Pandemic Alters FDA Inspection Process and Policies

New methods and policies necessitated by the global pandemic are slated to become permanent fixtures in FDA enforcement and regulatory programs. Over the last 18 months, FDA officials have tested and adopted a range of procedures to overcome restrictions on visiting facilities in person to evaluate pharmaceutical production and clinical testing operations. Many of these alternative compliance methods now are being retained even with the end of the current health emergency in sight. FDA has devised ways to monitor industry operations and to collaborate more routinely with foreign regulatory authorities to assess facilities and products, efforts important for ensuring continued patient access to needed therapies, vaccines and medical diagnostics.

With some 8000 site inspections of drug manufacturing facilities postponed during the height of the pandemic in 2020, FDA regulatory officials look to retain key operational changes as they work to catch up on their vast oversight obligations. During the hiatus in facility inspections, FDA’s Office of Regional Affairs (ORA) looked to evaluate the inspection status of a facility largely through the review of historical inspection records from the site plus reports conducted by reliable regulatory authorities. Now, even with the return to more normal inspections for domestic manufacturing facilities, ORA will continue to pre-announce domestic inspections “for the foreseeable future,” explained Alonza Cruse, director of the Office of Pharmaceutical Quality Operations in ORA. The aim is to avoid having inspectors turn up at a facility that is not fully operational, has altered hours, or has limited staff available.

While ORA aims to send inspectors to more facilities in the U.S., the agency will continue to limit foreign inspections to those deemed “mission critical,” Cruse noted at the PDA/FDA joint regulatory conference in September 2021. FDA also will utilize the tools expanded during the pandemic to assess product safety and quality more efficiently. This includes more extensive analytical testing and sampling of drugs, particularly at U.S. borders with an eye to denying entry to products with quality problems. In addition, FDA continues to request documents from facilities to review compliance histories off site and to conduct video livestreaming “visits” to plants. The agency updated information on how it was managing and revising its inspection program, initially in a Q&A guidance issued in August 2020 and expanded extensively through the following months through May 2021.¹

A main initiative has involved greater use of Remote Interactive Evaluations (RIEs) of drug manufacturing, compounding and bioresearch monitoring facilities, a process that FDA compliance offices plan to continue, as outlined in guidance issued in April 2021.² Cruse highlighted FDA’s process and policies for how the agency will notify, conduct and conclude RIEs and the impact on regulatory timeframes. And Donald Ashley, director of CDER’s Office of Compliance (OC), reported at the PDA/FDA conference that the agency completed over 50 REIs for BIMO programs and 8 for outsourcing facilities since Oct. 1 2020, as part of its effort to utilize all available oversight tools.

Advancing quality management

Even with reduced onsite inspections, manufacturers may gain regulatory flexibility in expanding or altering production or updating manufacturing methods by gaining FDA recognition for having high quality operations as described in its Quality Management Maturity (QMM) program. FDA has encouraged biopharma companies to establish QMM systems able to measure outcomes that reflect control of problems that lead to complaints, shortages and adverse events, noted Patrizia Cavazzoni, director of the Center for Drug Evaluation & Research (CDER), at the PDA/FDA conference. Now manufacturers stand to benefit from advancing QMM in gaining greater flexibility in scheduling facility inspections and for making post-approval changes in production and product characteristics.

Although industry has challenged earlier CDER efforts to devise measures and “report cards” on manufacturing operations, the pandemic has magnified the need to focus on risk management and to expand efforts by manufacturers to ensure the operation of more mature quality systems, Cavazzoni explained. A critical issue during the public health emergency has been to overcome shortages in medical products due to supply chain constraints and drug quality problems. To facilitate the development and timely production of new COVID-19 therapeutics, CDER expanded the data and analytics employed by its drug shortages program to assess risks of supply disruptions earlier and more effectively.

In the wake of the pandemic, which has heightened the importance of reliable, quality production of medical products, FDA is looking to further support and encourage QMM initiatives at firms able to demonstrate having consistent, reliable and robust business processes to achieve quality objectives, added Ashley Boam, director of CDER’s Office of Policy for Pharmaceutical Quality. FDA is launching two pilot programs to test how QMM may be implemented by domestic drug product manufacturers and by foreign producers of APIs. The pressures created by the pandemic, Boam observed, have supported alternative approaches for plant inspections, streamlined assessment of proposals to add or change manufacturing facilities and suppliers, and increased global collaboration and harmonization in these areas.

Notes

1. https://www.fda.gov/media/141312/download

2. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/remote-interactive-evaluations-drug-manufacturing-and-bioresearch-monitoring-facilities-during-covid

Jill Wechsler is Pharm Exec’s Washington Correspondent. She can be reached at jillwechsler7@gmail.com.