by Giuliana Miglierini
Hybrid inspections emerged during the pandemic as a new way to approach the assessment of pharmaceutical plants and productions by regulators. More in particular, under this approach regulatory authorities from different geographical areas join efforts to reach a shared regulatory decision based on results of either on-site or remote inspections (see here more information on EMA’s website).
Hybrid inspections are the focus of a pilot project launched by the International Coalition of Medicines Regulatory Agencies (ICMRA), following a workshop held in July 2023 and organised in collaboration with the International Federation of Pharmaceutical Manufacturers and Traders (IFPMA).
Among the main objectives of the collaborative hybrid inspection pilot (CHIP) is the assessment of existing technologies and virtual inspection methods in supporting a stronger collaboration among regulators. The development of a global Pharmaceutical Quality Knowledge Management System (PQ KMS) would be one of the main consequences of such collaboration. The CHIP pilot is now open to new applications from the pharmaceutical industry. More information is available on ICRMA website, together with the summary report of the PQ KMS workshop and related documentation. We summarise the main features of the pilot.
The CHIP pilot on hybrid inspections
The methodology used to run the CHIP pilot, together with inspection expectations to be met by the industrial partners, are described in the dedicated page of the ICMRA website. The implementation plan is available at this link.
The first phase of the pilot ran in 2023 and included the collaborative assessments of post-approval changes as a useful tool to improve cross-regional access to critical medicines. This part of the project led, in May 2023, the European Medicines Agency (EMA) and the US Food and Drug Administration to approve on the same day, without any delay between the two areas, the addition of three new manufacturing sites in the supply chain of a treatment for a rare type of cancer. The Japanese regulator PDMA also participated to the project as observer.
The new phase of the project will involve other regulators and will focus on the collaboration between regulatory authorities (RAs) and industry to implement and promote innovative regulatory approaches and technologies.
In hybrid inspections, only one leading RA is present on-site with its inspectors (the local RA, whenever feasible), while the other regulators participate from remote to follow the on-site inspection team procedures. The new approach is expected to reduce efforts, cost and time for both regulators and inspected pharmaceutical companies, as a single inspection will allow multiple authorities to agree on a site’s compliance. Marketing authorisation holders (MAHs) may also experience a smoother submission process, as they would possibly receive a single list of information requests, comments, and questions from multiple regulatory authorities. The pilot is also expected to lead to the definition of a suitable approach to handle post-authorisation inspections (routine inspection).
Preparing for the hybrid inspection
Hybrid inspections start with pre-inspections activities, to be launched 30-60 days prior to the actual inspection. The main goal of the pre-inspection is to ensure the target facility has all the needed resources to host, support and accommodate the hybrid inspection.
In this phase, the on-site lead inspectorate is called to liaise with the site to arrange for all the organisational and logistical aspects, as well as networking with all the other participating RAs to plan the activities to be observed during the inspection. The anticipated agenda and length of the hybrid inspection should be determined in advance by participating RAs and shared with the company by the lead inspectorate. Hybrid inspections should be no longer than normal on-site inspections.
The planned scope of the inspection has also to be agreed upon during pre-inspection, and it should be the same for each participating RA. To this instance, the leading on-site inspectorate is in charge of obtaining from the company all the requested information, on the basis of accepted global standards (i.e., Site Master File based on PIC/S). The inspected facility is entitled to receive details of the closing meeting between RAs prior to the conduct of the inspection.
As for the number of participants in the inspection (including investigators and coordinator roles), it should reflect realistic staffing levels for long-term implementation. The planning phase should also be comprehensive of the establishment of a communication channel (including testing the stability of the connection) between RAs and the facility, and a second one for RAs to communicate between the on-site and remote teams.
A coordinating officer, assigned by the lead inspectorate team, should oversee the logistics for the remote team, and a facilitator from the company should also be identified to manage the remote team’s requests and upload all the documentation. This last one should be shared using the appropriate exchange platforms, as specified by each authority, and agreed during the pre-inspection phase.
The actual hybrid inspection
The opening meeting is the first act of the hybrid inspection, during which all participants (both on-site and remote) introduce themselves and define the lead inspector in charge of the coordination of all activities. The coordinating officer is also nominated in the opening meeting, and the inspection team schedule is presented to the facility’s key personnel. The hosting site can introduce the facility, including the Quality management system and production schedule.
The possibility to run a virtual tour for remote RAs of the areas and activities to be inspected has to be assessed and agreed on during the pre-inspection phase. Should this not be possible due for example to difficulties with the Internet connection, remote RAs may rely on the observations made by the on-site team, which will inspect the plant according to the defined scope of the inspection, with reference to critical manufacturing activities.
Inspectors may start their tour of the plant following the same logical flow of the process they are assessing, from inwards warehouses to production areas, QC areas and outwards warehouses. Some breakout rooms may be created along this flux in order to allow inspectors to check the relevant documentation and run interviews with personnel. To this instance, the remote team should request in advance documents through the coordinating officer, and possibly access them off-line during the inspection should different time zones apply. Questions to be proposed during the interviews should also be provided in advance by the remote team to the lead inspector or through the coordinating officer.
The results of the activities performed during the inspection is discussed by RAs at the end of each-day, in order to plan the activities for the following day; the lead inspector shall then communicate them to the facility.
Closure of the inspection
The closing meeting is the final act of the inspection, during which the lead inspector should report on the observed GMP deficiencies. In case of a different perception of a certain issue by different RAs, they should try to reach a common position on its significance during a pre-meeting. Any difference in GMP deficiencies or outcomes should be illustrated to the company by the lead inspector during the closing meeting.
This should also be the place to discuss post-inspection activities and their timelines, that should be aligned between the different participating RAs. Collaboration between regulators should also extend to the coordinated assessment of the documentation on corrective and preventive actions (CAPAs) submitted by the manufacturer.
