Inspections relating to manufacturer’s authorisations

Remote Inspections / Distant Assessments

In light of the current travel restrictions and risk to public health posed by the COVID-19 pandemic, the HPRA initiated a process to conduct inspections remotely via distant assessment. The requirement to conduct a distant assessment will be determined on a case-by-case basis. Notifications will be sent in advance of the distant assessment in the same way as for an on-site inspection. The distant assessment process will, in general, follow a similar format to that for an on-site inspection and will commence with an opening meeting and conclude with a closing meeting via videoconference or alternative remote communication platform.

The communication platform used will be particularly important to facilitate the smooth running of the distant assessment. The sites hosting the distant assessment will be requested to propose a suitable communications platform and this will be agreed with the Inspector in advance of the distant assessment. The process will require electronic copies of documents and other information to be provided to the Inspector for review. Consideration should be given to the use of platforms which provide for live sharing of documents and videos, in addition to the use of cameras to allow for a virtual review of physical facilities, equipment and manufacturing operations, where applicable.

To avoid delays during distant assessment, companies will be requested to make certain documentation available prior to the commencement of the distant assessment. Documentation requirements will be specified in the pre-distant assessment notification. In certain circumstances, a distant assessment on its own may not be sufficient to enable a decision to be made regarding the level of compliance with GxP requirements and, as such, an on-site inspection may be performed at the earliest possible time. It is envisaged that this would generally focus on areas of the site that could not be inspected remotely and/or areas requiring further follow-up resulting from the distant assessment.

In certain circumstances, a hybrid approach may be adopted, in that a distant assessment and on-site inspection of limited duration are conducted in conjunction with each other. In these circumstances, COVID-19 protocols and associated arrangements will be discussed and agreed with the company in advance.

Companies can involve colleagues from within their wider organisation in the distant assessment but we would ask that they refrain from bringing international colleagues to the site to support the inspection.

About inspections relating to manufacturer’s authorisations

Manufacturers of medicines are regularly inspected by the HPRA’s GMP inspectors using a risk based approach to ensure compliance with GMP standards.

The HPRA is responsible for conducting inspections to determine whether manufacturing operations are in compliance with the EU Guide to Good Manufacturing Practice (GMP). In addition to routine inspections to determine ongoing compliance, non-routine (for cause) inspections may be performed, for example, in relation to a variation application or a serious quality defect.

Manufacturers located in Ireland are inspected on a routine basis, every 2 – 3 years. The frequency of inspections may increase depending on the activities of the site and the findings of previous inspections. A copy of the risk-based planning form can be requested upon close out of the inspection by contacting inspect@hpra.ie. The HPRA also conducts inspections of manufacturing sites located in third countries where it is a supervisory authority for the site concerned. The HPRA is deemed to be the supervisory authority when the site of batch certification for the imported product is located in Ireland.  The HPRA may also carry out inspections of third country manufacturers where the inspections have been delegated by a supervisory authority in another Member State. Third country inspections of manufacturing sites may also be requested by the European Medicines Agency (EMA).

Routine inspections of manufacturers located in Ireland follow the following procedure:

Notification of inspection:

The company will be notified usually 6 weeks prior to the proposed inspection date.

Inspection:

HPRA inspectors will perform the inspection. The duration of the inspection and the number of inspectors present on an inspection will vary depending on the complexity of the activities conducted at the site.

Issuance of a report

Following inspection, a report is issued to the inspected site with a conclusion regarding compliance with GMP. Deficiencies are classified into three categories; critical, major and other. A summary for the criteria for judging deficiencies as critical, major or other are detailed below. For the full definition please refer to the EMA compilation of community procedures on inspections and exchange of information.

  • Critical Deficiency:

    A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal.

  • Major Deficiency:

    A non-critical deficiency: which has produced or may produce a product, which does not comply with its marketing authorisation

    or

    which indicates a major deviation from EU Good Manufacturing Practice

    or

    (within EU) which indicates a major deviation from the terms of the manufacturing authorisation

    or

    which indicates a failure to carry out satisfactory procedures for release of batches

    or

    (within EU) a failure of the Qualified Person to fulfill his legal duties

    or

    a combination of several “other” deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such.

  • Other Deficiency:

A deficiency, which cannot be classified as either critical or major, but which indicates a departure from good manufacturing practice.

(A deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as a major or critical).

Inspected sites are requested to reply to the deficiencies stating proposed /actual corrective action(s) relating to the individual deficiency and date(s) for completion of the corrective action(s). It is expected that any critical or major findings are addressed immediately.

Company response to report and close out

The company must provide a response to the deficiencies and points to note outlined in the inspection report. The responses are reviewed by the inspection team to determine whether or not they are acceptable. A GMP certificate may be issued on the EudraGMDP database at the same time as the inspection report is issued to the company, where no critical or major deficiencies were observed. In other cases a GMP certificate will be issued on the EudraGMDP database upon receipt of responses which have been deemed acceptable. Where responses are deemed unacceptable a statement of non-compliance may be issued. The HPRA does not routinely issue hard copies of GMP certificates.  Authenticity of GMP certification may be verified on the EudraGMDP database. Hard copies of GMP certificates may be requested via the export certification process, details of which may be accessed on the Export Certification page.