Pharmacovigilance System Master File (PSMF) you need to know

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Q: What is need of Pharmacovigilance system master file (PSMF) in Pharmacovigilance?

A: The legal requirement for marketing authorisation holders to maintain and make available upon request a pharmacovigilance system master file (PSMF) was introduced by Directive 2010/84/EU.

Q: Location of PSMF?

A: The PSMF shall be located

  1. Either at the site in the EU where the main pharmacovigilance activities of the marketing authorisation holder are performed
  2. Or at the site in the EU where the qualified person responsible for pharmacovigilance operates

But must be located within the EU. Following European Economic Area (EEA) agreements, the PSMF may also be located in Norway, Iceland or Liechtenstein

Q: Is PSMF need to be submitted to Authorities?

A: Yes. It is a requirement of the marketing authorisation application that summary information about the pharmacovigilance system is submitted to the competent authorities. This summary includes information on the location of the PSMF.

Q: Is it mandate to maintain PSMF?

A: The PSMF is a legal requirement in the EU and is applicable for any medicinal product authorised in the EU

  1. irrespective of the marketing authorisation procedure
  2. irrespective of the organisational structure of a marketing authorisation holder
  3. irrespective any subcontracting or delegation activities
  4. irrespective of their location
  5. irrespective of the location of other activities, the qualified person

PSMF is applicable for traditional herbal medicinal products, herbal medicinal products, and homeopathic medicinal products.

Q: What to be included in PSMF?

A: The content of the PSMF should reflect

  1. Global availability of safety information for medicinal products authorised in the EU
  2. Presenting information on the pharmacovigilance system applied at global, regional and local levels
  3. PSMF shall describe the pharmacovigilance system and support/document its compliance with the requirements
  4. The appropriate planning and conduct of audits and inspections.
  5. Overview of the pharmacovigilance system
  6. Summary curriculum vitae with the key information on the role of the qualified person responsible for pharmacovigilance, including proof of registration with the EudraVigilance database
  7. QPPV details, responsibilities and back up in absence of QPPV

Q: Requirements for a manufacturer to register a drug for Marketing Authorization?

A: Marketing authorisation application must be with

  1. proof that the applicant has a qualified person responsible for pharmacovigilance
  2. Residence of the QPPV where person carries out his/her tasks
  3. The contact details of the QPPV
  4. Statement signed by the applicant
  5. A reference to the location where the PSMF for the medicinal product is kept
  6. the applicant should submit electronically the PSMF location information using the agreed format
  7. The PSMF reference number which is the unique code assigned by the EudraVigilance (EV)

Further to the granting of a marketing authorisation, the PSMF will be linked by the marketing authorisation holder to the EVMPD product code.

Q: What is the database from EU for MAHs to upload their information?

A: All PSMFs must be registered in the Article 57 database as per EU. Marketing authorisation holders shall continue to ensure that their entries in the Article 57 database for medicinal products for human use are up-to-date.

Q: Time line for MAH to update any change about their information in Article 57 database?

A: Article 57 database need to be updated by the marketing authorisation holder immediately if possible or else no later than 30 calendar days of any change.

Q: What is PSMF location?

A: PSMF location is

  1. Physical office address of the marketing authorisation holder or
  2. Website where the data stored can be directly accessed, if the PSMF is held in electronic form.

The marketing authorisation holder should have an appropriate rationale for the location of PSMF decision in the situations where the main activities take place outside the EU.

Q: How many PSMFs can be from single MAH?

A:  PSMF can be

  1. For different categories of medicinal products the marketing authorisation holder may have separate pharmacovigilance systems. Each such system shall be described in a separate PSMF.
  2. Single marketing authorisation holder may establish more than one Pharmacovigilance system e.g. specific systems for particular types of products (vaccines, consumer health, etc.)
  3. Where a pharmacovigilance system is shared by several marketing authorisation holders each marketing authorisation holder is responsible ensuring that a PSMF exists to describe the pharmacovigilance system applicable for his products.

When a pharmacovigilance system is shared, it is advised that the partners agree on how to mutually maintain the relevant sections within their own PSMFs.

Q: What Pharmacovigilance aspects need to be mentioned in PSMF?

A: A description of minimum set of written procedures for pharmacovigilance process need to be available such as

  1. Standard operating procedures, manuals, data handling and records for the performance of pharmacovigilance.
  2. The nature of the data held (the type of case data retained for ICSRs)
  3. safety database
  4. Continuous monitoring of product risk-benefit profiles applied, the results, evaluation and process for taking appropriate measures
  5. Risk management systems and monitoring of the outcome of risk minimisation measures.
  6. The procedure of ICSR collection, collation, follow-up, assessment and reporting
  7. PSUR scheduling, production and submission
  8. Communication of safety concerns to consumers, healthcare professionals and the competent authorities
  9. Implementation of safety variations to the summary of product characteristics (SmPC) and patient information leaflets

Q: Is it required to include the performance of Pharmacovigilance system in PSMF?

A: Yes. It is required.

  1. An explanation of how the correct reporting of ICSRs is assessed. In the annex, figures/graphs should be provided to show the timeliness of 15-day and 90-day reporting over the past year.
  2. A description of any metrics used to monitor the quality of submissions and performance of pharmacovigilance. This should include information provided by competent authorities regarding the quality of ICSR reporting, PSURs or other submissions.
  3. An overview of the timeliness of PSUR reporting to competent authorities in the EU (the annex should reflect the latest figures used by the marketing authorisation holder to assess compliance)
  4. An overview of the methods used to ensure timeliness of safety variation submissions compared to internal and competent authority deadlines, including the tracking of required safety variations that have been identified but not yet been submitted
  5. Where applicable, an overview of adherence to risk management plan commitments, or other obligations or conditions of marketing authorisation(s) relevant to pharmacovigilance.

Targets for the performance of the pharmacovigilance system shall be described and explained. A list of performance indicators and results of performance must be provided.

Q: What are parameters of Quality Management system for Document and Record Control in PSMF?

A: Well description of the archiving arrangements for electronic and/or hardcopy versions of the PSMF should be provided, as well as an overview of the procedures applied to other quality system and pharmacovigilance records and documents.

Q: What are Parameters of Quality Management system for Procedural documents in PSMF?

A: Must be included as follows

  1. Well description of the types of documents used in pharmacovigilance (standards, operating procedures, work instructions), the applicability of the various documents at global, regional or local level within the organisation, and the controls that are applied to their accessibility, implementation and maintenance.
  2. Information about the documentation systems applied to relevant procedural documents under the control of third parties.

A list of specific procedures and processes related to the pharmacovigilance activities and interfaces with other functions, with details of how the procedures can be accessed must be provided.

Q: What are Parameters of Quality Management system for Training requirements in PSMF?

A: A well description of the resource management for the performance of pharmacovigilance activities:

  1. The organisational chart giving the number of people (full time equivalents) involved in pharmacovigilance activities, which may be provided in the section describing the organisational structure.
  2. Information about sites where the personnel are located whereby the sites are provided in the PSMF in relation to the organisation of specific pharmacovigilance activities.
  3. List of site contacts, personnel and site information for sources of safety data.
  4. A summary description of the training concept, including a reference to the location training files.

Q: What are Parameters of Quality Management system for Auditing requirements in PSMF?

A: A well description of the approach used to plan audits of the pharmacovigilance system and the reporting mechanism and timelines should be provided in the PSMF.

The list should describe the following

  1. The dates of conduct and of report
  2. Scope and completion status of audits of service providers, specific pharmacovigilance activities
  3. Sites undertaking pharmacovigilance and their operational interfaces relevant to the fulfilment of the obligations and cover a rolling 5 year period.
  4. Shall also contain a note associated with any audit where significant findings are raised such as major or critical findings.
  5. The previous audit reports must be documented within the quality system in the PSMF.
  6. A brief description of the corrective and/or preventative action(s) associated with the significant finding, the date it was identified, the anticipated resolution dates.
  7. In case corrective and preventative action plans have not yet been agreed for a particular audit or finding, the PSMF should include the note required and stating that corrective and preventative action plans are to be agreed.
  8. The list of audits conducted. The note which is associated with corrective and preventative actions shall be documented in the PSMF until those actions have been fully implemented.
  9. The addition, amendment or removal of the notes must therefore be recorded in the logbook.
  10. Should also describe the process for recording, managing and resolving deviations from the quality system.
  11. The master file shall also document deviations from pharmacovigilance procedures, their impact and management until resolved.

Q: Is it required to train the staff on PV who are not within the department?

A: Staff should be appropriately trained for performing pharmacovigilance related activities and this includes not only staff within pharmacovigilance departments but also any individual that may receive safety reports.

Q: What need to be included in the PSMF Annex?

A: PSMF shall contain the following documents. A list of medicinal products covered by the PSMF including

  1. The name of the medicinal product
  2. The international non-proprietary name of the active substances
  3. The Member States in which the authorisation is valid
  4. The authorisation number, the type of procedure for authorisation and procedure number (e.g. centrally authorised, nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure).
  5. The Rapporteur country or Reference Member State
  6. The presence on the market in the EU
  7. Other (non EU) territories where the product is authorised or on the market.
  8. The list should be organised as per active substance, should indicate what type of product specific safety monitoring requirements exist.
  9. The monitoring information may be provided as a secondary list.
  10. For marketing authorisations that are included in a different pharmacovigilance system (for example, because the MAH has more than one pharmacovigilance system or third party agreements exist to delegate the system), reference to the additional PSMFs should also be provided as a separate list in the Annexes.
  11. For each MAH, the entire product portfolio can be related to the set of PSMFs Where pharmacovigilance systems are shared,
  12. All products that utilise the pharmacovigilance system should be included, so that the entire list of products covered by the file is available.
  13. The products lists may be presented separately, organised per MAH.
  14. Alternatively, a single list may be used, which is supplemented with the name of the MAHs for each product, or a separate note can be included to describe the products and the MAHs covered.
  15. A list of written policies and procedures.
  16. A list of contractual agreements covering delegated activities including the medicinal products and territories.
  17. A list of tasks that have been delegated by the qualified person for pharmacovigilance.
  18. A list of all completed audits, for a period of five years, and a list of audit schedules where applicable
  19. A list of performance indicators where applicable
  20. A list of other PSMFs held by the same marketing authorisation holder
  21. This list should include the PSMF numbers and the name of MAH of the QPPV responsible for the pharmacovigilance system used. If the pharmacovigilance system is managed by another party that is not a marketing authorisation holder, the name of the service provider should also be included.
  22. A logbook in accordance with EU Guidelines
  23. Other change control documentation should be included as appropriate
  24. Documented changes shall include at least the date, person responsible for the change and the nature of the change.

Q: Is it necessary for MAHs to implement change control systems and robust processes in place in order to maintain the PSMF?

A: Yes. It is necessary for marketing authorisation holders to implement change control systems and to have robust processes in place to continuously be informed of relevant changes in order to maintain the PSMF accordingly.

The competent authorities may solicit information about important changes to the pharmacovigilance system, such as, but not limited to:

  1. Changes to the pharmacovigilance safety databases, which could include a change in the database itself or associated databases
  2. The validation status of the database as well as information about transferred or migrated data
  3. Changes in the provision of significant services for pharmacovigilance, especially major contractual arrangements concerning the reporting of safety data
  4. Organisational changes, such as takeovers, mergers, the sites at which pharmacovigilance is conducted or the delegation/transfer of PSMF management

Q: Is it required the QPPV must know all the changes in the system?

A: Yes. The QPPV should always been kept informed of these changes.

Q: Changes done in the PSMF must be recorded?

A: Yes. Changes to the PSMF should be recorded in the log book, such that

  1. history of change,
  2. The date and the nature of the change,
  3. Description of change

Q: What is format of PSMF to be maintained?

A: The PSMF may be in electronic format. But, on request, a clearly arranged printed copy need to be made available to competent authorities.

Q: In which language the PSMF need to be maintained?

A: The PSMF should be written in English (unless the marketing authorisation holder only holds approvals in one Member State when it can be written in the EU official language for that territory.

Q: Layout of PSMF?

A: The PSMF must be with layout of details of  

  1. Cover letter:
    • The unique number assigned by the EV System to the PSMF when the XEVPRM is processed in the XEVMPD.
    • The name of the MAH, the MAH of the QPPV responsible for the pharmacovigilance system described (if different), as well as the relevant QPPV third party company name (if applicable).
    • The name of other concerned MAH(s) (sharing the pharmacovigilance system).
    • The list of PSMFs for the MAH (concerning products with a different pharmacovigilance system).
    • The date of preparation / last update.
  2. QPPV details such as:
    • The list of tasks that have been delegated by the QPPV, or the applicable procedural document
    • The curriculum vitae of the QPPV and associated documents
    • Contact details supplementary
  3. The Organisational Structure of the MAH including the lists of contracts and agreements
  4. Sources of safety data such as Lists associated with the description of sources of safety data e.g. affiliates and third party contacts
  5. Computerised systems and Databases
  6. Pharmacovigilance Process, lists of procedural documents and written procedures
  7. Pharmacovigilance System Performance such as lists of performance indicators, current results of performance assessment in relation to the indicators
  8. Quality System details such as Audit schedules, List of audits conducted and completed
  9. Product information such as list of products covered by the pharmacovigilance system, any notes concerning the MAH per product
  10. Document and Record Control information such as Logbook, documentation of history of changes and their content.

Q: Do MAHs required to place the Pharmacovigilance system and PSMF in place before the initial marketing authorisation application?

A: At the time of initial marketing authorisation application, applicants are required to have in place a summary of the pharmacovigilance system that records the system that will be in place and functioning at the time of granting of the marketing authorisation and placing of the product on the market.

During the evaluation of a marketing authorisation application the applicant may be requested to provide a copy of the PSMF for review.

Q: Time frame the MAH to submit the PSMF copy upon request from Authorities?

A: The marketing authorisation holder must submit the copy 7 days at the latest after receipt of the request from a national competent authority or the Agency. The PSMF should be submitted in a readable electronic format or clearly arranged printed copy.

Q: Is it required to make the PSMF information available to public?

A: Obviously Yes. Information on the PSMF location should be made available to the public via the European medicines web-portal for transparency and communication purposes.

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