In September 2025, the U.S. Food and Drug Administration (FDA) issued a new guideline titled “Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications”.  

Purpose and Scope  

This article outlines how the FDA intends to leverage innovative approaches—beyond traditional on-site inspections—to evaluate the readiness and compliance of facilities named in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs).   

This guideline applies to both foreign and domestic facilities. This guideline does not apply to other drug inspection programs, including:  

• Post approval inspections. 

• Surveillance inspections without preapproval or pre-license components.  

• Follow-up and compliance inspections (e.g., for-cause inspections such as Warning Letter follow-up inspections). 

• Bioresearch monitoring inspections. 

Why  

The FDA traditionally relies on onsite preapproval inspections (PAIs) and prelicense inspections (PLIs) to ensure manufacturing facilities can produce safe, effective, and high-quality drugs and biologics. The COVID-19 Pandemic underscored the need for flexible alternatives when travel and site access were limited.

The industry experienced a two- to three-year gap in FDA Inspections due to travel restrictions imposed by the FDA during the Pandemic.   

Several alternative tools were used during the COVID-19 Pandemic, including:  

• Requesting records and other information directly from facilities and other entities subject to inspection. 

• Performing remote interactive evaluations (RIEs) (e.g., remote livestreaming video of operations, teleconferences, screen sharing). 

• Requesting existing inspection reports and other information from trusted foreign regulatory partners through mutual recognition agreements and other agreements.  

The new FDA guideline builds upon lessons learned during that period and formalizes how the FDA can use alternative tools within everyday operations. 

I personally question the effectiveness of using these tools during the COVID-19 Pandemic. We saw numerous significant FDA 483s and Warning Letters issued to firms as FDA onsite inspections resumed in 2022 and 2023. 

FDA conducts a PAI (or a PLI) to ensure that any facility named or referenced in an application can do the following: 

• Perform the proposed manufacturing operations in conformance with applicable current good manufacturing practice (CGMP) requirements. 

• Confirm that the data submitted in the application is accurate and complete. 

• Verify conformance to the application. 

• Assess the facility’s ability to develop and manufacture drugs of consistent quality. 

In addition, the changes made to the PAI Compliance Program (Program 7346.832) required the FDA Investigator conducting the PAI to assess the firm’s commitment to quality in pharmaceutical development. 

Risk-Based Approach 

The FDA will apply the alternative tools selectively, based on risk. Key factors influencing the decision include: 

• The facility’s prior inspection history, including evaluations by trusted foreign regulators. 

• The complexity of the product or process, such as new technologies or dosage forms. 

• Urgent public health needs, including drug shortages. 

• Situations where inspections are not feasible due to travel or safety limitations. 

I believe the FDA will also consider the intended use and patient population in addition to the risk factors outlined above. 

Alternative Tools FDA Will Utilize 

Remote Regulatory Assessments (RRAs) 

FDA may request facility records under section 704(a)(4) of the FD&C Act or conduct remote interactive evaluations (RIEs) using livestream video, teleconferences, and screen sharing. While responding to records requests is mandatory, participation in an RIE remains voluntary. Still, declining an RIE could delay application decisions. 

Collaboration With Trusted Foreign Regulators 

Through mutual recognition agreements, the FDA can access inspection reports and compliance information from regulatory partners, including the EU, Switzerland, and the UK. In some cases, the FDA may also participate remotely in inspections led by foreign regulators, thereby reducing redundancy and facilitating faster access to global markets. 

Remote Subject Matter Experts (SMEs) 

FDA may supplement on-site inspections with remote SMEs who connect virtually to provide technical expertise. This approach enables the FDA to draw on specialized knowledge without requiring additional travel, streamlining the inspection process while maintaining rigorous oversight. 

I see the first two of these three options in use at the FDA today and believe we will see an increased use of the first two alternative tools referenced above. 

Effects of Using Alternative Tools 

By employing these tools, the FDA aims to: 

• Meet Prescription Drug User Fee Act (PDUFA) and Biosimilar User Fee Act (BsUFA) performance goals. 

• Maintain timely review and approval of new therapies. 

• Ensure patient access to critical medicines without compromising safety or quality standards. 

Facilities should be prepared for either traditional inspections or alternative assessments at the time of application submission. The FDA emphasizes that it—not the applicant—will decide whether alternative tools are appropriate. 

I would add one additional thought… 

In today’s inspections, whether traditional or alternative, the quality of the firm’s written documentation must be exceptionally high. The need for verbal discussion, explanation, storyboards, and other techniques used to “augment” a less-than-high-quality Nonconformance/Deviation or CAPA must be minimized as much as possible. 

The opportunity to verbally explain and discuss the content of the documentation is limited for both types of inspections.   

For those companies with IT tools in place for document management and other key Quality Management Systems, such as Nonconformance/Deviation, CAPA, Change Control, FDA frequently reviews documentation online during the inspection and/or requests electronic documents and datasheets/data files to be loaded into Dropbox or on a memory stick to review back at their office.  In some instances, I have seen over 75% of an on-site FDA inspection conducted in a “hybrid manner,” where the FDA comes onsite to request and gather documents, while all documentation review occurs back at the FDA offices. 

We still see inadequate investigations and CAPAs in the top 3 FDA 483 Observations each year.  This suggests that the depth and breadth of investigations, along with the written investigation reports, corrective actions, and effectiveness checks, require improvement across the industry. 

Looking Ahead 

This guidance reflects the FDA’s broader move toward flexible, technology-enabled oversight. While inspections remain central to ensuring compliance with current good manufacturing practice (CGMP), alternative tools offer options for maintaining regulatory rigor in a rapidly evolving global landscape, where budget and resource constraints within the FDA persist. 

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