This article aims to provide a regulatory overview of the situation, to carry out a review of documents produced by different health authorities or working groups, to share reports of meetings conducted with inspectors from different agencies from all parts of the world. This article in no way represents the official positions of the health authorities present at these meetings. These are points that were noted during different meetings and may have been interpreted by the author.

Let us go back eighteen months, we have had to learn to work remotely, to create, lead, moderate meetings on several sites, with each person staying at home or on their site. We have all learned to work differently. As the health agencies could no longer visit the site to carry out inspections, they have also had to reinvent themselves to continue to ensure that pharmaceutical regulations are complied with on production sites. This has led them to use digital tools (virtual meetings, use of cameras, use of document exchange platforms), to carry out inspections while complying with local laws concerning data ownership, confidentiality, etc. At the same time, manufacturers have organized themselves to carry out supplier and subcontractor audits. Without having real regulatory support, we have had to be flexible to adapt to these new practices.

During this period, some agencies such as the EMA and FDA published guides for inspectors, as well as for pharmaceutical companies to express their expectations in terms of the content and practical application of remote audits. The health authorities also took part in numerous webinars, virtual conferences on this subject in order to share their experiences and their expectations, to respond to concerns and questions from pharmaceutical manufacturers.

1. Terminology and definitions

We can now look at the terminology. Numerous terms, paraphrases have been used to avoid the use of the word inspection in the context of activities carried out remotely, whether in France or in all regions of the world, as inspectors wish to reserve the term inspection for a physical practice on site which allows the observation of events and of production tools in operation. The terms most often identified are: “remote evaluation”, “remote assessment”, “remote inspections”, “desktop inspections”, “distant assessment”). We did note that one agency, in two documents released several weeks apart, had used two different terminologies for clinical inspections and GMP inspections “distant assessment” and “remote inspection”. Here we sense a need for everyone to clarify and standardize the terminology used by all health agencies. This work has been entrusted to the ICMRA (International Coalition of Medicines Regulatory Authorities).

We will conclude this section on “definitions and terminology“, with what the health authorities consider to be an inspection, elements that are found in the ICMRA reflection paper as well in numerous communications produced by the different inspectors who have shared their experiences during recent months: “ An inspection means, for the purpose of this document, an act by regulatory authorities of conducting an official review of activities, documents, facilities, records, and any other resources that are deemed by the authorities to be related to the work performed and that may be located at a manufacturing site or at other establishments deemed appropriate by the regulatory authorities. (Taken from the ICMRA reflection paper).

2 . The performance of remote audits by the Health authorities

It emerges from various exchanges that have taken place between manufacturers and the health authorities, that they assessed the need to conduct or to not conduct inspections on the basis of risk analyses before launching their remote audits. These assessments were carried out by senior inspectors and operational management and after discussions with those inspected. (ICMRA Covid-19 group: remote GCP and GMP regulatory oversight inspection.)

The risk analyses carried out may also enlighten us regarding the assessments that we can perform to determine whether or not to conduct remote audits of our suppliers. The points which were taken into consideration by the authorities are listed below without being exhaustive.

• The local or international restrictions that had been put in place to cope with the public health emergency.
• The need to protect the health and safety of the inspector, of the inspection staff and the staff of the establishment inspected.
• The history of regulatory compliance of the entity inspected.
• The scope and the objectives (preapproval, routine or for cause) of the inspection.
• The type of site and its complexity (for example, sterile manufacture, solid forms) and the intrinsic risks/the appropriateness of remote assessment in the context of the inspection.
• The date on which there was an on-site inspection of the site and the conclusions of the inspection.
• The changes that have occurred on the site since the previous inspection.
• The accessibility of electronic systems held and managed by the service providers.
• Document access while complying with regulations and/or the applicable institutional policies.
• The inherent risk associated with the activities conducted by the site, product types and the need for the product (for example, if a substantial, unmet medical need is involved).
• The capacity of the persons inspected and of the inspectors to carry out the remote inspection given the resources, technical skills and adequacy of the site.

3. The definitive guides or drafts published by the health authorities

Over the last two years, several agencies have published guides (either in the form of drafts or definitive documents) to clarify the practices to be implemented both for inspectors and the companies inspected.

• Guidance related to GMP/GDP and PMF distant assessments EMA
• Guidance-remote-gcp-inspections-during-covid-19-pandemic EMA
• Remote-Interactive-Evaluations-of-Drug-Manufacturing- Establishments FDA
• Remote Inspection guide ANVISA

The analysis of guides produced by the agencies yields recommendations on audit planning, content definition. These elements are not very different from guides for on-site inspections that already exist.

We find more significant recommendations which more particularly target items requiring attention.

4 . Organization

• Taking account of time differences, those taking part in inspections may be in different time zones. This may have an impact on organization in order to hold the audit in shared business hours.
• Remote working also requires shorter sessions to avoid long days in front of a computer screen. The total duration of inspections may as a result be extended.
• Before the audit, schedule the inspection of the tests on the tools used, check for the presence on each side of IT support systems and support for the tools used.
• The tools used must comply with the local rules of the competent authorities.
• Provide document exchange tools allowing consultation of documents.

5 . Technological requirements

The guides published by the agencies form a very important part of the communication tools to be used and highlight certain precautions for the conduct of such inspections.

• Quality of remote connections, and bandwidths in order to allow the use of cameras to have a view of what is happening on the site. The videos proposed allow a site to be presented but do not allow a fully confident inspection of what happens in reality.
• The tools to be used must be compliant with agency requirements. For example, the FDA has had specific Team, Zoom and Adobe applications developed.
• Data integrity and cybersecurity are also points to be taken into account during such inspections, audits, in order to avoid data corruption.
• It should be possible to set up contacts with experts in the different areas covered by the inspection.

6. After the inspection

All of the agencies issue reports not in the usual formats but adapted to the circumstances and to the practice of remote inspections:

• The FDA does not produce form 482 or form 483, they conclude their inspection with a list of points of non-compliance.
• The EMA produces GMP / GDP certificates but it is mentioned that the inspection was conducted remotely.
• The EMA has extended the GMP certificates of different production sites so as to not penalize them for delays of inspections, up to the end of 2022.

7. In the future 

A number of agencies wish to return as quickly as possible to on-site inspections, which they consider the only way of conducting inspections. In some discussions we also encounter possible developments in the direction of hybrid inspection models, with one part on site and one part conducted remotely on the document element.

8. Expectations of agencies for future audits

– The availability of documents From the ICMRA working group it emerges that agencies wish to retain document availability up to the conclusion of the inspection, a point that also emerges in the last ANVISA guide which forms part of the ICMRA group moderated by the MHRA.

– Data It also emerges in this ICMRA document that certain agencies have equipped themselves with software packages used in control laboratories for gas chromatography, HPLC and wish to be able to review the raw data remotely.

Conclusion

This period of pandemic has led manufacturers and health authorities to reinvent themselves, to allow production operations to continue while maintaining the level of quality required by the necessities associated with products, and with regulatory requirements.

While all the stakeholders have adapted and published guides in order to ensure that this type of exercise is correctly understood, the need to return to on-site inspections is becoming increasingly urgent. The guides and information produced by the agencies will remain valid and some agencies are thinking of a hybrid inspection model, which will also require adaptation on the part of manufacturers.

This part was covered in the “Distant Assessment” workshop in Biarritz with some supplementation from new published guides such as that of ANVISA and the “reflection paper” published by ICMRA.