FDA’s Updated Inspectional Approach in the Post-Pandemic Landscape

Arif S. Noorani, Partner and Priyanka Amirneni, Associate- Food, Drug and Medical Device Compliance and Enforcement, Sidley Austin LLP

Introduction

The COVID-19 pandemic posed unprecedented challenges to the U.S. Food and Drug Administration’s (FDA) inspection program. Emergency public health measures, including global travel restrictions and lockdowns, forced FDA to essentially suspend its inspection activities, creating a significant inspections backlog.¹ Both the pharmaceutical industry and Congress voiced concerns over the backlog and the potential ramifications for the American public. In response, FDA piloted new inspection techniques and strengthened its reliance on mutual recognition of inspections by international regulatory bodies.² Based on the relative success of these initiatives during the pandemic, FDA is now adopting them beyond the COVID-19 pandemic as “modernized approaches to protecting public health.”³

FDA’s Inspectional Authority

To protect consumers in the United States, FDA closely regulates pharmaceutical manufacturing, and in order to do so, the agency has broad statutory authority to physically inspect any factory, warehouse, or establishment in which drugs are manufactured, processed, packed, or held for introduction into U.S. commerce.⁴ This authority allows the agency to inspect “all things,” including “records, files, papers, processes, controls and facilities”⁵ bearing on an establishment’s compliance with current Good Manufacturing Practice (cGMP).⁶ The authority to inspect in person extends not only to manufacturers located in the U.S., but to any site around the world that either manufactures drugs to the U.S. market or seeks approval to do so.⁷ Among other things, onsite inspections permit FDA investigators to tour the facilities and laboratories to observe the day-to-day operating environment, conduct comprehensive reviews of manufacturing and quality records such as deviations and changes from the approved process, and directly interview factory employees regarding their cGMP compliance. The FDA investigators who perform the inspections are subject matter experts in a range of relevant areas (e.g., chemistry, microbiology, engineering, aseptic practices), and are specifically trained to identify manufacturing or quality deficiencies that can become serious problems if not corrected. As a result, FDA heavily relies upon its inspections to ensure that U.S. marketed drugs are safe and effective.

Inspections During the Pandemic

Although FDA has seen a general decline in domestic and foreign inspections since 2016 due to staffing vacancies,⁸ the unprecedented obstacles posed by COVID-19 and the related public health measures triggered an extremely sharp drop in inspections.⁹ Limitations on in-person contact due to the COVID-19 virus such as lockdowns and travel bans created substantial obstacles for investigators to continue inspecting facilities in person.¹⁰ In March 2020, FDA announced it would temporarily halt foreign and domestic inspections other than those it deemed “mission critical.”¹¹ Following this announcement, FDA only conducted three foreign inspections for the rest of the fiscal year, compared to hundreds more during the same time period in each of the prior two years.¹² This is especially noteworthy given that approximately 70 percent of facilities which manufacture active pharmaceutical ingredients and more than 50 percent of facilities which manufacture finished drugs for the U.S. market are located outside the U.S.¹³ FDA’s domestic inspections also decreased significantly.¹⁴ And the decline in inspections continued through Fiscal Year 2021, creating a substantial backlog of thousands of inspections,¹⁵ raising concerns from both public and private entities.¹⁶

The inability to inspect “remove[d] a critical source of information about the quality of drugs manufactured for the U.S. market,” which raised warning bells.¹⁷ In particular, members of Congress sent a letter to then-acting FDA Commissioner Janet Woodcock with questions about FDA’s efforts to “mitigate the backlog of […] inspections.”¹⁸ Congress expressed “concern[…] that more than one year into the pandemic, the strategy for resuming all inspections and addressing the backlog of delayed inspections remains unclear.”¹⁹ The letter pressed FDA to resume onsite inspections and make improvements to its current inspectional techniques due to the extended time between inspections to “ensure patient access to safe and effective medicines.”²⁰ Relatedly, FDA has also faced pressure from industry for increased inspections to ensure the continuous supply of necessary drugs in the United States.²¹

FDA’s New Inspectional Approach and Techniques

In order to decrease the backlog of inspections and bolster assessments of foreign manufacturers, beginning in 2021, FDA modified its approach to inspections in three key ways: (1) conducting remote assessments, (2) sharing and relying upon information from international regulatory bodies, and (3) initiating unannounced inspections for foreign manufacturers.²²

First, to continue its inspections during the pandemic, FDA piloted and increasingly relied on remote regulatory assessments (RRAs), which are reviews of records and other information submitted upon request from FDA.²³ The reviews are conducted entirely remotely, and the agency has frequently requested and assessed documents remotely during the COVID-19 pandemic. Records requests are mandatory since FDA is statutorily authorized to review documents remotely in advance or in lieu of onsite inspections.²⁴ Only establishments engaged in the manufacture, preparation, propagation, compounding, processing, or importation of a drug may be subject to mandatory RRAs. FDA also unveiled non-mandatory or voluntary assessments such as remote interactive evaluations using technologies such as live streaming of video operations, teleconferences, and screen sharing.²⁵ FDA plans to use these remote interactive evaluations to “verify corrective actions taken in response to inspections of previously compliant manufacturers and in gaining compliance insight.”²⁶ The agency’s recent draft guidance on RRAs provides helpful context for how it will conduct records reviews and remote interactive evaluations going forward, and notes the types of records that could be requested. These include test results, deviation and non-conformance reports, process validation records, standard operating procedures, and product complaints, among many other examples.

FDA has stated it will use a risk-based approach to determine which establishments to initiate or request RRAs, considering “firm location, inspection history, complexity of product and process, and travel restrictions.”²⁷ FDA has also begun factoring more up-to-date data from its quality metrics program and other sources in its risk-based inspection prioritization system since the pandemic.²⁸ Historically, FDA has relied only on facility scores (which consider factors such as type of establishment, number of products manufactured, and inspection history), product scores (which consider factors such as type of product, dosage form, and sterility), and time since last inspection in determining which sites to inspect.²⁹ Due to decreased resources and opportunities during the pandemic, FDA has sped up modifying its risk-based inspection scheduling model to incorporate risk scores that rely on additional quality metrics and other data, such as more precise facility types, geographical locations with higher compliance rates, recall and inspectional history, and results from inspections conducted by foreign regulators.³⁰

Second, FDA began to increasingly rely on information and reports from international regulatory bodies. FDA is statutorily authorized to rely on information and observations collected by competent foreign regulatory authorities through mutual recognition.³¹ While mutual recognition has existed in the U.S. since 2014 and for longer in the European Union, the agency rarely relied upon mutual recognition prior to the COVID-19 pandemic.³² Mutual recognition provides regulators greater efficiency and allows agencies to synchronize inspection schedules and allocate sufficient resources toward higher-risk inspections, without duplicating efforts. Because of these strategic benefits, FDA will likely continue to take into account inspections conducted by other international regulators, and companies should prepare for all inspections with the same level of readiness. The expansion of mutual recognition is part of FDA’s larger goal to globalize its inspection program, by facilitating greater coordination and oversight of medical products among foreign regulatory bodies.³³ FDA believes that information sharing with competent foreign regulatory bodies will allow it to become “more efficient” and the “industry can implement innovations and quality systems in a more rapid and effective manner.” Going forward, FDA is considering expanding the scope of mutual recognition with the UK and EU to include vaccines and plasma-derived pharmaceuticals.³⁴

Third, FDA has begun conducting unannounced inspections of foreign manufacturers. Prior to the COVID-19 pandemic, facilities based outside of the U.S. were typically provided with advance notice of an upcoming inspection, sometimes as much as three months’ time. FDA initially began performing unannounced foreign inspections during the pandemic following criticism from the industry that notice to international facilities can “harm an FDA inspector’s ability to get transparent information about a company’s standard operating practices.”³⁵ A report from the U.S. Government Accountability Office (“GAO”) noted the issue of establishments quickly fixing potentially serious problems prior to FDA inspections, and recommended that FDA should adopt a pilot plan for unannounced foreign inspections to ensure inspection integrity.³⁶ Arriving unannounced, particularly after the long the delays in time between inspections due to the pandemic, certainly bolsters the credibility of the foreign inspection program. In response, FDA has begun to conduct unannounced inspections in India, with plans to expand to China, where FDA already has field offices and inspection staff.³⁷ FDA stated the unannounced inspection program was launched in India first since foreign inspections in certain parts of China are still paused due to local COVID-19 restrictions.³⁸ Regarding other parts of the world, in January 2022, the Creating Efficiency in Foreign Facility Inspections Act, S. 3509 was introduced in the United States Senate, proposing to expand FDA’s ability to perform unannounced inspections of foreign facilities. While this would strengthen FDA’s mandate, logistical challenges for FDA investigators such as arranging travel and securing visas would remain.

Now that the COVID-19 pandemic has begun to subside in 2022 and public health measures such as travel restrictions are largely lifted, FDA has resumed onsite inspections. However, the agency continues to use the inspectional techniques it piloted during the pandemic and rely on updated quality data metrics to focus its resources on inspections of highest risk to the public health.³⁹ The new approach offers significant advantages which FDA can benefit from beyond the pandemic for all types of FDA-regulated products. FDA has stated that its revised approach will enhance oversight and “improve […] the efficiency of how [they] operate, furthering [their] mission to protect the public health.” The adoption of these inspection techniques also reflects FDA’s “modernization effects” in implementing “advanced tools, including technology.”⁴⁰

Conclusion

In light of FDA’s updated inspectional approach, pharmaceutical manufacturers should also update and revise their standard operating procedures on inspection management. With increased visibility to manufacturers through remote review and information sharing, it is highly likely that an FDA investigator’s first impression of a facility will occur before their arrival. This also means that documents such as manufacturing and data integrity-related investigations and reports, which are typically viewed onsite, are now particularly susceptible to advance review. Regulators may use these documents to prepare for an upcoming inspection or base regulatory decisions solely on them. Manufacturers should, as a result, consider creating or updating policies related to FDA record requests and remote interactive evaluation requests. Companies should prepare in advance for the disclosure of challenging manufacturing deviations discovered over the past few years and be in position to explain the corrective and preventive measures taken to demonstrate sustainable cGMP compliance. Finally, practicing how to handle, manage, and respond to an unannounced inspection helps, and companies should conduct regular “mock audits” and document reviews to stay in a state of inspection readiness, including identifying the best subject matter experts for potential interactions with an investigator.

References

1. FDA, Resiliency Roadmap for FDA Inspectional Oversight (May 2021).
2. Supra Note 1.
3. FDA, FDA Details Optimized Approach for Regulatory Oversight Tools to Better Protect Public Health (July 22, 2022).
4. 21 U.S.C. § 374(a)(1).
5. Id.
6. The Federal Food, Drug, and Cosmetic Act (the “Act”) states that a drug not made in accordance with cGMP is deemed “adulterated.” The Act goes on to say that the cGMP regulations are “to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.” Food, Drug, and Cosmetic Act Section 501(a)(2)(B).
7. 21 U.S.C. § 381.
8. United States Government Accountability Office, DRUG SAFETY: COVID-19 Complicates Already Challenged FDA Foreign Inspection Program (June 2, 2020).
9. The New York Times, Pandemic Forces F.D.A. to Sharply Curtail Drug Company Inspections (March 9, 2021).
10. FDA, Coronavirus (COVID-19) Update: FDA Outlines Inspection and Assessment Activities During Pandemic, Roadmap for Future State of Operations (May 5, 2021).
11. Id.
12. United States Government Accountability Office, FDA’s Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog (March 4, 2021), at page 7.
13. Supra Note 9.
14. Supra Note 2.
15. FDA, Resiliency Roadmap for FDA Inspectional Oversight (May 2021).
16. Supra Note 1.
17. Id.
18. Committee on Energy and Commerce, EC Letter to FDA (July 22, 2021).
19. Id.
20. Id.
21. Supra Note 2.
22. The FDA has also piloted other inspectional initiatives such as sampling and testing regulated products at the U.S. border. The agency used this tool during the pandemic to specifically target high risk drugs manufactured at foreign facilities where inspections had been postponed. United States Government Accountability Office, DRUG SAFETY: FDA’s Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog (March 4, 2021), at page 7.
23. FDA, FDA Provides Guidance on Remote Interactive Evaluations for Oversight of Drug Facilities During COVID-19 (April 14, 2021).
24. FD&C Act Section 704.
25. FDA, Guidance for Industry: Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency (April 2021).
26. Id.
27. Id.
28. FDA, CDER Quality Management Maturity (October 31, 2022).
29. United States Government Accountability Office, Drug Safety: FDA Should Take Additional Steps to Improve Its Foreign Inspection Program (January 7, 2022).
30. Id.
31. Food, Drug and Cosmetic Act Section 909.
32. FDA, Mutual Recognition Agreement (MRA) (November 8, 2021).
33. FDA, FDA Details Optimized Approach for Regulatory Oversight Tools to Better Protect Public Health (July 22, 2022).
34. FDA, Mutual Recognition Agreement (MRA) (November 8, 2021).
35. Bloomberg Law, Quality Concerns to Resurface as FDA Resumes Foreign Inspections (March 17, 2022).
36. United States Government Accountability Office, Drug Safety: FDA Should Take Additional Steps to Improve Its Foreign Inspection Program (January 7, 2022).
37. RAPS Regulatory Focus, Unannounced FDA inspections in India, China to begin soon (December 15, 2021).
38. Alliance for a Stronger FDA, Webinar Transcript (April 6, 2022).
39. FDA, FDA Details Optimized Approach for Regulatory Oversight Tools to Better Protect Public Health (July 22,2022).
40. Id.

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