III.B.1. Inspection types

III.B.1. Inspection types

III.B.1.1. System and product-related 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).

III.B.1.2. Routine and “for cause” pharmacovigilance inspections

Routine pharmacovigilance 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 to optimize supervisory activities should be implemented. These inspections are usually system inspections but one or more specific products may be selected as examples to verify the implementation of the system and to provide practical evidence of its functioning and compliance. Particular concerns, e.g. raised by assessors, may also be included in the scope of a routine inspection, in order to investigate the specific issues.

For cause pharmacovigilance inspections are undertaken when a trigger is recognised, and an inspection is considered an appropriate way to examine the issues. For cause inspections are more likely to focus on specific pharmacovigilance processes or to include an examination of identified compliance issues and their impact for a specific product. However, full system inspections may also be performed resulting from a trigger. For cause inspections may arise when, for example, one or more of the triggers listed below are identified:

• risk-benefit balance of the product:
  • change in the risk-benefit balance where further examination through an inspection is considered appropriate;
  • delays or failure to identify or communicate a risk or a change in the risk-benefit balance;
  • communication of information on pharmacovigilance concerns to the general public without giving prior or simultaneous notification to the national competent authorities or Agency, as applicable;
  • non-compliance or product safety issues identified during the monitoring of pharmacovigilance activities by the national competent authorities and/or the Agency;
  • suspension or product withdrawal with no advance notice to the competent authorities;
• reporting obligations (expedited and periodic):
  • delays or omissions in reporting;
  • poor quality or incomplete reports;
  • inconsistencies between reports and other information sources;
• requests from competent authorities:
  • failure to provide the requested information or data within the deadline specified by the competent authorities;
  • poor quality or inadequate provision of data to fulfil requests for information from the competent authorities;
• fulfilment of commitments:
  • concerns about the status or fulfilment of risk management plan (RMP) commitments;
  • delays or failure to carry out specific obligations relating to the monitoring of product safety, identified at the time of the marketing authorisation;
  • poor quality of reports requested as specific obligations;
• inspections:
  • delays in the implementation or inappropriate implementation of corrective and preventive actions;
  • information such as non-compliance or product safety issues from other types of inspections (GCP, GMP, GLP and GDP) ;
  • inspection information received from other authorities (EU or non-EU), which may highlight issues of non-compliance;
• others: − concerns following review of the pharmacovigilance system master file;
  • non-inspection related information received from other authorities, which may highlight issues of non-compliance;
  • other sources of information or complaints

III.B.1.3. Pre-authorisation inspections

Pre-authorisation pharmacovigilance inspections are inspections performed before a marketing authorisation is granted. These inspections are conducted with the intent of examining the existing or proposed pharmacovigilance system as it has been described by the applicant in support of the marketing authorisation application [REG Art 19]. Pre-authorisation inspections are not mandatory, but may be requested in specific circumstances. Principles and procedures for requesting pre-authorisation inspections should be developed to avoid performing unnecessary inspections which may delay the granting of a marketing authorisation. The following aspects shall be considered during the validation phase and/or early during the assessment phase:

• the applicant has not previously operated a pharmacovigilance system within the EU or is in the process of establishing a new pharmacovigilance system;
• previous information (e.g. inspection history and non-compliance notifications or information from other authorities) indicates that the applicant has a poor history or culture of compliance. If the marketing authorisation holder has a history of serious and/or persistent pharmacovigilance noncompliance, a pre-authorisation pharmacovigilance inspection may be one mechanism to confirm that improvements have been made to the system before a new authorisation is granted;
• due to product-specific safety concerns, it may be considered appropriate to examine the applicant’s ability:
  • to implement product specific risk-minimisation activities; or
  • to meet specific safety conditions which may be imposed; or
  • to manage routine pharmacovigilance for the product of concern (e.g. anticipated significant increase in adverse reaction reports when compared to previous products).

In most cases, a risk assessment based on a combination of product-specific and system-related issues should be performed before a pre-authorisation pharmacovigilance inspection is requested.

If the outcome of the pre-authorisation inspection raises concerns about the applicant’s ability to comply with the requirements laid down in the Regulation and the Directive, the following recommendations may be considered:

• non approval of the marketing authorisation;
• a re-inspection prior to approval of the marketing authorisation to confirm that critical findings and recommendations have been addressed;
• granting of the marketing authorisation with the recommendation to perform an early postauthorisation pharmacovigilance inspection. In this case, the findings would influence the timing of an inspection conducted as part of the EU routine programme of pharmacovigilance inspections (see III.B.2.);
• imposition of safety conditions to the marketing authorisation based on DIR Art 21a and REG Art 14.8.

III.B.1.4. Post-authorisation inspections

Post-authorisation pharmacovigilance inspections are inspections performed after a marketing authorisation is granted and are intended to examine whether the marketing authorisation holder complies with its pharmacovigilance obligations. They can be any of the types mentioned under III.B.1.1 and IIIB.1.2.

III.B.1.5. Announced and unannounced inspections

It is anticipated that the majority of inspections will be announced i.e. notified in advance to the inspected party, to ensure the availability of relevant individuals for the inspection. However, on occasion, it may be appropriate to conduct unannounced inspections or to announce an inspection at short notice (e.g. when the announcement could compromise the objectives of the inspection or when the inspection is conducted in a short timeframe due to urgent safety reasons).

III.B.1.6. Re-inspections

A re-inspection may be conducted on a routine basis as part of a routine inspection programme. Risk factors will be assessed in order to prioritise re-inspections. Early re-inspection may take place where significant non-compliance has been identified and where it is necessary to verify actions taken to address findings and to evaluate ongoing compliance with the obligations, including evaluation of changes in the pharmacovigilance system. Early re-inspection may also be appropriate when it is known from a previous inspection that the inspected party had failed to implement appropriately corrective and preventive actions in response to an earlier inspection.

III.B.1.7. Remote inspections

These are pharmacovigilance inspections performed by inspectors remote from the premises of the marketing authorisation holder or firms employed by the marketing authorisation holder. Communication mechanisms such as the internet or telephone may be used in the conduct of the inspection. For example, in cases where key sites for pharmacovigilance activities are located outside the EU or a third party service provider is not available at the actual inspection site, but it is feasible to arrange interviews of relevant staff and review of documentation, including the safety database, source documents and pharmacovigilance system master file, via remote access. This approach may also be taken where there are logistical challenges to an on-site inspection during exceptional circumstances (e.g. a pandemic outbreak or travel restrictions). Such approaches are taken at the discretion of the inspectors and in agreement with the body commissioning the inspection. The logistical aspects of the remote inspection should be considered following liaison with the marketing authorisation holder. Where feasible, a remote inspection may lead to a visit to the inspection site if it is considered that the remote inspection has revealed issues which require on-site inspection or if the objectives of the inspection could not be met by remote inspection.