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Pharmacovigilance Inspections: Human Medicines

In order to determine that Marketing Authorisation Holders (MAHs) of human medicinal products comply with pharmacovigilance obligations established within the EU, and to facilitate compliance, pharmacovigilance inspections of MAHs or any firms providing pharmacovigilance services to MAHs  are performed.

The objectives of pharmacovigilance inspections are;

  • to determine that the marketing authorisation holder has personnel, systems and facilities in place to meet their pharmacovigilance obligations,
  • to identify, record and address non-compliance which may pose a risk to public health,
  • to use the inspection results as a basis for enforcement action, where considered necessary.

 

Types of inspections

Pharmacovigilance system inspections ​​are designed to review the procedures, systems, personnel and facilities in place and determine their compliance with regulatory pharmacovigilance obligations. As part of this review, product specific examples may be used to demonstrate the operation of the pharmacovigilance system.

Product-related pharmacovigilance inspections are primarily focused on product-related pharmacovigilance issues, including product-specific activities and documentation, rather than a general system review. Some aspects of the general system may still be examined as part of a product-related inspection (e.g. the system used for that product)

Routine inspections are inspections scheduled in advance as part of inspection programmes. There is no specific trigger to initiate these inspections, although a risk-based approach may be used when developing the inspection schedule.

For cause inspections are undertaken when a trigger is recognised, and an inspection is considered an appropriate way to examine the issues.

Pre-authorisation inspections may be performed to verify the accuracy and successful implementation of the existing or proposed pharmacovigilance system. Pharmacovigilance inspections may be performed on a routine basis or may be scheduled in response to a request from another department or committee of the HPRA where there is a specific cause for concern with respect to compliance with guidelines or regulations. A request for a routine or triggered inspection may also be received from Committee for Human Medicinal Products (CHMP).

Notification of inspection

The MAH or pharmacovigilance service provider will generally be notified four to six weeks prior to the proposed inspection date. The HPRA reserves the right to provide shorter notice or conduct an unannounced inspection if required. An inspection plan is usually provided to the inspectee a maximum of two weeks in advance of the inspection date, which gives details of the time inspection activities are planned to be conducted and the general areas to be covered during the inspection.

Information is typically requested before the inspection, including:

  • An up to date version of the Pharmacovigilance System Master File (PSMF).
  • Organisation charts/lists of key personnel involved in pharmacovigilance activities.
  • Written procedures and processes relating to the pharmacovigilance system.
  • Line listings of adverse events.
  • List of any organised data collection systems.
  • Periodic Safety Update Reports (PSURs) and Risk Management Plans (RMPs).
  • Lists of safety signals identified by the MAH and associated key dates of processing.
  • Lists of safety variations submitted/due for submission by the MAH.
  • Current copies of approved reference safety information (e.g. Summary of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs)).

 

Inspection conduct

At the start of an inspection, the inspectors conduct an opening meeting, which gives an opportunity for the inspectors to provide introductions, explain the planned conduct of the inspection and gain a better understanding of the organisation being inspected. Pharmacovigilance inspections are a mixture of interview sessions and document review. A tour of facilities may be performed. On the final day of the inspection, a closing meeting is held where preliminary verbal feedback on the inspection (including deficiencies) is provided to the inspectees.

Grading of findings

Deficiencies found during inspections are graded as follows;

 

  • Critical; a deficiency in pharmacovigilance systems, practices or processes that adversely affects the rights, safety or well-being of patients or that poses a potential risk to public health or that represents a serious violation of applicable legislation and guidelines.

     

  • Major; a deficiency in pharmacovigilance systems, practices or processes that could potentially adversely affect the rights, safety or well-being of patients or that could potentially pose a risk to public health or that represents a violation of applicable legislation and guidelines.

     

  • Minor; a deficiency in pharmacovigilance systems, practices or processes that would not be expected to adversely affect the rights, safety or well-being of patients or pose a risk to public health.

 

Comments; the observations might lead to suggestions on how to improve quality or reduce the potential for a deviation to occur in the future. Unless otherwise indicated, the inspectee is not required to respond to these, however, they should be taken into account as a way to improve the pharmacovigilance system.

Inspection report

A written report outlining any deficiencies observed during inspection is issued to the company after the inspection. The HPRA aims to issue this within 15 calendar days from the last day of inspection if possible.

The inspectee is required to provide a response to the deficiencies outlined in the inspection report within the date outlined in the inspection report. This is usually within 35 days after the last day of inspection. The inspectors will review these responses to determine if they are acceptable. Should further response updates or clarifications be required, the inspectors will inform the company in writing. After acceptable report responses are received, the inspection may be closed. Inspection reports with major and/or critical findings will be shared with the EMA and other EU NCAs, according to European regulations.

Inspection outcome

MAHs/service providers who receive critical findings or multiple major findings may be inspected more frequently, to ensure they are brought into compliance. Where serious non-compliances are identified, particularly if persistent in nature, further actions may be taken by the HPRA.