What are the current and future anticipated states of biologics inspections regulated by CDER?

At the annual GMP by the Sea conference in Cambridge, Md. in August, FDA Office of Pharmaceutical Manufacturing Assessments (OPMA) deputy director Derek Smith provided insight into the inspection landscape of biologics regulated by CDER.

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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 examines the current state and future anticipated states of inspections of biologics regulated by CDER.
  • Part III will focus on the model used to evaluate whether biologics manufacturing site assessments should be conducted remotely or in person.

COVID-19 Changed Approach, Not Standards

During the COVID-19 pandemic, the agency conducted risk‐based assessments of product, process, and facility risks to determine the need for an inspection. However, the inspections were limited and challenging, and not possible in most instances. So, different mechanisms were sought to evaluate the facility when an inspection could not be conducted onsite.

The agency used its existing authority under 704(a)(4) of the FD&C Act to request records from manufacturing facilities to support the application assessment. During the pandemic, it also developed Remote Interactive Evaluations, (RIEs) which are voluntary interactions through video and audio, to enhance the 704 processes.

In addition, Mutual Recognition Agreements (MRAs) with the European Medicines Agency (EMA) and UK’s Medicines and Healthcare products Regulatory Agency (MHRA), as well as other inspectorates, were used to leverage information from those foreign regulatory counterparts to support the application assessment.

On the Biologics License Applications (BLA) side, OPMA continues to perform quality assessments of all applications per normal assessment processes and evaluate manufacturing facilities using a risk-based approach and the use of alternative tools.

Smith stressed that the agency conducted mission-critical and prioritized inspections when possible throughout the pandemic. It notified the applicant if a pre-licensing or pre-approval inspection (PLI/PAI) was required before the application could be approved and that the inspection may not be completed during the review cycle.

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Remote and Paper Inspections

Current Biologics Inspection Landscape

Smith reported that inspection operations have returned to normal, excluding China, due to the ongoing travel restrictions in that country. “We have been able to complete all the delayed inspections outside of India and China. And the India inspections are targeted to be completed by the end of this calendar year.

“We are beginning to leverage the close tie between the review and inspection teams where the OPMA inspectors and OBP assessors are ingrained into the inspection program. And we hope to continue to use the remote regulatory assessment processes, as well as the information that we are gaining from our other regulatory partners to continue to incorporate ways to use those decision-making processes so that we can employ the inspection resources in the most effective way.”

He said, “during the pandemic, we really had to change our thinking. And by leveraging the review teams, risks, and challenges, and concerns with the application we were able to understand how to deploy those resources.”

Remote Assessments Can Be Revealing

The agency continues to leverage the integrated review and inspection approach and use risks identified in the application review to look at where it can weigh inspections and use records requests and remote interaction with facilities to streamline the assessment. The goal is to be more efficient in the assessment but maintain a high-quality standard in terms of the approvability and licensure of BLAs.

“I think one of the things that have been great for us during the pandemic is really employing these alternative tools to the inspection and the impact we felt that it had on the assessments. We struggled to understand how we could remotely evaluate facilities and what that impact could be and how we could learn things and make sure that the facilities were following GMPs and implementing the control strategies in the BLAs.”

…we hope to continue to use the remote regulatory assessment processes…

He cited “several examples” where his office has been able to leverage remote tools to make approvals and make decisions that facilities were not in compliance and were not meeting the standards that were necessary to the core BLA assessment. 

Smith specifically pointed to important insights the agency has been able to gain by looking through media fill and environmental monitoring records. Upon “thorough investigation” of the environmental monitoring records, his team found evidence that gave them confidence in negative decisions by FDA. “And that was just remotely,” he added.

“In other situations, we have seen, even though there were no interactive evaluations, looking at an isolator design, we could tell that the line design was challenging related to placing your hand in the glove and manipulating things within the isolator, and other challenges or issues in the facilities, even remotely. We had one where we found issues with chromatography columns remotely.”

The OPMA deputy director stressed that there is a lot of hesitancy to move away from in-person inspections, especially in the biologics space, because of the licensure requirement in the regulations that have an inspection component. “But we have been able to leverage the tools and find great information.”

Also discovered during the pandemic were situations where dialogue in terms of being proactively open with the agency about ongoing issues and challenges was beneficial.

“We had one situation where a facility was having challenges with a cell line and having trouble continuing to manufacture batches after the regulatory submission passed. And if we had had a dialogue and understanding prior to showing up for the inspection, we would have been able to work things out in a different way.”

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Additional Resources

Desk Inspections, Missed Action Dates Take Place of FDA In-Person Site Visits

FDA Chooses Not to Perform Virtual Inspections in Contrast with Non-U.S. Agencies

Health Canada GMP Inspectors Turning to Video, Teleconferencing

A State-of-the-Art Virtual Inspection Methodology Using Mixed Reality Technology Gets High Marks from EMA Inspector

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