Comply with good pharmacovigilance practice and prepare for an inspection.
Good Pharmacovigilance Practice (GPvP) is the minimum standard for monitoring the safety of medicines on sale to the public in the EU.
MHRA inspects marketing authorisation holders (MAH) to determine that they comply with pharmacovigilance obligations established within the EU. We have been conducting statutory GPvP inspections since 2003, and any UK MAH or marketing authorisation applicant (for any authorisation procedure) can be subject to GPvP inspection by MHRA, which may also include any of their partners or service providers.
If pharmacovigilance activities are performed outside the UK, MHRA may ask company personnel from other country sites to participate in an inspection at a UK site and/or may request inspectorates in other member states of the EU to perform an inspection at site(s) in their country or to share results from recent inspections.
Types of inspection
Inspections are typically scheduled by pharmacovigilance system than by MAH. A pharmacovigilance system is defined as the system used by an organisation to fulfil its legal tasks and responsibilities in relation to pharmacovigilance and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance.
If a group of associated MAHs share the same pharmacovigilance system, all MAHs may be included within the scope of a single inspection of that pharmacovigilance system. Conversely, if an MAH operates more than one pharmacovigilance system, we usually review these through separate inspections.
Routine national inspections
GPvP inspections are scheduled as part of the MHRA’s national inspection plan according to a risk-based approach, largely founded on the risk factors listed in EU statutory guidance (Good Vigilance Practice (GVP) Module III), and considering an MAH’s previous inspection history.
The MAH is usually notified of these inspections in advance.
Our GPvP inspectorate shares the list of planned and conducted UK national inspections with the EMA and this is made available to all member states, in line with the European Union procedure on the preparation, conduct and reporting of EU pharmacovigilance inspections (EMA/INS/PhV/192230/2014).
If an inspection results in a critical finding it is likely the MAH will be subject to a triggered re-inspection within 12 to 18 months, with a focus on the actions that were agreed following the last inspection.
If no critical findings are identified there is no specific timeline by which an MAH must be inspected again. The frequency of inspection will be decided using the risk-based approach, and an inspection may be performed at any time.
As of 2016, we no longer require routine GPvP compliance reports to be submitted by MAHs, which were previously used to inform our risk-based inspection programme, as we now have access to a variety of information sources that can support our scheduling and planning activities.
Occasionally, an organisation may be specifically requested to provide information relating to their authorisations and pharmacovigilance systems. Should this information be required, the MAH will be contacted directly by the GPvP Inspectorate.
The European Medicines Agency (EMA) co-ordinates a programme of inspections for pharmacovigilance systems that include centrally authorised products. The programme is based on a routine four-yearly cycle adopted by the Committee on Human Medicinal Products (CHMP), however, the outcome from national risk assessment may lead to a more frequent scheduling of inspections. The MHRA perform inspections as part of the EU programme in its capacity as supervisory authority for MAHs that have located their pharmacovigilance system master file (PSMF) in the UK. The conduct of these inspections typically follows the same approach as for routine national inspections.
MHRA may perform a triggered inspection of an MAH in response to receiving specific risk information. For example, if we’re informed about possible GPvP breaches by:
- a whistleblower
- other MHRA departments
- another regulatory authority
Triggered EU inspections of MAHs may also be requested by the Committee on Human Medicinal Products (CHMP).
We may send little or no notification of these inspections in advance.
CHMP requested inspections
GPvP inspections may be requested by the EMA’s CHMP. The supervisory authority for the inspected organisation will typically lead such an inspection.
Often, inspections are requested by CHMP to address a specific issue that may concern more than one national competent authority, and therefore the supervisory authority may be supported by other authorities in the inspection.
The inspection site may be in a non-EU country dependent on the scope of the inspection and the primary location of pharmacovigilance activities conducted by the MAH.
Service Provider inspections
Increasingly, MAHs are outsourcing all or some of their pharmacovigilance activities to contract service providers; such activities conducted by these organisations on behalf of MAHs are subject to supervision by MHRA, including by means of inspection.
Following a pilot programme of stand-alone service provider inspections, we concluded that a routine programme of inspections of pharmacovigilance service providers is not currently viable for MHRA GPvP inspectorate.
We continue to assess the activities performed by service providers in the context of MAH inspections. We may conduct stand-alone inspections of these organisations where it is deemed necessary to evaluate the overall system and procedures implemented by a service provider based on risk information available to MHRA.
Contracts with pharmacovigilance service providers should include provisions that cover the availability of data, documentation and appropriate support to the MAH and inspectors during a GPvP inspection.
Working with other regulators
MHRA GPvP inspection reports are shared with the EMA and European Economic Area (EEA) member states. Similarly, MHRA GPvP inspectors have access to inspection reports from other EEA member states. This information is taken account of when planning our inspections.
It’s important to note that a pharmacovigilance inspection by us at a site in the UK does not preclude other EEA member states from performing pharmacovigilance inspections at sites in their own country or in third countries (to fulfil national statutory obligations).
Other EEA competent authorities can contact MHRA if they wish a site to be inspected in the UK.
Looking further afield, Agency level agreements are in place to enable discussion of topics of mutual interest with several non-EU authorities and we have conducted GPvP inspections in non-EU countries such as Japan, USA and India.
Preparing for a GPvP inspection
The majority GPvP inspections are announced and are typically scheduled on a quarterly basis. As part of the inspection notification, the pharmacovigilance system master file (PSMF) will be requested. You must acknowledge you have received the notification and provide details of the relevant contact person for future correspondence about the inspection.
If you have concerns about the authenticity of a notification, contact firstname.lastname@example.org
Prior to the inspection the lead inspector will contact the MAH and QPPV and provide the draft plan as well as any specific requirements of the team. In addition to the PSMF, inspectors may require supplementary information to confirm the scope of the inspection and to be well prepared. The lead inspector will explain how our document request system works.
MAHs can expect to receive requests for documentation prior to the inspection and throughout. Where substantial document review is required prior to the inspection, inspectors may incorporate remote inspection time in to the inspection plan.
We expect any documents listed in the PSMF to be readily available for inspection. This includes (but is not limited to):
- procedural documents (such as SOPs, working instructions and guides)
- outputs from pharmacovigilance activities such as safety review meeting minutes
- documented product safety reviews
- audit risk assessments
- agreements in place with partners and service providers
To achieve the objectives in reviewing the pharmacovigilance system, inspectors will aim to be flexible with the plan and to accommodate changes as required, if possible. It is always preferable to conduct face to face interviews, however the inspection team can accommodate interviews by telephone if interviewees are unable to attend the site, provided facilities are adequate to support this.
If the MAH does not have a UK site and is using a vendor site or hiring office space for the inspection, consideration should be taken to ensure access to WIFI and teleconference facilities (if required) throughout the inspection, as well as prompt access to printing and copying facilities, and access to all electronic documentation and systems including the live safety database. The inspection will typically require the use of at least one main inspection room and the company may wish to have a ‘back-room’ for the preparation of document requests.
Under the EU Directive 83/2001 (as amended) inspections may be unannounced. Under UK law, an inspector acting on behalf of MHRA (as competent authority) has the right, at any reasonable time, to enter premises (not limited to those of the MAH) to determine if there has been a contravention of the regulations laid out in SI 2012 No 1916 (per Regulation 325) and the right to inspect information and documents relating the requirements for pharmacovigilance laid out in Part 11 of SI 2012 No 1916 (as per Regulation 327).
In short, although rarely done, MHRA GPvP inspectorate can arrive at, and enter UK sites relating to the conduct of pharmacovigilance activities without notifying the MAH first. In this instance, on arrival at site the lead inspector will identify the most appropriate person on site as a point of contact and will explain the purpose and logistics of the inspection.
During an inspection the inspection team will:
- conduct site visits
- interview relevant personnel
- review documents
- carry out computer system reviews including searching pharmacovigilance databases
The inspection team will ask for additional documentation during the inspection. They may also change the focus of the inspection if they suspect serious non-compliance.
The team and inspection duration
Inspection teams are comprised of between one to four inspectors, spending between two and five days on site. This can vary based on type of products marketed by the company, the complexity of the pharmacovigilance system and the type of inspection (for example routine, triggered, or requested by CHMP).
Occasionally observers may also be present at our inspections. This may include representatives from MHRA Vigilance and Risk Management of Medicines (VRMM) and Enforcement Groups or other competent authority inspectorates.
The PSMF is used as a tool in determining the resource required to perform the inspection, however this can be subject to change and inspections may be extended at short notice based on arising issues.
Extension to inspections may take the form of office-based review of documentation following the on-site inspection, or a return to the inspection site for additional days. This would be communicated to the MAH at the time along with the rationale for extending the inspection.
Inspectors normally interview operational personnel that are involved in pharmacovigilance activities or activities associated with pharmacovigilance including regulatory affairs, and management of post-authorisation safety studies.
If considered necessary, for example if serious issues are identified relating to a business area, it might be necessary to interview a senior executive and senior executive(s) might be requested to attend the closing meeting.
The inspectors typically discuss issues with the MAH as they arise during the inspection to allow for clarification. For this reason, inspectors do not provide daily summaries or ‘wrap ups’ until the closing meeting at end of the inspection. At the closing meeting the inspector will provide feedback and discuss any deficiencies and actions required after the inspection with the MAH.
The inspected party will be invoiced following the inspection.
Grading of inspection outcomes
Deficiencies found during inspections are graded at three levels.
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.
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.
A deficiency in pharmacovigilance systems, practices or processes that would not be expected to adversely affect the rights, safety or wellbeing of patients.
Routine inspection outcomes
Following the inspection, the lead inspector will hold a closing meeting to outline observations from the inspection and clarify logistics for the next stage of the inspection process. There may be outstanding documentation to receive and to review following the inspection. The inspection report will be written, usually peer reviewed, and provided to the MAH within 25 working days of the closure of the inspection or receipt of the last document, whichever comes last.
On receipt of the inspection report, the MAH has the opportunity to formally respond to the inspection report in writing, using the template and instructions provided. The template responses consist of a root cause analysis and further assessment of impact of each of the findings and proposing corrective and preventative actions with associated deliverables and due dates. The MAH will have 25 working days to provide the responses to the lead inspector. Please see guidance for responding to inspection findings.
The lead inspector will review proposed actions and may request clarifications until satisfactory responses can be agreed upon. This can take the form of written requests for clarification, discussions via teleconference or, less commonly, a face to face meeting. Once agreed, a final inspection report will be sent to the MAH and the inspection will be closed. The lead inspector will typically work with the MAH to reach agreed actions that will bring the MAH’s pharmacovigilance system into compliance.
It is expected that MAHs will share inspection reports with their service providers so that they may assess the impact of any inspection findings relating to their activities for the MAH across their wider client base and remediate where required.
Non-routine inspection outcomes
Escalation to GPvP Compliance Management Team (CMT)
The GPvP CMT is a non-statutory group constituted to coordinate and advise the GPvP inspectorate on compliance management issues following an inspection or detection from other intelligence sources; recommendations for referrals to IAG2 for action (see below); recommendations for enforcement action.
Cases considered by the GPvP CMT include:
- all critical inspection findings from MHRA GPvP inspections
- findings from MHRA GPvP inspections that require referral to the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) due to concerns about, or the impact of non-compliance on, the safety of a product
- organisations that have not had critical findings but where there are major findings that are at high risk of developing into critical issues (for example due to the management culture or a history of poor CAPA management)
- critical (or comparatively graded) findings arising from non-MHRA inspections, to assess any risk to UK public health and patient safety, compliance with national requirements and the need for specific UK remediation
For MHRA GPvP inspections that have not initially resulted in a referral to the GPvP CMT, the lead inspector may refer the case to the CMT if the responses to the inspection report are considered inadequate despite requests for clarification.
Escalation to Inspection Action Group (IAG2)
There are two Inspection Action Groups (IAG) at MHRA, IAG2 covers clinical trials of investigational medicinal products and/or the pharmacovigilance activities of MAHs and also advises the director of the Vigilance and Risk Management of Medicines (VRMM) Division.
Where recommended by CMT, cases will be referred to IAG2 for action or for information. IAG2 meets regularly to deal with ongoing business and to consider new referrals. Criteria to be met for making referrals to the IAG2 in relation to pharmacovigilance inspections include, but are not limited to:
- conditions that are likely to cause or lead to a significant risk to public health
- an inspection identifies one or more unresolved critical deficiencies
Early re-inspection has been the most common recommendation made by IAG2 to date. In most cases adequate progress has been observed on re-inspection; in some cases, a further re-inspection has been required and a minority of cases have been referred back to IAG2 for consideration of other actions, which may include meetings with MAH senior representatives to discuss the issues and consequences of continued non-compliance.
An infringement notice may be issued when instances of serious or serious and persistent non-compliance with pharmacovigilance requirements have been identified.
Companies who have been issued an infringement notice.
|Company name||Date issued||Reason||Infringement notice||Status|
|Omega Pharma Limited||9 October 2013||Regulatory action||Infringement notice||Closed: MHRA has confirmed the measure set out in the infringement notice have been implemented successfully|
Annual pharmacovigilance inspection metrics dating back to 2009 are published on the MHRA website.
In addition, anonymised findings from MHRA pharmacovigilance inspections are presented at MHRA symposia and other conferences attended by inspectors. MHRA GPvP inspection reports are available on request under the freedom of information act.
Legislation and further guidance
The process for pharmacovigilance inspections is described in the Guideline on good pharmacovigilance practices (GVP) Module III (Pharmacovigilance inspections)
The GPvP inspectorate welcomes ongoing feedback on the conduct of inspections. These can be sent to the GPvP inspectorate’s mailbox: email@example.com
Pharmacovigilance Inspectorate Unit
10 South Colonnade,
London E14 4PU
020 3080 6000