The Pharmacovigilance System Master File (PSMF) is a detailed description of all aspects related to how a pharmaceutical company is conducting pharmacovigilance. The purpose of the PSMF is first to provide the QPPV with a constantly updated oversight of the Pharmacovigilance System and in addition to ensure that all regulatory and company requirements are met. It is also a tool for planning and for conduct of internal audits of the separate components of the pharmacovigilance system. Lastly it is a tool for the competent authorities to get an overview of how the pharmacovigilance system works in a company that holds a marketing authorization in EU. This is for instance needed for the competent authorities when they are planning and conducting inspections. It is important to understand that while the PSMF is an essential tool for the QPPV in conducting the legal obligation to maintain oversight with a marketing authorization holder – it is the responsibility of the marketing authorisation holder to ensure that the information provided in the PSMF i correct at all times.
[A suite of templates for implementation of the PSMF in a pharmaceutical company can be found in the document shop.]
The information in the PSMF spans a great variety of information from procedures, policies, guidelines, staff training and compliance to IT systems structure and validation. The term Pharmacovigilance System Master File was introduced first in the 2010 revision of the 2001/83/EC European Union Directive identified as 2010/84/EU as well as Regulation 1235/2010 which jointly govern pharmacovigilance activities in the EU.
In Regulation 1235/2010, Article 1(28e) the PSMF is defined as: “Pharmacovigilance system master file: A detailed description of the pharmacovigilance system used by the marketing authorisation holder with respect to one or more authorised medicinal products.” It is the intention to have only one PSMF in a company, but there can be situations where two or more may be appropriate. Splitting the PSMF up in several separate PSMFs can be relevant if the company sells products of very different nature like for instance both pharma products and vaccines. Normally it is much simpler to have only one PSMF. When setting up a PSMF it is important to go through the list of items that have to be included in detail and note where the information will come from and who is responsible for maintenance as a regulatory agency can request access to an updated version with short notice (max 7 days). You have to ensure that all components are continuously updated at predefined intervals. When an agency request the information there won’t be time to start updating it has to be ready pretty much immediately.
PSMF MAIN SECTIONS
The PSMF consist of a main body that is structured in sections according to the headings described in GVP module II and some of the specific records are separated out in annexes. The information the goes into these documents may come from different parts of the marketing authorization holders organization. For instance information about CAPAs would be in the CAPA system and information about reporting compliance could be in the safety system etc. Note that the PSMF location and contact details may be made public via the agency web-portal for transparency and communication purposes
Annexes can include the following in a typical PSMF: A) QPPV B) PSMF location and registration information C) Company Organization Structure D) Safety Data Sources E) IT systems and Databases F) Pharmacovigilance process documents, policies and work instructions G) Pharmacovigilance System Performance H) Quality Management System I) Product and registration listings J) Logbook of changes
The development and maintenance of the PSMF must be described in a specific PSMF Standard Operating Procedure (template available in the PSMF template package) and the contents of the PSMF must be retained for 30 years. Just managing the PSMF and controlling the distribution of a document with multiple sources can be a daunting task. Often companies utilize technologies like Veeva, Box, SharePoint, Office 365 or Google Docs in order to keep track of versioning of the different information components/annexes. Each of these with own benefits and risks, so here there is also a need for careful planning. For most organizations there is a need for a dedicated coordinator to maintain the information in the PSMF and to ensure that everything is compliant and up to date. Normally this PSMF coordinator function will report directly to the QPPV, but especially in smaller organizations there may be other arrangements for example through external service providers. The PSMF coordinator will also serve as the contact point for all the different functions in a pharmaceutical company that are stakeholders in the information contained in the PSMF which will include the following function in a big pharmaceutical company. Smaller companies must cover the same information but they usually have some of the below functions merged into one. Examples are:
- Regulatory Affairs
- Regulatory Operations
- Medical Information
- Clinical Development
- Clinical Operations
- Local Operating Companies
- Local QPPV functions
- Corporate Quality/Auditing
- Inspection Management
- Safety IT
- Safety Operations
- Medical Review
- Global Safety Officers
- QPPV office
PSMF CONTINUOUSLY UPDATED
In order to keep the PSMF updated so it can be provided in 7 days or less it is necessary to have routine update sequences for each of the components of the PSMF. Normally such routine updates would be done on a quarterly basis. Significant changes for instance in the form of changed contracts, new database or big organizational changes the PSMF must be updated immediately and ad hoc. Such ad hoc updates can also be triggered by a request by a regulatory agency, but normally you would have to stick with what you have from the latest routine update (quarterly) as it is often impossible to make a full update within 7 days so it is necessary to be prepared.
IMMEDIATE (7 DAY) AGENCY REQUEST FOR PSMF
If there is a request from an agency for immediate delivery of the PSMF you will have to deliver it fully updated and correct within 7 days. To be able to do that it is important to work closely with other functions in the company to hopefully get the last details correct. Some of the areas that has proven difficult to get updated with short notice are – just to mention a few:
- Product lists
- Clinical trials lists
- Post market surveillance studies lists
- Marketing support studies lists
- Patient outreach programs lists
- Information regarding local operating companies
- outsourced activities
- local QPPVs
AUDIT INFORMATION IN THE PSMF
It is important to note that there is a requirement to present information related to internal audits in the PSMF. This information must include a description of the approach taken to plan the audits (to ensure that all components are audited at least every 5 years). All significant audit finding must be noted with a brief description, CAPA details like date identified and anticipated resolution date. Such CAPAs can only be removed once the CAPA is officially closed. This is one of the items you will have to record in the PSMF logbook. As this information is included in the main body of the PSMF it is a challenge to keep to logbook updated.
THIRD PARTY CONTRACTS
There are usually many third party contract and mostly companies are not ready to deliver all these in a structured way so the relevant ones can be included in the PSMF. Keep in mind that any contract with a 3rd party that has any potential interactions with the public need to contain safety language ensuring that any AEs reported to the 3rd part is reported to the company – this is often an area where marketing authorization holders fail. Many organizations have multiple levels above country and country level procurement procedures/databases. Hence many ‘B’ annexes = listings from multiple databases. Are all these databases, even at a country level, required to be validated? A recent MHRA symposium comment on sources of potential inspection findings “the list of contractual agreements in the annex is not comprehensive. If a licensing partner has agreements with other partners to collect safety data for the concerned products, these should be listed (even though they are not direct agreements with the MAH)” You will have to ensure that content from commercial partners and suppliers is updated as well. Initially focus on major partners (who holds the safety database? whose QPPV is named?).Request and provide written assurance that a compliant PSMF is in place. You also have to make sure updates to Safety Data Exchange Agreement template to ensure agreement that ‘relevant sections’ of the PSMF will be shared on demand and can be made available to a competent authority in the event of inspection
QPPV AND COMPANY SIGN-OFF
Each time the PSMF is updated the QPPV and the Head of Drug Safety in the company must sign off to document that the QPPV is aware of the most recent changes and that the Head of Drug Safety confirms that the information in the PSMF is correct. This sign off can be on paper or now more appropriately by electronic means.