Inspecting GMP at a Distance

A temporary system, under which good manufacturing practice (GMP) inspections have been performed virtually or remotely during COVID‑19, appeared to have been seen as such a success among pharmaceutical companies that they want it to become a permanent alternative. The Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA) said in a recent reflection paper that there could be ‘added value’ in retaining a ‘virtual’ inspection system beyond the pandemic (1).

Virtual inspections combine the use of paper and digital documentation, such as reports on previous GMP inspections, and electronic IT technologies, such as video conferencing. “We think the pandemic situation has demonstrated the effectiveness of using virtual inspections as one potential tool to support the determination of (GMP) compliance,” Pär Tellner, EFPIA’s director, regulatory, drug development, and manufacturing told Pharmaceutical Technology Europe. “The technology is now fit for purpose and therefore can be implemented,” he added.

The principle of virtual inspections is also supported by the Geneva-based International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). “The term ‘virtual inspection’ applies to inspections that are performed off-site through the use of enhanced communication and information technology to fulfil legal requirements of on-site inspections,” IFMPA said in an updated document on virtual inspections in July (2).

However, the regulators in Europe are generally being cautious about virtual inspections. The International Coalition of Medicines Regulatory Authorities (ICMRA) has set up a working group on ‘office-based’ GMP inspections led by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). The Pharmaceutical Inspection Co-operation Scheme (PIC/S), a regulatory authorities’ organization headquartered in Geneva, is holding an appropriately virtual seminar in Finland in December 2020 on the subject.

The current policy of agencies—at least in Europe—is that the results of remote, desktop inspections should be confirmed by on-site inspections once GMP inspectors can travel freely again. There are doubts among regulators about whether distant inspections can be sufficiently reliable, even with the help of e-technologies.

The European Medicines Agency (EMA), Heads of Medicines Agencies (HMA), representing national authorities, together with the European Commission have introduced a system during the pandemic under which the validity of GMP certificates for European manufacturing and importing sites for finished products and active substances will be extended to the end of 2021 (3). But it leaves open the question of how the certificates could then be renewed.

For new sites and facilities in Europe that do not have documentation on previous inspections, GMP certificates can be issued on the basis of distant assessments. But on-site inspections should take place once COVID-19 restrictions are lifted, according to EMA (3).

Future opportunities

There may be opportunities for a different approach to facilities with a history of a high level of GMP compliance with which a brief site visit may only be necessary. Regulatory authorities are reported to have introduced some flexibility into inspection schemes by combining virtual inspections with short, targeted on-site visits, according to Tellner.

Changes to some local GMP guidance documents may be necessary to bring them up to date with the new e-technologies and then use of virtual methods.“We think there is no need to change intentions in GMP guidance as virtual inspections can be a tool in addition to on-site and paper-based inspections,” added Tellner. “We understand agencies can issue GMP-certificates (along the lines required by the European Union) legislation if the inspector can ensure compliance.”

On-site inspections by foreign inspectorates could become unnecessary or at least be required “only in exceptional circumstances,” EFPIA reported in a reflection paper on GMP and good distribution practice (GDP) inspections, published in May 2020 (1). Instead desktop assessments could be complemented by “an on-site inspection by an acknowledged local supervisory inspectorate,” the paper specified.

“The advantage of an assessment/inspection/certification by a local inspectorate includes knowledge of the site-specific history, insight into culture, optimization of (regulatory agency) resources, and benefits from improved inspection logistics (e.g., no language barriers, less travel),” the EFPIA paper explained.

Advisory tools

Inspectors performing desktop GMP assessments already have advisory tools available, mainly provided by PIC/S through its 2018 Guidance on GMP Inspection Reliance (4). This guidance was originally drawn up by ICMRA, which then transferred it to the care of PIC/S.

The guidance was issued in response to the growing complexity of pharmaceutical global supply chains, which made inspection of overseas sites beyond the capacity of national regulatory authorities. The guidance helped authorities use inspection reports on sites by other agencies as a basis for providing GMP certificates without a new inspection.

The guidance suggested ways of vetting the regulatory authorities doing the original inspections. It also recommended examining the original GMP certificates or, when not available, the inspection reports themselves, which were often held by the pharmaceutical companies whose products were being made at the sites.

PIC/S has been reviewing the guidance’s implementation based on desktop assessments made in 2019, after which it set up a working group on inspection reliance. “This new working group will investigate how to further facilitate reliance and how any barriers which may exist can be removed,” explained a PIC/S spokesperson to Pharmaceutical Technology Europe.

At the same time, a clear distinction between inspection reliance and distant assessment of GMP reliance is emerging. While the former is a system for relying on another inspection report from another inspectorate to avoid a duplicate on-site inspection, the latter is much broader in scope, covering a range of information sources whose assessment is considered to be equivalent to an inspection. The real-time communication of confidential data in virtual inspections also requires its own security measures.

The planning stage in remote and virtual inspections is the time when it becomes clear what data and documents are required to make a distant assessment. A major requirement should be details of the history of GMP/GDP compliance and the occurrence of major deficiencies, according to the EFPIA reflection paper (1).

Risks should be assessed taking into account the complexity of a site, processes and products produced, consistency of output levels, and reported events and deficiencies since the last GMP inspection. A key to the success of remote or virtual inspection systems is the willingness between national regulatory agencies to share information with each other and between agencies and pharmaceutical companies.

Political impediments

Politics could also intervene in the exchange of information between national authorities from documents. The UK’s regulatory agencies have been facing the prospect of having access to information from EU regulatory authorities restricted from the beginning of January 2021 as the transition period for the country’s departure from the EU ends.

Gaining similar access to data from EU countries as it had when it was a member of the Union would have to be covered by an EU-UK free trade agreement, which was still being negotiated in November with a distinct prospect of no deal. Or it would have to be provided by a mutual recognition agreement embracing GMP/GDP standards and inspections, which would take time to finalize.

MHRA claimed that any EU restrictions on exchange of data would not be a major problem. “[We] will accept imports from EU and EEA [European Economic Area] countries, which are on an approved country for import list, so it is anticipated that relatively limited information will be required from these countries,” an MHRA spokesman told Pharmaceutical Technology Europe.

Creating a smoothly operating remote or virtual international inspection system with unimpeded exchange of information on an agency-to-agency and company-agency basis could turn out to be a lengthy process.

References

1. EFPIA, “Alternative GMP/GDP Inspection Practices in a Pandemic Situation (COVID-19) and Beyond,” Reflection Paper (Brussels, 28 May 2020).
2. IFPMA, “Points to Consider for Virtual GMP Inspections—an Industry Perspective,” Living Document (Geneva, Last Updated 23 July 2020).
3. EMA, HMA, EC, “Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the COVID-19 Pandemic” (Brussels, 10 April 2020, revised 1–3 July 2020)
4. PIC/S, GMP Inspection Reliance, Guidance (Geneva, 1 June 2018).

About the Author

Sean Milmo is a freelance writer based in Essex, UK.

Article Details

Pharmaceutical Technology Europe
Vol. 32, No. 12
December 2020
Pages: 6–8

Citation

When referring to this article, please cite it as S. Milmo, “Inspecting GMP at a Distance,” Pharmaceutical Technology Europe 32 (12) 2020.