How does FDA decide whether to conduct a biologics manufacturing inspection in person or perform a remote assessment?

At the GMP by the Sea annual conference in Cambridge, Md. in August 2022, FDA Office of Pharmaceutical Manufacturing Assessments (OPMA) deputy director Derek Smith explained that the agency makes decisions based on a variety of risk factors, which he outlined in his talk.

[Related: For more insights on FDA inspection trends, download a report from author Jerry Chapman that includes four inspection case studies.]

Our coverage of Smith’s presentation at the August conference is in three parts.

Part I included background and the rationale behind the inclusion of reviewers and investigators from different offices in FDA and how a partnership between OPQ and ORA improves the efficiency of the process and leverages each team member’s expertise.
Part II examined the current state and future anticipated states of inspections of biologics regulated by CDER.
Part III focuses on the model used to evaluate whether biologics manufacturing site assessments should be conducted remotely or in person.

A Risk-Based Decision Process for Biotech Inspections

Smith emphasized that remote regulatory assessments (RRAs) will continue to be part of the agency’s inspection paradigm in addition to onsite inspections.

“We have created an overarching oversight strategy, a decision tree, that guides the assessment teams on when to consider a remote assessment rather than an onsite assessment, or performing a remote assessment prior to doing an onsite assessment, to leverage some of the lessons that we have learned throughout the pandemic,” he explained.

The following are important elements in the agency’s determination of whether an onsite, physical inspection of a biologics manufacturing facility will be needed:

– Prior inspection history

– New facility/building/filling line without inspection history

– Prior experience with a similar manufacturing process

– Information shared by other regulatory agencies

– CGMP issues relevant to application product

– Product and process-specific risks

– Application-specific concerns

– Significant process changes for supplements

Smith provided a flow chart that shows how alternative approaches to facility assessment are evaluated (Figure 1).

Figure 1 Alternative Approaches to Facility Assessment — **FIGURE 1 | Alternative Approaches to Facility Assessment**

The OPMA deputy director explained how the flow chart he shared has been used.

“We conducted facility assessments looking at the risk factors. We determined whether a pre-approval inspection(PAI), pre-license inspection (PLI) was indicated. If no, there would be an inspection waiver. And, if yes, we would then determine whether we could use the alternative tools for facility assessment. We could either use those alternative tools to support the inspection or conduct the evaluation.”

“One of the takeaways I think was interesting for me…is that these tools started giving us means to waive more inspections through records requests, specifically, prior to the pandemic, and that just further expanded upon the use of the tool.”

The new draft guidance document out for comment on remote regulatory assessments provides for leveraging these tools in the future, he explained.

“We are going to continue to evaluate the use of these tools, the impact of these tools, to move the program forward, because there are an ever-increasing number of biologics submissions and there are only a finite number of inspection resources. So, we really do need to be mindful of the use of the resources in a more strategic way.”

Smith shared the impacts of using RRAs to date on the Biologics License Applications (BLA) program.

RRAs have been used to support Emergency Use Authorizations and approval of new biologics. New biologics have also been approved using a combination of remote regulatory assessments and inspections.

There have been over 230 individual assessments for inspection or alternative facility assessment since March 2020, including over 170 BLA submissions, which led to approximately a 30% reduction in PAI/PLI needed to support BLAs.

Insights on Pre-Approval Inspection Trends

Are you anticipating a pre-approval inspection (PAI)? Redica Systems can provide you instant access to the latest trends for 483s observations on human drug and biologics PAIs, making your inspection preparation more efficient.

For example, if you have a site in the Asia-Pacific region, Redica Systems data shows that you can expect a 483 observation to follow a PAI.