Preparing for the New Era of Hybrid Regulatory Inspections

The U.S. Food and Drug Administration (FDA) has long aimed to strengthen its use of remote inspection and integrate desk-based assessments with traditional on-site visits. The pandemic has dramatically accelerated that evolution. Welcome to the new era of hybrid pre-approval and pre-licensing inspection. What do you need to know?

Evolutionary Forces

Hybrid inspections involve on-site audits performed by a team of investigators and simultaneous remote records assessment with another group of investigators. This approach is happening more frequently and will likely become the new normal. Multiple forces are at work:

• The pandemic brought about needed investment by manufacturers in technology infrastructure. Now, nearly every manufacturer, from sponsors to contract manufacturing organizations (CMOs), has remote inspection-hosting capabilities. The FDA has also invested in enhancing virtual support tools so regulators can continue working remotely when appropriate.
• The regulators are facing a serious staff shortage. The FDA recently reported challenges in recruiting, hiring, and retaining personnel, likely resulting from increased operational pressures and workload during the pandemic. The FDA also noted challenges in filling investigator positions, which typically require significant training by more experienced staff.
• The unpredictable travel situation will likely persist. While mission-critical inspections are being prioritized, some still are impossible in certain regions.

Regulators have found that remote inspections are a very useful and cost-effective tool complementing CGMP compliance verification. The virtual platform enables direct real-time dialogue with on-site personnel. This way, regulators can more rapidly attain the process and product-control strategy data they need to approve a submission under expedited timelines and limited resources. With the addition of the virtual component, there is a corresponding increase in the number of investigators and subject matter experts on the inspection team. In some recent U.S. domestic and international hybrid pre-licensing inspections for biologics, an inspection team size totaling around ten investigators was reported. 

The Need to Be Prepared

Sponsors and CMOs must be ready for this new modality of inspection. Beyond the technical capabilities, they must be prepared to host a group of investigators online, who will likely focus on conformance to the submission and implementation details of the control strategy proposed. This emphasis on conformance is the case whether the inspection is performed virtually or on-site.

They will also need to have resources available to host the regulators on-site. Working with them in person, the on-site team will act as ears and eyes to answer questions from regulators and read reactions. The Quality experts, in particular, will be on point. They will be responsible for discussions with the inspection team lead from the regulatory agency, which will require them to understand the point of view of each of the various investigator teams – often representing different FDA offices or departments.

Crucially, the Quality group will need to have a comprehensive grasp of the Regulatory matters and details of the submission. In many organizations, because of their structure, Quality and Regulatory teams work independently. Consequently, on-the-ground manufacturing operations are opaque to the Regulatory group, and Regulatory Affairs are likewise opaque to Quality. Before the inspection, the two will need to establish close interaction. Lack of on-time communication between the two groups is the leading root cause of application nonconformance, which invites stringent regulatory scrutiny. Many questions will arise if the FDA investigators observe the manufacturer is doing something on-site that differs from that described in the marketing application submitted to the agency. In the regulator's view, these types of discrepancies are often potential indicators of a data integrity concern.     

How the FDA Determines Its Approach

What type of manufacturing site is a candidate for a hybrid inspection? Essentially, this is a risk-based decision. Sites well-known to investigators, and those with a history of successful inspections, are most likely to avoid an on-site assessment and will be granted remote assessment instead. Those with a higher risk of a hybrid inspection have no previous inspection history, or their previous inspections have resulted in 483 lists of required corrections. Also at higher risk are sites with a complex manufacturing process and products with complex analytical characterization assays.

In any case, sponsors and CMOs should do everything in their power to be prepared for these inspections. Suppose things do not go well, and a long list of 483 observations is issued. In this case, the follow-up inspection may not be scheduled for some time, delaying regulatory approval and commercial manufacturing. And keep in mind that a negative result could discourage the regulators from performing remote inspections in the future.

How Parexel Can Help

The best practice is to prepare for inspection about one year before the planned regulatory submission. Whether hybrid, remote, or fully on-site, the inspections are thorough, structured, and detailed. Parexel can help. Our group of experts includes 1,000 consultants and over 80 former regulators and policymakers with direct experience in the world's most influential pharmaceutical Regulatory Agencies, including the US FDA, NMPA, and EMA. Our services cover readiness for commercial manufacturing, conformance with the application (assurance that on-site activities are in line with the submission), a data integrity audit, and much more.

Parexel offers unique strength in biosimilar pre-licensing inspection. Our staff of subject matter experts, who include former FDA employees, align perfectly with FDA inspection teams for biologics (representation from FDA office of CDER/OPQ/OPMA & OBP, and occasionally ORA). We cover everything from CGMP compliance audit of the laboratory site, where the comparative analytical assessment of biosimilarity is conducted, to helping the firm host FDA inspections. We can thereby assist your subject-matter experts in aligning with the organizational structure of the FDA and coach your team accordingly.

With deep experience in both virtual and on-site inspections, we can help you prepare – and give you a better chance of getting your product approved for commercial manufacturing and market access.

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