosting of computer systems, etc.). A list of contracts is provided in the annexes (see subsection II.B.4.8.NNPF), and the contracts themselves must be available upon request of the competent authority or during audits, inspections, or an audit of the pharmacovigilance system by an authorized body^N.

II.B.4.3. Section of the pharmacovigilance system master file on safety data sources

The description of the main safety data collection units should include information on all responsible parties at the global level for organized and spontaneous collection of medicinal product safety data. Such a description should include medical information websites as well as affiliates of the organization, and may be presented as a list indicating the country, nature of activity and medicinal product(s) (if the activity is related to a specific medicinal product) and the contact details (address, telephone and e-mail) of the site. This list may be placed in the annexes to the PSMF. Information about third parties (partners or local distribution/marketing agreements) should also be included in the section describing contracts and agreements (see II.B.4.2. and II.B.4.8 of the GVP).

The information may be presented as flowcharts indicating the main stages, timelines and parties involved. Regardless of the presentation, the description of the processes from collection to submission of adverse reaction reports to the authorized bodies must reflect the departments and/or third parties involved.

For the purposes of an audit, inspection, or audit of the pharmacovigilance system by the authorized institution^N, safety data sources must include data coming from studies, including any studies, registries, surveillance or support programs funded by the applicant (registration certificate holder), through which reports of adverse reactions can be collected. Applicants (registration certificate holders) must be able to prepare and provide a list of such sources during an audit, inspection, or audit of the pharmacovigilance system by the authorized institution^N and oversight by the QPPV/local PV contact person^N. For the purposes of harmonization, it is recommended that the list be comprehensive for the registered medicinal products, regardless of their indications, dosage forms or route of administration. The list must indicate, at the global level, the status of each study/program, the countries involved, the medicinal product(s) and the main objectives. It must also be indicated whether the study is interventional or non-interventional, and the list itself must be organized by the international nonproprietary name of the active substance of the medicinal product. The list must be exhaustive and include all ongoing studies/programs, as well as studies/programs completed during the last two years, and may be contained in an annex or provided separately.

II.B.4.4. Section of the pharmacovigilance system master file on computerized systems and databases

The PSMF must describe the location, functionality and operational responsibility for the computerized systems and databases used to receive, process, record and provide safety information, and must present an assessment of the suitability of such systems and databases for fulfilling their purpose (Article 2(3) IR 520/2012 [6], provision of the Procedure [2]) ^N.

If several computerized systems/databases are used, their suitability for pharmacovigilance activities must be described in such a way as to give a clear picture of the degree of computerization within the pharmacovigilance system. The validation status of the key aspects of the computer system must also be described; information on change control procedures, the nature of testing, backup procedures and electronic data repositories that are important for pharmacovigilance compliance must be included in the summary information, and the nature of the available documentation must be described. For paper-based systems (where an electronic system may be used only for submitting expedited adverse reaction reports), data management and mechanisms for ensuring the integrity and availability of safety data must be described, in particular the consolidation of information on adverse reactions to medicinal products.

II.B.4.5. Section of the pharmacovigilance system master file on pharmacovigilance processes

An important element of any pharmacovigilance system is the existence of clear written procedures. Module I of the Good Pharmacovigilance Practice (GVP) describes the minimum set of written procedures required for pharmacovigilance. The PSMF must contain a description of the available procedural documentation (standard operating procedures, instructions at the central and/or national level, etc.), the type of data stored (for example, the type of case data stored for reports of adverse reactions), and the method of record keeping (for example, a safety database, paper documents at the site of receipt).

The PSMF must contain a description of the processes, data handling, and records for carrying out pharmacovigilance, covering the following aspects:

• continuous monitoring of the benefit/risk profile of the medicinal product(s), of the assessment results, and of the decision-making process in order to take appropriate measures; signal generation, detection and evaluation. As well as a number of written procedures and instructions concerning the output data of the safety database, interaction with clinical departments, etc.;
• risk management system(s) and monitoring of the outcomes of risk minimization measures; several units may be involved in this activity, and their interaction must be regulated in written procedures or agreements;
• collection of individual case safety reports, consolidation of report data, follow-up, evaluation and reporting; the procedures applied for this purpose must specify the activities at the global and national levels;
• planning the timelines for generating periodic safety reports, their preparation and submission (see GVP Module VII);
• informing consumers, healthcare professionals, and the authorized body on safety issues;
• introduction of safety-related changes to the summary of product characteristics/instructions for medical use; the procedures must cover both internal and external communication (Article 2(4) IP 520/2012 [6], provisions of the Procedure [2], provisions of the Procedure for Conducting Expert Evaluation of Registration Materials [7]). ^N

With regard to each of these aspects, the applicant (registration certificate holder) must be able to provide evidence of a system ensuring proper and timely decision-making and action.

The description must be accompanied by a list of the processes specified in Article 11(1) of the Implementing Regulation 520/2012 [6], provisions of the Procedure [2] ^N concerning compliance monitoring, as well as interaction with other functions. Interaction with other functions includes (but is not limited to) the functional duties and responsibilities of the QPPV/local PV contact person^N, responses to requests of the competent authority for information, literature search, medical scientific literature ^N , control of changes in the safety database, safety data exchange agreement, archiving of safety data, pharmacovigilance audit, quality control and staff training. This list may be placed in annexes, and must contain the registration number of the procedural document, title, effective date and type of document (for all standard operating procedures, work instructions, guidelines, etc.). Procedures relating to service providers and other third parties must be clearly identified. The list is not required to include documents relating to the relevant legislative requirements of the country where the medicinal product covered by this pharmacovigilance system is registered, but a list of them may be required at the legislative level of the country where the medicinal products covered by this procedure are registered. If none or only some countries use specific local (national) procedures, this must be indicated, specifying where the medicinal products covered by this system are registered.

II.B.4.6. Section of the pharmacovigilance system master file on the effectiveness (performance ^N) of the pharmacovigilance system

The PSMF must contain data on the ongoing monitoring of the performance (efficiency ^N) of the pharmacovigilance system, including compliance with requirements regarding key pharmacovigilance outcomes. The PSMF must include a description of the monitoring methods applied and contain at least:

• description of the procedure for assessing the correctness of submission of reports of individual safety cases. The annex must include numerical data/graphs demonstrating the timeliness of report submission within the 15- and 90-day deadlines in the previous year;
• description of the target indicators used to monitor the quality of data submission and pharmacovigilance. This includes information provided by the competent authority on the quality of submitted individual case safety reports, periodic safety update reports, or other information submitted by the applicant (registration certificate holder);
• general information on the timeliness of submission of periodic safety update reports to the authorized bodies (the annex must contain the latest data used by the applicant (registration certificate holder) to assess compliance);
• a brief description of the methods used to ensure timely submission of applications for safety variations in comparison with internal deadlines and the deadlines provided for by legislative requirements, as well as tracking of required safety variations that have been identified but for which applications have not yet been submitted;
• where appropriate, summarized data are provided on compliance with commitments to implement the risk management plan or other commitments or conditions related to pharmacovigilance, compliance with which was a condition for the issuance of the registration certificate.

It is necessary to describe and explain the target indicators of effectiveness (performance ^N ) of the pharmacovigilance system. The list of effectiveness (performance ^N ) indicators must be provided in an annex to the PSMF (Art. 3(6), Art. 9 IR 520/2012 [6], provision of the Procedure [2]) ^N together with the actual results of the evaluation of such effectiveness (performance ^N ).

II.B.4.7. Section of the pharmacovigilance system master file on the quality system

A description of the quality management system must be presented within the structure of the organization and the application of the quality system to pharmacovigilance. Such a description must include:

Control of documentation and records

A description of the mechanisms for archiving electronic and/or printed versions of the PSMF must be provided, as well as a brief description of the procedures applied to other quality systems and pharmacovigilance records and documents (see also Module I of the GVP).

Procedural documents

• A general description of the documents used in pharmacovigilance (standards, standard operating procedures, work instructions, etc.), the availability of different documents at the global, regional or local level within the organization, and the methods for controlling their availability, implementation and maintenance.
• Information on the documentation systems used for the relevant procedural documents under the control of third parties.

A list of specific procedures and processes related to pharmacovigilance activities and interaction with other functional units must be provided, with detailed information on how these procedures can be assessed (Art. 2(5)(a) IR 520/2012 [6], provisions of Annex 11 to the Procedure [2] ^N ). Detailed instructions on including them are described in subsection II.B.4.5 of the GVP Guideline.

Training

• Description of resource management for carrying out pharmacovigilance activities:
  • an organizational structure indicating the number of staff (full-time) involved in pharmacovigilance activities, which may be provided in the section describing the organizational structure (see subsection II.B.4.3 of the Guidelines on Good Pharmacovigilance Practices)
• Information on the location of personnel (this information is described in sections II.B.4.2 and II.B.4.3 of the guideline), specified in the PSMF in accordance with the organization of each pharmacovigilance activity, and in the annex that provides contact information on the locations of safety data sources. However, an explanation of how training is organized should be provided in line with the information on personnel and their location;
• A brief description of the training concept, including links to the location of training files.

Personnel (not only employees of pharmacovigilance units, but also any employees who may receive reports of individual safety cases) must be appropriately trained to carry out pharmacovigilance activities.

Audit

Information on the quality assurance audit of the pharmacovigilance system must be included in the PSMF. The annex must describe the approach used to plan audits of the pharmacovigilance system, the reporting mechanism and timelines, as well as the current list of planned and completed audits relating to the pharmacovigilance system, in accordance with subsection II.B.4.8 (Art. 3(5) IR 520/2012 [6], provision of the Procedure [2]) ^N. This list must contain the date of the audit, the date of submission of the report, and the purpose and status of the audits of service providers, specific pharmacovigilance activities, or units carrying out pharmacovigilance activities, and their interaction with other units of the organization relevant to the fulfillment of pharmacovigilance obligations specified in Directive 2001/83/EC [1], provision of the Procedure [2] ^N, and must cover a 5-year period.

The PSMF must also contain brief information on all audits that resulted in significant findings. This means that the existing findings that fall under the criteria of major or critical non-compliances must be indicated (see GVP Module IV). The audit report must be documented in the quality system, and in the PSMF it is sufficient to provide a brief description of the corrective and/or preventive actions for significant audit findings, the date of their identification and the expected date(s) of their resolution, with a cross-reference to the audit report and the documented corrective and preventive action plan(s). If the corrective and/or preventive action plans or findings have not been agreed for a particular audit, a necessary note should be included in the PSMF indicating “corrective or preventive action plans are to be agreed”. In the annex to the list of audits conducted, audits marked with the note “not agreed” in the PSMF must be indicated. The note and the related corrective and/or preventive actions must remain in the PSMF until the corrective and/or preventive actions have been fully implemented. That is, the note is removed only after appropriate measures have been applied and/or a significant improvement of the system has been confirmed by an independent party (Art. 104(2) of Directive 2001/83/EC [1], provisions of the Procedure [2]) ^N. Additions, changes or deletions of information about audits must be recorded in the log, adjustments.

As a tool for managing the pharmacovigilance system and as a basis for conducting an audit, inspection or audit of the pharmacovigilance system by the competent authority^N, the PSMF should also describe the process of recording, managing and resolving identified deviations in the quality system. The PSMF should also document deviations from pharmacovigilance procedures, their impact and their management until they are resolved (Art. 4(3) IR 520/2012 [6], provisions of the Procedure [2]) ^N. These deviations can be documented in the form of a list with a reference to the deviation report, its date and the relevant procedure.

II.B.4.8. Annex to the pharmacovigilance system master file

The appendix to the PSMF must contain the following documents:

• List of medicinal products covered by the PSMF, including the name of the medicinal product, the international nonproprietary name of the active substance(s) and the name of the country in which a valid registration exists (Art. 3 IP 520/2012 [6], provisions of the Procedure [2]) ^N.

The list of medicinal products must also include the registration number and information on:

• type of registration procedure of the medicinal product and procedure number (for example, the medicinal product is registered under the centralized procedure, at the national level, including those registered under the mutual recognition procedure and the decentralized procedure);
• availability on the pharmaceutical market of the EU and Ukraine ^N (Art. 23(a) of Directive 2001/83/EC [1], Art. 13(4) of Regulation (EC) No. 726/2004 [5], provisions of the Procedure [2], provisions of the Procedure for conducting expert evaluation of registration materials [7] ^N);
• other countries where the medicinal product is registered or available on the pharmaceutical market.

The list should be structured by the international nonproprietary name of the active substance and, where appropriate, product-specific safety monitoring requirements should be indicated (for example, risk minimization measures contained in the risk management plan or imposed as a condition of the registration certificate, a non-standard frequency of generating periodic safety update reports, a referral procedure under Article 31 of Directive 2001/83/EC [1], or inclusion in the list described in Article 23 of Regulation (EC) No. 726/2004 [5], etc.). More detailed information on monitoring may be provided in a separate list.

For medicinal products included in different pharmacovigilance systems, for example, when the applicant (registration certificate holder) has more than one pharmacovigilance system or when the pharmacovigilance system is delegated to a third party under an agreement, references to the other PSMFs must be provided in the annexes as a separate list, so that the entire range of medicinal products of the applicant (registration certificate holder) is matched to the corresponding PSMFs.

In the case of shared pharmacovigilance systems, all medicinal products for which such a pharmacovigilance system is used must be included, so that the entire list of medicinal products included in the PSMF is available. These lists may be presented as separate lists grouped by applicant(s) (marketing authorization holder(s)) for each medicinal product, or a separate note may be included to describe the medicinal product(s) and applicants (marketing authorization holders).

• List of written norms and procedures for compliance with Article 11(1) of IP 520/2012 (Art. 3 of IP 520/2012) [6], provisions of the Procedure [2] ^N.
• List of agreements relating to the delegation of activities, including medicinal products and territory(ies), in accordance with Article 6(2) of IP 520/2012 (see II.B.4.3) (Art. 3(3) of IP 520/2012) [6], provisions of the Procedure [2] ^N.
• List of tasks delegated to the QPPV/LCPPV^N (Art. 3(4) IR 520/2012 [6], provisions of the Procedure [2]). ^N
• List of all completed audits over a five-year period and list of audit schedules (Art. 3(5) IP 520/2012 [6], provisions of the Procedure [2]) ^N.
• List of the organization’s pharmacovigilance performance indicators (^N) (if applicable), in accordance with Article 9 IR 520/2012 [6] (Art. 3(6) IR 520/2012), provision of the Procedure [2] ^N.
• List of other PSMFs, if maintained by the same applicant (registration certificate holder) (art. 3(7) IP 520/2012 [6], provisions of the Procedure [2]) ^N.

This list must contain the number(s) of the PSMF(s) and the name of the applicant (registration certificate holder) QPPV/LCP^N responsible for the pharmacovigilance system in use. If a third party that is not the applicant (registration certificate holder) is involved in managing the pharmacovigilance system, the name of the service provider must also be indicated.

• Change log pursuant to Article 5(4) of IR 520/2012 (Art. 3(8) of IR 520/2012) [6], provisions of the Procedure [2] ^N . Other change control documentation should be included as necessary. When documenting changes in the PSMF, at least the date of the change, the full name of the person responsible for the change, and the substance of the change must be indicated (Art. 5(4) of IR 520/2012 [6], provisions of the Procedure [2]) ^N.

II.B.5. Change control, correction log, versions and archiving

Applicants (registration certificate holders) must establish change control systems and have robust processes that allow them to be constantly informed about relevant changes for the proper maintenance of the PSMF. The competent authority may request information on important changes in the pharmacovigilance system. Such important changes include, but are not limited to, the following:

• changes in the safety database(s) or databases directly related to it, the validation status of the database, and information on data transferred or migrated to another platform;
• changes in the provision of significant services in the field of pharmacovigilance, especially contracts relating to the submission of safety data;
• organizational changes, such as acquisitions, mergers, changes in the premises where pharmacovigilance is carried out, or delegation/transfer of management of the PSMF.

These changes must be documented in the PSMF for change control (in the correction log), and the QPPV/ LPPV^N must always be informed of such changes.

Changes to the PSMF must be recorded in such a way that the history of changes can be traced (indicating the date and substance of the changes). The description of PSMF changes must be contained in the log of corrections described in Article 5(4) IP 520/2012 [6], and in the provisions of the Procedure [2] ^N.

The history of changes to the information contained in the annexes may be provided "on request". In this case, the revision log must contain the date of review of the PSMF content and/or update of the annex(es); the history of changes to the annexes must also be updated. Regularly updated information contained in the annexes, such as lists of medicinal products and standard operating procedures or compliance indicators, may be obtained from controlled systems (for example, electronic document management systems or databases). Versions of these documents may be maintained separately from the PSMF, provided that the history of their changes is kept and can be provided on request of the competent authorities. If the PSMF has not been requested or remains unchanged for a certain period (for example, when changes to the content of the annexes are made outside the PSMF), its regular review is recommended. Applicants (marketing authorization holders) must ensure fulfillment of the obligation to submit the PSMF in a timely manner. The QPPV/PV contact person ^N must have access to up-to-date and accurate information about the pharmacovigilance system, and therefore must be provided with permanent access to the PSMF, including the information contained in the annexes (directly through the PSMF, or through access to the systems used to create the annexes).

Applicants (registration certificate holders) must be able to justify the chosen method and develop document control procedures for the proper management of the PSMF maintenance process. As a basis for an audit, an inspection, or an audit of the pharmacovigilance system by an authorized body^N, the PSMF must contain a description of the current state of the pharmacovigilance system; however, there may be a need to understand how the pharmacovigilance system functioned in the past.

Changes to the PSMF must also take into account joint pharmacovigilance systems and delegated activities. To ensure complete control of changes, the date and substance of change notifications submitted to the competent authorities, the QPPV/ contact person for pharmacovigilance^N, and the relevant third parties must be recorded and stored.

The PSMF must be stored in a manner that ensures its accuracy and accessibility (Art. 5 and Art. 7 of IP 520/2012 [6], provisions of the Procedure [2]) ^N.

II.B.6. Submission of the pharmacovigilance system master file

The QPPV/LPPV^N must have permanent access to the PSMF (Art. 7(2) IR 520/2012 [6], provisions of the Procedure [2] ^N), and the authorized body must have access on demand (Art. 16(3a) of Regulation (EC) No. 726/2004 [5], Art. 23(4) of Directive 2001/83/EC [1], Art. 7 IR 520/2012 [6], provisions of the Procedure [2] ^N). The information contained in the PSMF must be concise, accurate and reflect the current state of the pharmacovigilance system. Regardless of the PSMF format, it must be possible to keep the information up to date and, where necessary, make changes taking into account accumulated experience, technical and scientific progress and changes in legislative requirements (Art. 4(1) IR 520/2012 [6], provisions of the Procedure [2] ^N). The PSMF must be provided within 7 days at the request of the authorized body (Art. 23(4) of Directive 2001/83/EC [1], provisions of the Procedure [2] ^N). However, the authorized body may also require immediate access to the PSMF either at the PSMF location or at the place of work of the QPPV or LPPV in Ukraine (if different) ^N.

II.B.6.1. Format and structure

The PSMF may be maintained in electronic format provided that an orderly printed version can be provided upon request of the competent authority (Art. 5(3) IR 520/2012 [6], provisions of the Procedure [2]) ^N. Regardless of format, the information contained in the PSMF must be legible, complete, and presented in a way that ensures accessibility of all documentation and allows full traceability of changes. It is advisable to restrict access to the PSMF to ensure proper control over its content and to assign specific responsibilities for PSMF management regarding change management and archiving.

The PSMF must be written in Ukrainian or ^N English, indexed in accordance with the headings described in this module (Art. 5(2) of IP 520/2012 [6], provisions of the Procedure [2] ^N), and must ensure ease of navigation through the contents. If the PSMF is written in English, a Ukrainian translation of the PSMF sections must also be available in Ukraine^N. The use of electronic bookmarks and a text search system is recommended. Documents such as copies of signed statements or agreements must be included as annexes and described in the index.

The documents included in the ASMF, and the ASMF itself, must be presented with the following headings, and in the printed version – in the following order:

The title page must contain:

• unique number; a unique number assigned by the EV System to the pharmacovigilance system master file when the XEVPRM is processed in the XEVMPD (database under Art. 57 of Regulation (EC) No. 726/2004 [5]). Registration in the EudraVigilance database in the territory of Ukraine is not required by legislation.
• the name of the applicant (registration certificate holder), the name of the applicant (registration certificate holder) of the qualified person responsible for the described pharmacovigilance system (if different), and the name of the third party of the qualified person responsible for the described pharmacovigilance system (if applicable);
• names of other interested applicants (registration certificate holders) (in case of joint use of the pharmacovigilance system);
• list of the applicant’s (registration certificate holder’s) PSMFs (for medicinal products with different pharmacovigilance systems);
• date of preparation/last update.

The headings described in section II.B.4 of the Guideline should be used to organize the main content of the PSMF. The minimum required content of the annexes is described in subsection II.B.4.8 of the Guideline. Additional information may be included in the annexes, provided that the requirements for the content of the main sections are met (II.B.1-7). The procedure for compiling the annexes is described below; the list items describe the possible content (and not mandatory headings):

UOVF, Appendix A

• List of tasks delegated by the qualified person responsible for pharmacovigilance, or the relevant procedural document.
• PSMF summary and related documents
• Contact information (including data on the QPPV) ^N. If necessary, contact information additional to that contained in the database referred to in Article 57 of Regulation (EC) No. 726/2004 [5].

Organizational structure of the applicant (registration certificate holder), Annex B

• Lists of contracts and agreements

Safety data sources, Annex C

• Lists describing safety data sources, for example, partners and third parties

Computerized systems and databases, Appendix D

Pharmacovigilance process and written procedures, Annex E

• Lists of procedural documents

Effectiveness (performance ^N ) of the pharmacovigilance system, Annex F

• Lists of performance indicators
• Current results of the performance assessment relative to the effectiveness indicators

Quality control system in pharmacovigilance, Annex G

• Audit schedule
• List of audits being conducted and those completed

Medicinal products, Annex H

• List(s) of medicinal products covered by this pharmacovigilance system
• Any comments regarding the applicant (registration certificate holder) for each medicinal product

Control of documentation and records, Appendix I

• Adjustment log
• Documentation on the history of changes to the content of the annexes, indexed according to the order of the annexes, and their content, if not provided directly in the relevant annex.

Documentation on notifications and signatures related to the PSMF, if provided. If an annex has no content, there is no need to submit empty pages with headings; however, the annexes that are provided must be named according to the described format. For example, annex E cannot be renamed annex D. Where the annex on computerized systems and databases is not used, annex D should simply be marked as "not used" in the index so that the recipients of the PSMF can be certain that the annex is absent not as a result of an error.

II.C. Functioning of pharmacovigilance systems in the EU and Ukraine^N

II.C.1. Responsibilities

II.C.1.1. Applicants (registration certificate holders)

Applicants (registration certificate holders) must have a pharmacovigilance system in order to ensure control and oversight of the safety of medicinal products. They are also responsible for creating and maintaining a PSMF containing data on the pharmacovigilance system for one or more medicinal products (Art. 23(4), Art. 104(3)(b) of Directive 2001/83/EU [1], Art. 16(3a) of Regulation (EU) 726/2004 [5]). In accordance with Articles 8(3)(ia) and 104(3) of Directive 2001/83/EU [1] and the provisions of the Procedure [2] ^N), a single qualified person responsible for establishing and maintaining the pharmacovigilance system described in the PSMF must be appointed.

At the time of submitting an application for a registration certificate, applicants (registration certificate holders) must have a brief description of the pharmacovigilance system that will be used from the moment the registration certificate is obtained and the medicinal product is placed on the pharmaceutical market of the country. During the expert evaluation of registration materials, the applicant (registration certificate holder) may be required to provide a copy of the PSMF for assessment.

The applicant (registration certificate holder) is responsible for establishing the PSMF in an EU country, Ukraine ^N (at any site of the applicant (registration certificate holder) or partner, including a contractor or marketing partner) and for indicating the PSMF location in the application for registration of the medicinal product ^N and in the database under Article 57 of Regulation (EC) No. 726/2004 [5]. In accordance with the provisions of the Procedure for Conducting Expert Evaluation [7] ^N, the PSMF must describe the pharmacovigilance system existing at the current moment. The PSMF may include information on elements of the system that will be implemented in the future, but they must be clearly indicated as planned rather than implemented or current.

Creation and maintenance of the PSMF in an up-to-date and accessible state (permanently available for the purposes of audits, inspections, audit of the pharmacovigilance system by the authorized institution^N and its submission to the competent authority may be entrusted to a third party, however the applicant (registration certificate holder) bears full ultimate responsibility for compliance with the requirements of legislation.

The applicant (marketing authorization holder) is also responsible for promptly notifying the competent authority of any changes to the QPPV (or deputy) data ^N, as well as changes in the location of the PSMF. The EMA must update the data accordingly in the EudraVigilance database, as specified in Article 24(1) of Regulation (EC) No. 726/2004 [5] and, if necessary, on the EMA web portal, as specified in Article 26(1) of Regulation (EC) No. 726/2004 [5] (Article 4(4) of the IR 520/2012 [6]).

In Ukraine, the applicant (registration certificate holder) must notify any changes in the data on the QPPV/contact person for the QPPV, as well as in the event of a change of location, in the manner established by legislation (provisions of the Procedure for conducting expert evaluation [7] ^N).

II.C.1.2. Competent authority

The authorized body is obliged to supervise the pharmacovigilance systems of applicants (registration certificate holders) (recital 7 of Directive 2010/84/EC [3], provisions of the Procedure [2]) ^N. In accordance with this requirement, the authorized body must conduct an expert evaluation of the summary of the pharmacovigilance system included in the application for registration of a medicinal product. A full PSMF may be requested at any time, for example, to verify the description of the pharmacovigilance system of an applicant (registration certificate holder) that has not previously registered medicinal products in Ukraine ^N or when there are specific questions about the pharmacovigilance system and/or the safety profile of medicinal products, as well as in preparation for an inspection or an audit of the pharmacovigilance system by the authorized institution^N (see GVP Module III). Information on changes in the summary or in the content of the PSMF will also be used for planning and conducting inspections or audits of the pharmacovigilance system by the authorized institution^N .

With regard to medicinal products registered under the centralized procedure, the EU Member State in which the master file is located will be the supervisory authority (recital 22 of Regulation 1235/2010 [4], Art. 18(3) of Regulation (EU) No. 726/2004 [5]). With regard to pharmacovigilance systems that include medicinal products registered under the centralized procedure as well as under the national procedure, including medicinal products registered under the mutual recognition procedure or the decentralized procedure, the national competent authorities supervise the pharmacovigilance system in cooperation with the supervisory authority and the EMA. With regard to pharmacovigilance systems that do not include medicinal products registered under the centralized procedure, the national competent authorities of the countries remain responsible for supervising the pharmacovigilance system and cooperate with each other to minimize duplication of effort.

National competent authorities jointly use information on pharmacovigilance systems and use the information to inform national inspection programs and pharmacovigilance system audits by the competent institution^N, conducted on the basis of risk assessment. Inspectors/auditors^N of competent authorities/institutions^N will report non-compliance with legislation and GVP, including non-compliance with PSMF and pharmacovigilance system requirements (see GVP Module III).

II.C.1.3. European Medicines Agency/Ministry of Health of Ukraine^N

With regard to medicinal products authorized under the centralized procedure, the EMA coordinates inspections of applicants (marketing authorization holders) or their service providers. Supervision of the pharmacovigilance system is based on the location of the PSMF, and the EU Member State in which the master file is located becomes the supervisory authority (Article 18(3) of Regulation (EU) No. 726/2004 [5]). The EMA may request the pharmacovigilance system master file in order to perform its coordinating role.

The main duty of the EMA in relation to the PSMF is to maintain a Europe-wide database, disseminate information and coordinate activities across the EU. To this end, the EMA, in cooperation with EU Member States and the European Commission, is responsible for creating and maintaining the EMA web portal for the dissemination of information on medicinal products registered in the EU (Article 26 of Regulation (EU) No. 726/2004 [5]). The EMA coordinates the list of medicinal products described in Article 57 of Regulation (EU) No. 726/2004 [5], which provides a practical mechanism for updating information on the location of the PSMF, the contact information of the QPPV, and the medicinal products associated with the pharmacovigilance system described in the PSMF. The list of locations in the EU where pharmacovigilance system master files are kept must be publicly available, through publication on the EMA web portal (Article 26(1)(e) of Regulation (EU) No. 726/2004 [5]).

In Ukraine, the Ministry of Health of Ukraine establishes the rules and requirements for applicants (registration certificate holders) of medicinal products, vaccines, tuberculin, and their obligations, set out in the Procedure [2]. Pharmacovigilance is carried out by the Center in fulfillment of the powers vested in it regarding pharmacovigilance in accordance with legislative requirements. The Center audits the pharmacovigilance system of the applicant (registration certificate holder). The Center may require the applicant (registration certificate holder) to provide the pharmacovigilance system master file (provisions of the Procedure [2] ^N).

II.C.2. Access to the pharmacovigilance system master file

The PSMF must be kept up to date and be permanently available to the AUPV/PVAA^N (Art. 4(1), Art. 7(2) IP 520/2012 [6], provisions of the Procedure [2]) ^N. The PSMF must also be permanently available during an inspection or an audit of the pharmacovigilance system by the authorized institution^N at its location (at the specified address), regardless of whether prior notice of the inspection or the pharmacovigilance system audit by the authorized institution^N was given or not (Art. 7(3) IP 520/2012 [6], provisions of the Procedure [2]).

In accordance with Article 104 (3)(b) of Directive 2001/83/EC [1], the provisions of the Procedure [2], and the provisions of the Procedure for expert evaluation of registration materials [7] ^No. the applicant (registration certificate holder) must have and provide, at the request of the competent authority, a copy of the PSMF. The applicant (registration certificate holder) must provide the copy no later than 7 days after receiving the request from the competent authority. The PSMF must be provided in a readable electronic format or as a hard copy.

If one PSMF is used by more than one applicant (marketing authorization holder) (in the case of a shared pharmacovigilance system), it must be accessible to each of the applicants (marketing authorization holders) so that any of them, if necessary, is able to submit the PSMF to the competent authority within 7 days (Art. 23(4) of Directive 2001/83/EC [1], Art. 7(4) of the IR 520/2012 [6], provisions of the Procedure [2]) ^N.

The PSMF should not be required routinely during the expert evaluation of registration materials for medicinal products submitted for state registration, but its submission may be required on a situational basis, in particular if a new pharmacovigilance system is being implemented or if safety issues related to the medicinal product or issues of compliance with pharmacovigilance requirements have been identified.

II.C.3. Transparency

To ensure transparency and for communication purposes, information on the location of the PSMF must be published on the EMA web portal (Article 26(1)(e) of Regulation (EC) No. 726/2004 [5]).

Ukrainian legislation does not provide for the publication of information on the location of the MFSF^N.