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Trends in FDA FY2022 Inspection-Based Warning Letters

This article originally appeared as a guest column in Outsourced Pharma.

The COVID-19 pandemic continued to impact FDA’s inspection activities in FY2022 despite efforts to shift more of the agency’s focus beyond the public health emergency. This article will analyze FDA warning letters issued in FY2022 (Oct. 1, 2021, to Sept. 30, 2022). Specifically, this article will review certain inspection-based warning letters issued to drug manufacturers and offer reflections on current trends and predictions for the upcoming year.

FDA inspection activities began to normalize in 2022, despite years of COVID-19 related disruptions. FDA initially paused all inspections in March 2020 due to the COVID-19 public health emergency, but soon thereafter resumed limited domestic inspections in July 2020 based on priority. The agency then resumed prioritized foreign inspections in October 2020. COVID-19 variants continued to delay the regular course of inspection activities throughout 2021 and into 2022, including a short return to only mission critical inspections from Dec. 29, 2021, to Feb. 7, 2022. Although most of FY2022 saw a return to regular domestic inspection operations, FDA did not resume all foreign inspections until April 2022.

Based on our review, we observed some continued trends from the COVID-19 era, as well as signs that the agency may be expanding its focus beyond the pandemic, shifting its operations back to a more regular course. FDA notably took an interest in repeat violations observed during inspections, OTC drug products including hand sanitizers, responsibilities for contract manufacturers, and testing of incoming components and raw materials. This article discusses each of these themes before examining what this may mean for FDA’s drug GMP enforcement focus in 2023 and beyond.

In FY2022, FDA issued 165 drug product warning letters. Of the 165, 74 were based on observations from an on-site inspection, 16 letters stemmed from tested samples, and three from a records request under section 704(a)(4) of the Federal Food, Drug and Cosmetic Act (FD&C Act) (referred to as 704(a)(4) requests in this article).1 The remainder of the warning letters were generally the result of review of product labels, registration materials, and/or websites.2

Of the 74 letters following on-site inspections, seven followed bioresearch monitoring (BIMO) inspections,3 eight focused on human cell, tissue, or cellular products (HCTP),4 two followed good laboratory practice (GLP) inspections,5 nine were issued to pharmaceutical compounding firms,6 and one was issued to a PET drug manufacturer.7 This article excludes warning letters following GLP inspections, those issued to pharmaceutical compounding firms, and the warning letter issued to the PET drug manufacturer in an effort to focus our analysis on the most relevant 62 warning letters prompted by violations observed during an on-site inspection.

BIMO Inspections

BIMO inspections are designed to evaluate the conduct of FDA-regulated research to ensure the quality and integrity of data submitted to the agency in support of marketing applications and to protect the rights, safety, and welfare of human subjects. In FY2022, the FDA primarily observed failures associated with study execution and inappropriate enrollment of human subjects. The majority of the letters were issued to firms within the U.S. (five). One warning letter was also issued to a firm in Ukraine and one was issued to a firm in Canada. Three of the seven warning letters cited failure to conduct investigations according to an investigational plan pursuant to 21 CFR 312.60.8 Specifically, the FDA voiced concern about investigational plan deviations to enroll subjects who did not meet eligibility criteria, which jeopardizes subjects’ safety and welfare and raises concerns about the validity and integrity of the data collected.9 FDA also found lack of adherence to safety-related testing requirements by Joseph A. Zadra for failing to complete tests at specific timepoints. Smitha C. Reddy also failed to follow protocols for randomizing specific groups and appropriately blinding studies to prevent bias among staff.

Two letters cited failure to submit an Investigational New Drug (IND) application for clinical investigations with an investigational new drug, per 21 CFR 312.2(a).10 Two of the seven letters found improper usage of an institutional review board (IRB), as set forth in 21 CFR 56, for review and approval of the proposed clinical study protocol.11 Additionally, two letters included observations for failure to obtain informed consent from participants in accordance with 21 CFR 5012 and failure to retain documentation for two years pursuant to 21 CFR 312.13

Human Cell and Tissue Products (HCTPs)

The FDA issued eight warning letters to U.S. firms manufacturing HCTPs in FY2022. Of the eight, four observed insufficient evaluation or testing for communicable disease in samples.14 The FDA’s website includes information about tests that are currently recommended to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents and diseases, including a complete list of donor screening assays and specific requirements for donor testing. This is a top consideration in the agency’s approach to HCTP safety and availability for all patients but especially for fertility-focused products for which donor history is relevant to preventing sexually transmitted disease.

The remaining four letters cite 21 CFR 1271.3(f)(1), the requirement for minimal manipulation of HCTPs, and warn companies with products that have been processed to the point where the original characteristics have been altered.15 The statute defines minimal manipulation of HCTP products to mean (1) processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement, and (2) for cells or non-structural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.16 If a product is more than minimally manipulated, it does not qualify as an HCTP, and is instead subject to premarket review and approval as a drug or biologic under a biologics license application (BLA).17

The agency also cited five of the eight HCTP manufacturers for failure to establish written procedures designed to prevent microbiological contamination. All concern the failure to validate processes for products purporting to be sterile. The failure to establish and follow written procedures has been a theme across all inspection-based warning letters; the agency typically views these types of issues as “low-hanging fruit” indicative of an immature quality system. Interestingly, these warning letters do not include a recommendation to engage a third-party consultant to assist with GMP compliance as is included in most inspection-based drug warning letters analyzed below.

Drug Products

The remaining 47 inspection-based warning letters issued to drug manufacturers are less geographically diverse than in years past, with three firms located in India, two in China, and one each in Germany and Spain. The remaining 40 warning letter recipients are in the U.S. (including one from Puerto Rico). This is not surprising, given the limited ability of FDA to conduct foreign inspections for a significant portion of FY2022.

A majority of the letters went to OTC manufacturers (32 in total), which includes the sole homeopathic product manufacturer, as well as one company that manufactures OTC drugs and medical devices.18 The remaining warning letters went to six finished prescription drug manufacturers and nine API manufacturers.19 FDA also noted that three recipients were contract testing laboratories (one contract testing lab tested OTC products, one tested API, and one tested finished pharmaceuticals).20

Notably, 16 warning letters were for hand sanitizer products, and another five were for topical skin lightening products.21 As we discuss later in the article, the focus on hand sanitizers is directly related to the COVID-19 pandemic and FDA’s regulatory efforts to expand the available supply of hand sanitizer while ensuring the safety of the product.

Other general trends identified across analyzed warning letters are also worth highlighting. For example, a large majority of warning letters (42) included a recommendation for the retention of an expert consultant to assist firms in their remediation efforts, a trend that has become increasingly standard in recent years.

Moreover, although inspections in 2021 and 2022 were far less numerous than in non-pandemic years, investigators were prompt in issuing letters. All but one of the 47 warning letters were issued within 12 months of the last day of an inspection.22 Of these, the shortest turnaround time was just shy of four months, with the inspection concluding on Nov. 19, 2021, and receipt of the warning letter occurring on March 14, 2022.23 This timeframe is impressive given the agency’s pandemic workload.

Finally, although much has changed since 2019 and early 2020, FDA hasn’t forgotten about violations that predate the pandemic, with 19 of the 47 warning letters specifically calling out repeat observations.

Key Emerging Themes

Component Testing

Concerns surrounding component product quality was a particular theme in FY2022 warning letters. Overall, 13 warning letters included component testing observations: nine hand sanitizer product warning letters included this language, as well as one skin lightening product and three non-hand sanitizer OTC products. The agency observed companies relying on certificates of analysis (COAs) for identification of product components and raw materials (without first establishing the reliability of those COAs), rather than performing the appropriate testing to ensure the product met required acceptance criteria for use in manufacturing. The agency noted that those firms relying on COAs had no assurance that the product conforms with appropriate specifications for identity, strength, quality, and purity.

For example, the Premier Trends LLC letter articulated the need to test incoming API and components of a product. In it, FDA explained:

“Though you receive raw materials with a certificate of analysis from your suppliers, you have not performed appropriate incoming analysis of component lots upon receipt, including confirming the identity prior to use in production of your finished drug product. You also relied on your supplier’s certificate of analysis without establishing the reliability of your component supplier’s test analyses at appropriate intervals.”24

Not surprisingly, this observation was frequently included in warning letters for hand sanitizer products, specifically due to the presence of methanol and other harmful impurities found in products tested at the border. For example, language was included in the letter to Yusef Manufacturing Laboratories for failing to test API used for its hand sanitizer product:

“You failed to adequately test your incoming components for identity before using the components to manufacture your over-the-counter (OTC) drug products. Additionally, you relied on [COAs] from unqualified suppliers for specifications such as purity, strength, and quality. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.”25

Contract Manufacturing Responsibility and Accountability

Another theme observed in FY2022 warning letters was the close attention paid to contract manufacturers and contract testing laboratories, a possible product of the agency’s more recent whole supply chain focus. Overall, letters issued in FY2022 drive home the twin requirements that: (1) contract manufacturers are subject to cGMPs and quality requirements just like other manufacturers; and (2) the product sponsor is responsible for the finished product and has a duty to oversee its contractors and suppliers. The agency included contract manufacturing or testing language in 18 warning letters.

Notably, 11 of those 18 warning letters included a separate section for this information at the bottom of the letter. The title for this section varied, but the placement of this language at the end of a warning letter, similar to recommendations to engage a third-party cGMP expert or calling out specific concerns surrounding data integrity, shows the agency’s desire to clearly communicate the significance of this message, including the need for effective quality agreements.

For example, Sanitizer Supply produced hand sanitizers as a contract manufacturer. FDA found that Sanitizer Supply failed to test incoming components and also failed to validate and establish the reliability of their component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)). In this case, even though Sanitizer Supply is a contract manufacturer, FDA points out that they are still required to manufacture drugs in conformance with cGMP, regardless of any agreements with product owners. FDA included the following paragraph emphasizing this point at the end of its letter to Sanitizer Supply.

“Responsibilities as a Contractor

Drugs must be manufactured in conformance with cGMP. The FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. The FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with application sponsors and product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See the FDA’s guidance document Contract Manufacturing Arrangements for Drugs: QualityAgreements at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.”26

This reminder also appears in the letters sent to Sanitor Corporation, NDAL Mfg Inc., Vitae Enim Vitae Scientific Inc., and Sterling Pharmaceutical Services, among others. In the case of Sterling, the firm, acting as a contract manufacturer, received findings related to sterility failures. Specific incident investigations into contamination risks, which included microorganisms recovered from ISO 5 areas, routinely identified poor aseptic behaviors among manufacturing personnel, despite the company’s findings that there was a “very low” contamination risk posed to drug products.

Warning letters to other firms contained language emphasizing the firm’s responsibility for oversight of its contractors, such as the letter to Specialty Process Labs LLC stating:

“Your firm’s quality unit (QU) failed to perform routine QU functions to ensure drug manufacturing operations were adequate. For example, your QU failed to:

  • Establish and maintain adequate evaluation procedures for third-party laboratories that are utilized for finished drug testing, such as fat analysis, inorganic iodides and residual solvents. Your quality unit has not qualified or evaluated any of the contract laboratories used for these tests.”27

Failure to Cooperate With the FDA for Inspection

Interestingly, two warning letters were issued to companies that failed to cooperate with FDA for the purpose of facility inspection. Mexican firm Glicerinas Industriales, S.A de C.V., refused entry to FDA (via phone) for a planned inspection at their manufacturing site scheduled to occur in May 2022 and, as a result, received a warning letter that drugs manufactured at the facility were adulterated.28 A domestic contract testing lab, Green Wave Analytical LLC, also failed to cooperate with FDA. Green Wave delayed FDA’s on-site inspection for three days by falsely representing that the firm did not perform cGMP testing of finished drug products under contract. FDA’s warning letter to Green Wave states that because of the partial refusal, its products are adulterated.29

In addition, Global Sanitizers was subject to an on-site inspection after it twice refused to respond to a 704(a)(4) records request. FDA noted the refusals in the warning letter, reminding the firm that failure to respond to a 704(a)(4) request is a prohibited act under the FD&C Act, and then cited the company for several significant cMPG violations based on the on-site inspection.30

FDA expends significant resources to complete inspections in a timely manner and utilizes a risk-based site selection model to prioritize on-site inspections, thus it is not surprising that firms that were unwilling to cooperate with the agency received warning letters.31

Heightened FDA Scrutiny on Two Key Product Types

Hand Sanitizer Products

Hand sanitizer products continued to be an area of heightened interest in FY2022, again demonstrating the agency’s continued focus on safeguarding the public against COVID-19-related products. As threats of the public health emergency continued and many returned to daily in-person activities, the public relied on masking and hand sanitization as a way to limit transmission of the disease. Hand sanitizer products flooded the market beginning in 2020 and continuing into 2022.

An extensive review of FDA’s approach to the regulation of hand sanitizers during the pandemic as a whole is beyond the scope of this article. Suffice it to say that after issuing a guidance providing flexibility for manufacturing hand sanitizer to meet growing public demand, FDA began to notice a significant uptick in safety concerns with such products, including contamination with methanol, a toxic and potentially lethal substance that resulted in several poisonings and deaths.32 While many hand sanitizer warning letters were issued following detention and testing at the U.S. border, 16 warning letters were issued to hand sanitizer manufacturers after an on-site inspection.

Artnaturals33 stands out as an example of FDA’s diligence in ensuring violative products are removed from the market. Artnaturals offered a variety of hand sanitizing products that included a scent-free hand sanitizer product found to be contaminated with benzene, acetaldehyde, and acetal impurities. In this case, FDA repeatedly attempted to reach the manufacturer regarding violative sample results. After the company failed to respond, FDA issued a public notification. The company subsequently voluntarily recalled the product in October 2021. They were inspected in the months following the recall. In light of the concerns regarding contamination and impurities, numerous other manufacturers of hand sanitizers were issued warning letters with citations for failure to adequately test components or finished drug product to ensure they met standards for identity, strength, and purity.34

Global Sanitizers was similarly unresponsive to two attempts to request records under 704(a)(4) and other information from the company before their Las Vegas, NV, facility was inspected in February 2021. Global Sanitizer served as a repackager and relabeler of bulk consumer hand sanitizing products. FDA tested product samples from the facility and found two products contained methanol. Medically Minded Hand Sanitizer Gel Antimicrobial Formula contained an average of 58% methanol, and Medically Minded Hand Sanitizer Gel Antimicrobial with Vitamin E & Moisturizer contained an average of 32% ethanol and an average of 7.4% methanol. Both products were labeled to contain 70% of the active ingredient ethanol. As noted above, methanol is toxic and can cause dermatitis and transdermal absorption with systemic toxicity when absorbed by the skin and can be more injurious if consumed orally.

American Cleaning Solutions is another blatant example of cGMP failures by a domestic hand sanitizer manufacturer. This company manufactures insecticides and industrial cleaners in addition to hand sanitizing products and failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)). FDA noted in the warning letter that “[i]t is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture pesticides or other non-pharmaceutical products due to the risk of cross-contamination.”35 FDA also found that the active ingredient isopropanol was substituted wholly or in part with ethanol and cited the company for inadequate release testing, among other violations.

In addition to GMP failures, unapproved drug claims were another common observation made among violative hand sanitizer products. For example, the Spartan Chemical Company’s hand sanitizer product claims to be “effective in shortening the duration of infection and preventing infection or disease from the novel coronavirus that causes COVID-19.”36 The agency found this language concerning because it goes beyond merely describing the general intended use of a topical antiseptic.

In short, FDA acted quickly and decisively when it came to hand sanitizer products in FY2022, particularly those containing acetaldehyde, which appears to be genotoxic (and potentially carcinogenic), methanol, and other impurities that may pose risk to consumers and those that made unapproved drug claims.

Skin Lightening Products

Another interesting trend in FY2022 was FDA’s focus on products in the beauty industry. Specifically, topical OTC products like sunscreens and skin lightening products were significantly represented, with five warning letters issued to companies manufacturing skin lightening products.37 This may signal that the agency intends to shift toward products that may have flown under the radar during the pandemic, especially OTC drugs popularized by advertising and promotion. These products caused serious and permanent skin damaged and often made unapproved drug claims.

Notably, a warning letter sent to Generitech Corporation encompasses many of the key themes of FY2022. FDA found that the firm’s “quality system for investigations is inadequate and does not ensure consistent production of safe and effective products.”38 It also found that it failed to conduct adequate testing for components and API used for the production of the skin lightening products, including the salicylic acid API used in the product. Instead, the firm relied on COAs from suppliers. Without adequate testing, there is no assurance that a final product conforms to appropriate specifications. Additionally, and significantly, this was a repeat observation from an untitled letter sent in January 2014.

Predictions for 2023 and Beyond

As our analysis demonstrates, in FY2022 COVID-19 remained an issue for FDA, although the agency has shown signs that it is shifting toward regular business — for example, circling back on repeat offenses, holding firms accountable up and down drug supply chains, and enforcing against non-COVID-19 related products, such as skin bleaching agents.

We expect COVID to continue to have effects on enforcement and inspections in 2023, but we also predict that the agency will operate under more typical conditions in 2023. This almost certainly means more oversight of foreign entities now that COVID-era restrictions have been lifted and more foreign inspections are taking place. Given the pandemic inspection pauses of the past few years, it’s possible we may see an uptick in inspection-based warning letters in the years to come.

That said, certain policy changes and shifts in enforcement priorities made during the pandemic are likely here to stay. For example, we expect FDA to continue to focus on OTC products and to pay close attention to enforcement activities across different types of manufacturers, including contract testing labs and CMOs, as part of its broader efforts to enhance entire supply chain resiliency and to prevent drug shortages. And perhaps most notably, we anticipate FDA will seek to understand lessons learned from the pandemic and how to apply those lessons moving forward, including how to best leverage alternatives to on-site inspections, such as 704(a)(4) records requests, voluntary remote regulatory assessments, mutual reliance on inspectional findings from foreign authorities, product sampling and testing, and other tools. The agency will also need to implement the inspection-related provisions of the Food and Drug Omnibus Reform Act (FDORA), attached to the FY2023 omnibus appropriations bill that was enacted in December 2022. Many of the FDORA provisions relate to FDA’s use of alternative tools.

Although we have centered this article on inspection-based drug warning letters, it is worth noting that several warning letters falling outside that narrow scope shed light on the potential areas of focus for FY2023. For example, in FY2022 FDA issued the first warning letter for a delta-8 THC product, in the midst of the exploding market for cannabis- and hemp-derived products.39 FDA will also almost certainly continue to monitor websites, online labeling, and marketing materials, as we saw this year, and issue warning letters citing unapproved drug charges (for both COVID- and non-COVID-related products). In FY2022 FDA sent warning letters to three companies marketing skin tag and mole removing products that are unapproved new drugs. Notably, one of the three was issued to online retailer giant Amazon, which could signal further attempts to regulate similar large third-party sellers.40

Finally, although not a warning letter, a recently issued untitled letter again points to the agency’s focus on whole supply chain accountability and resiliency. The letter, issued to Valisure, LLC on Dec. 5, 2022, cited the analytical laboratory for problems with its contract testing services, which are aimed at fulfilling drug manufacturers’ cGMP requirements, as well as for violations under the Drug Supply Chain Security Act41 (DSCSA). Although it came after our FY22 timeframe, the letter is worth mentioning because, in this case, the agency held the firm responsible for potentially causing downstream cGMP violations due to their inadequate testing methods. Moreover, the letter notably calls out the firm’s DSCSA violations, an area that has yet to see much enforcement focus to-date. With DSCSA requirements coming into full effect in November 2023, greater emphasis on similar violations moving forward is another reason manufacturers should be aware of their responsibilities to the drug supply chain as a whole.

References/Notes

  1. Cosmo Bio Co., Ltd., Dr Retter Ec Wladyslaw Retter, and Guangzhou Orchard Aromatherapy & Skin Care Co., Ltd. (all OTC manufacturers) received warning letters based on a 704(a)(4) records request.
  2. One company, Glicerinas Industriales, S.A. de C.V., received a warning letter on June 13, 2022, for refusing to allow FDA entry to conduct an on-site inspection.
  3. Warning letters issued following BIMO inspections include Daniel C. Tarquinio, Daniel Fred Goodman, Joseph A. Zadra, Richard J. Obiso, Sabine S. Hazan, Smitha C. Reddy, Vasyl Melnyk.
  4. BioLab Sciences, Inc.; Surgenex LLC; Cooper Institute; Smart Surgical, Inc. dba Burst Biologics; OsteoLife Biomedical I LLC; Re-Gen Active Lab, Inc.; Zhang Medical P.C. dba New Hope Fertility Center; and Vitti Labs, LLC.
  5. This includes GLP Warning Letters issued to Toxikon Corporation/LabCorp Bedford LLC on Feb. 10, 2022, and Valley Biosystems on Aug. 3, 2022.
  6. Texas Longhorn RX, LLC; Hybrid Pharma, LLC; New Vitalis, LLC dba New Vitalis Pharmacy; Age Management Institute Santa Barbara; Med Shop Total Care, Inc.; Advanced Nutriceuticals, LLC dba The Guyer Institute of Molecular Medicine; Empower Clinic Services, LLC dba Empower Pharmacy; Sagent Pharmaceuticals, Inc.; and Innoveix Pharmaceuticals Inc.
  7. Brigham and Women’s Hospital, Inc.
  8. Daniel C. Tarquinio, D.O./Center for Rare Neurological Diseases, Joseph A. Zadra, M.D., and Smitha C. Reddy, M.D./ACRC Studies, LLC.
  9. Daniel C. Tarquino, D.O./Center for Rare Neurological Diseases, April 5, 2022.
  10. Richard J. Obiso, PhD dba Avila Herbals, LLC and Daniel Fred Goodman, M.D./Goodman Eye Center.
  11. Richard J. Obiso, PhD dba Avila Herbals, LLC and Sabine S. Hazan, M.D. See also 21 CFR 312.66.
  12. Daniel Fred Goodman, M.D./Goodman Eye Center.
  13. Vasyl Melnyk, M.D.
  14. Cooper Institute, OsteoLife Biomedical, LLC, Smart Surgical, Inc dba Burst Biologics, and Zhang Medical P.C. dba New Hope Fertility Center.
  15. BioLab Sciences, Inc., Re-Gen Active Lab, Inc., Surgenex LLC and Vitti Labs, LLC.
  16. 21 CFR 1271.3(f).
  17. 21 CFR 1271.10; 21 CFR 1271.3.
  18. OTC homeopathic drug manufacturer Sterling Pharmaceutical Services, LLC and Dental Technologies Inc., an OTC drug and device manufacturer, are included in this category.
  19. This includes Fagron Group B.V., which operates as a repackager and relabeler of API product.
  20. Miami Univ (contract testing API); Green Wave (contract testing finished Rx); Accu-Biochem (contract testing OTC); Sterling (contract manufacturer).
  21. Sanitor Corporation manufactures both hand sanitizer and skin lightening products and thus is included in the count for both categories.
  22. Custom Research Labs Inc., an OTC manufacturer of hand sanitizer products, received a warning letter on July 8, 2022, approximately 13 months following the end of an inspection on June 4, 2021.
  23. Ultra Seal Corporation’s facilities in New Paltz, NY, were inspected between Aug. 16, 2021, and Nov. 19, 2021, and a warning letter was issued on March 14, 2022.
  24. FDA Warning Letter to Premier Trends LLC, Mar. 14, 2022.
  25. FDA Warning Letter to Yusef Manufacturing Laboratories, Feb. 8, 2022
  26. FDA Warning Letter to Sanitizer Supply LLC, Sept. 2, 2022.
  27. FDA Warning Letter to Specialty Process Labs, LLC, May 3, 2022.
  28. FDA Warning Letter to Glicerinas Industriales, S.A. de C.V., Jun. 13, 2022.
  29. FDA Warning Letter to Green Wave Analytical LLC, Aug. 19, 2022.
  30. FDA Warning Letter to Global Sanitizers LLC, Nov. 8, 2021.
  31. The agency recently updated is guidance on Circumstances that Constitute Delaying, Denying, Limiting or Refusing a Drug or Device Inspection. The new draft was issued in December 2022 to include device firms as well as drug facilities. See, https://www.fda.gov/media/163927/download.
  32. See e.g., https://www.fda.gov/drugs/coronavirus-covid-19-drugs/hand-sanitizers-covid-19 and https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use
  33. Virgin Scent Inc. dba Artnaturals.
  34. See e.g., Yusef; Agropharma Laboratories, Inc.; American Cleaning Solutions; Custom Research Labs Inc.; Fresh Farms LLC; Froggy’s Fog LLC; Sanitizer Supply LLC; and Global Sanitizers LLC.
  35. FDA Warning Letter to American Cleaning Solutions, Sep. 6, 2022.
  36. FDA Warning Letter to Spartan Chemical Company, Inc., Dec. 15, 2021.
  37. The five firms include Monarch PCM, LLC, Sanitor Corporation (which manufacturers both hand sanitizing products and skin lightening products), Generitech Corporation, Clinical Resolution Laboratory Inc., and Bi-Coastal Pharma international. 
  38. FDA Warning Letter to Generitech Corporation, Mar. 1, 2022.
  39. FDA Issues Warning Letters to Companies Illegally Selling CBD and Delta-8 THC Products, May 4, 2022, https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letters-companies-illegally-selling-cbd-and-delta-8-thc-products
  40. FDA Warning Letter to Amazon.com, Inc., Aug. 4, 2022.
  41. The DSCSA establishes a system for the electronic, interoperable tracking and tracing of certain prescription drugs at the package-level in the U.S. FDA has been implementing DSCSA requirements in a phased manner since the law’s enactment in November 2013. These requirements apply to all trading partners involved in the exchange of prescription drugs along supply chains, including manufacturers, repackagers, distributors, and dispensers.

The 8 Key Takeaways for FDA Inspections in the Food And Drug Omnibus Reform Act

This article was originally published as a guest column in Outsourced Pharma.

With President Biden’s signature, the Food and Drug Omnibus Reform Act of 2022 (FDORA), part of the larger Consolidated Appropriations Act of 2023 (Public Law 117-328), became law on Dec. 29, 2022. FDORA expands and modifies the inspection authority of the FDA in several key areas, including alternative tools to inspection, mutual recognition agreements, bioresearch monitoring, and unannounced foreign inspections.

1. Expanding the Availability of Alternative Tools to Inspection

FDORA expands FDA’s authority to make mandatory requests to industry for “records and other information” in advance, or in lieu, of an inspection. Section 704(a)(4) of the Food Drug and Cosmetic Act (FDCA) had previously limited use of this authority to drug establishments.1 Section 3611 of FDORA expands this authority to include device establishments and Section 3612 expands this authority further to bioresearch monitoring (BIMO) sites and facilities.

In guidance issued during the pandemic, FDA began to refer to section 704(a)(4) requests directed to drug establishments as a mandatory “remote regulatory assessment” (or RRA).2 Similar requests directed to non-drug establishments were categorized as voluntary RRAs, given the lack of a statutory basis to make a mandatory request. Despite this absence of specific statutory authority, CDER has made very robust use of voluntary RRAs seeking records and other information as part of its BIMO program.3 That practice should not only continue but increase, as responding to these requests will no longer be voluntary on the part of regulated industry.

Balanced against these expansions of agency authority under Section 704(a)(4), Section 3611 includes a new requirement that, whenever making a Section 704(a)(4) request, FDA must include a “rationale for requesting” the records and other information sought. In addition, by December 2023, the agency is required to issue guidance on the use of Section 704(a)(4) requests, including electronic processes for responding to such requests and the factors the FDA will use to determine whether requested records are provided within a reasonable timeframe and within reasonable limits, considering resource and other limitations, including for small businesses.

Arguably, FDORA’s most significant inspection related change is that Section 3613(b) now permits the FDA to rely on records and other information collected pursuant to Section 704(a)(4) “to satisfy requirements that may pertain to a preapproval or risk-based surveillance inspection, or to resolve deficiencies identified during such inspections, if applicable and appropriate.” This new authority is welcome news to those in industry advocating that FDA increase the use of inspection alternatives. How the agency utilizes this new permissive authority remains to be seen.

We predict this new provision will prove most useful in the area of risk-based surveillance, as Section 3613(b) removes the barrier that previously prevented FDA from relying on records and other information collected pursuant to Section 704(a)(4) to satisfy surveillance inspection requirements. The agency is required to inspect (“shall inspect”) drug establishments in accordance with a risk-based surveillance schedule pursuant to FDCA Section 510(h)(3). The agency has also interpreted the definition of inspection under FDCA Section 704(a)(1) to require a physical entry into the inspected establishment. Consequently, the agency’s view was that it could not satisfy surveillance inspection requirements in any manner short of a physical inspection. Given the nature of risk-based surveillance inspections and the backlog of such inspections resulting from the pandemic, we predict the agency will make great use of this new authority in the surveillance arena. 

While Section 3613(b) also applies to pre-approval inspections and warning letter follow-up inspections, there was never a legal requirement to rely on an inspection in either of those two contexts. In fact, the agency frequently determines it is not necessary to conduct a pre-approval inspection when considering a drug application and has also used “remote interactive evaluations” in lieu of pre-approval inspections during the pandemic.4 Regarding warning letter follow-up inspections, FDA has never taken the position that verification of post-warning letter corrections requires an inspection in all cases.5 The big question is whether the agency will amend its practice of steadfast reliance on re-inspections of drug establishments that have received warning letters. There may be some slight movement here, but the Section 3613(b) change is permissive only and FDA is very likely to maintain its strong preference for post-warning letter inspections based on historical post-warning letter inspection results. Historically, more than 50% of drug facilities have failed their post-warning letter re-inspections, despite having provided records and other information to the agency in advance of the inspection purporting to show that the firm had adequately remedied past violations at the facility and was ready to be re-inspected. 

2. Clarifying the Statutory Basis for Bioresearch Monitoring Inspections

In addition to extending Section 704(a)(4) to BIMO sites and facilities, FDORA Section 3612 establishes a specific statutory basis clarifying FDA’s authority to conduct BIMO inspections.6 Section 3612 provides a comprehensive framework describing the sites and facilities subject to BIMO inspections, the permitted purposes of such inspections, as well as the records and other information subject to inspection, including electronic information systems holding such information. In case you were wondering, this new statutory language also notes that it should not be inferred that FDA previously lacked the authority to conduct BIMO inspections. FDA is required to issue draft guidance describing the processes and practices applicable to BIMO sites and facilities by June 2024.

3. Recognition of Foreign Government Inspections

FDORA Section 3613(c) promotes further FDA use of mutual recognition agreements with foreign counterparts in two ways. It amends FDCA Section 809 to expressly permit FDA to include pre-approval inspections within the scope of foreign mutual recognition agreements. Section 3613(c) also adds a new provision to Section 809 requiring the agency to periodically assess whether additional mutual recognition agreements are appropriate and to report to Congress the results of those assessments every four years. The existing mutual recognition agreements with the EU and the U.K. are considered a great success in the agency. A new mutual recognition agreement was also just signed between the FDA and Switzerland on January 12. FDA is already routinely considering additional such agreements, but this new legislation should encourage further action in this area. Interestingly, the EU, U.K., and Swiss agreements already permit FDA to ask a treaty partner to conduct a pre-approval inspection.7 In the case of the agreement with the EU, FDA reports that implementation of the pre-approval inspection provision in the treaty has been held up by delays in developing a U.S.-EU joint work plan for pre-approval inspection capability assessments.8

4. Regional Compliance History Added as a Surveillance Inspection Criterion

In 2012, the Food and Drug Administration Safety Innovation Act (FDASIA) eliminated the requirement to inspect domestic drug facilities every two years and directed the FDA to remove any distinction between foreign and domestic facilities when determining surveillance inspection frequency. FDORA Section 3613(a) can be seen as a bit of backtracking on this point, as it directs the agency to now consider the compliance history of establishments in a particular country or region when determining the schedule for risk-based inspections of facilities located there. Some are also criticizing the provision for fear that it will work to the detriment of a facility with a good compliance history that happens to be in a country with a relatively poorer rate of compliance. However, we think these concerns are overblown, as decisions on surveillance inspection frequency are based on several factors, one of the most important of which is the compliance history of the specific facility being considered for inspection, which will surely be weighed more heavily by FDA than the overall compliance history of the region or country where the facility is located. Interestingly, one result of Section 3613 is that, everything else being equal between two facilities, a U.S. based facility may now be flagged by FDA for a surveillance inspection more frequently than a comparable European facility, as the data indicates that facilities in Europe have a lower overall level of Official Action Indicated (OAI) classifications than do those in the U.S.9  

5. GAO Directed to Prepare Report on Alternative Tools Used by FDA and Foreign Counterparts

FDORA Section 3614 directs the U.S. Government Accountability Office (GAO) to prepare a wide-ranging report on how the FDA and foreign counterparts use alternative tools to inspection, no later than June 2024.  Among other factors, the report must cover:

  • what alternative tools, including remote inspections/evaluations, other countries are using to facilitate inspections;
  • how frequently trusted foreign regulators conduct inspections that FDA could review in lieu of conducting its own inspections;
  • how frequently FDA is using mutual recognition agreements (MRA) and whether use of such agreements could be expanded;
  • whether FDA has accepted reports of inspection of facilities in China and India conducted by FDA’s MRA partners; and
  • what other countries has FDA considered and rejected for a possible MRA treaty. 

6. Expect More Unannounced Foreign Inspections

Foreign drug establishments should expect more unannounced FDA inspections due to FDORA Section 3615. Prior to the pandemic, FDA inspections of domestic drug establishments were almost always unannounced, while foreign establishments generally received advanced notice of their inspections. This disparity in treatment raised concerns, including within Congress and the GAO, that foreign facilities were being given the opportunity to fix problems before FDA investigators arrived. So much so, in a report accompanying FDA’s fiscal year 2021 appropriation, the House Appropriations Committee directed FDA to begin piloting the use of unannounced and short notice inspections in India and China and provided FDA funding to implement those pilots.10 In April 2022, FDA reported that unannounced foreign inspections had begun in India but had not yet begun in China due to local pandemic-related restrictions.

Section 3615 doubles down on direction to FDA in this area, requiring for the first time in statutory language that FDA conduct a pilot program to “increase[] the conduct of unannounced surveillance inspections of foreign human drug establishments[.]” Section 3615 further directs FDA to evaluate the observed differences between announced and unannounced inspections under the pilot, including the violations identified, costs, benefits, and any other significant differences, among other factors. Finally, FDA must produce a report on its findings and recommendations within 180 days after completion of the pilot. 

​​7. Previously Sunset Provisions to Prevent Shortages in Enforcement Cases are Revitalized

In 2012, FDASIA established new statutory requirements in the FDCA to help prevent drug shortages, including FDCA Sections 506(D)(b),(c), and (e) requiring, before FDA takes an enforcement action or issues a warning letter that could reasonably be anticipated to lead to a drug shortage: 1) advance coordination with CDER’s Drug Shortage Staff; and 2) an evaluation of the relative risks associated with the violations at issue and the likely patient impact resulting from the anticipated shortage. Pursuant to FDASIA’s original sunset provision, however, these coordination requirements ceased to be effective in July 2017. FDORA Section 3616 reestablishes and makes permanent those coordination requirements. It is worth noting that coordination efforts on drug shortages have remained strong within FDA since July 2017, despite these provisions having sunset. Nevertheless, permanently building these coordination requirements into the statute is a welcome development. In addition, Section 3616 inserts a new provision, FDCA Section 506D(g), directing FDA to ensure timely and effective coordination between ORA, CDER Compliance, and CDER’s Drug Shortage Staff concerning the review of inspection reports and follow-up actions taken in response to those reports, concerning inspections of facilities that raise potential drug shortage implications. 

8. Annual Report on Inspections

FDORA Section 3617 amends the requirements, first established in 2017 by Section 902 of the FDA Reauthorization Act (FDARA) (Public Law 115-52), for the FDA’s annual report on human drug and device inspections. Previously, the required report focused exclusively on inspections of facilities necessary to approve a drug or device, including: 1) the time it took to begin a requested facility inspection, as well as the timing for compliance actions following completion of the inspection (e.g., warning letters); and 2) the number of application approvals delayed or withheld because of these inspections. The Section 3617 amendments include a requirement to track the same information for drugs on the FDA shortage list as well as to convert the report from an annual to a fiscal year basis.

References/Notes

  1. FDCA Section 704(a)4) was previously limited to requests directed to “a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug[.]”
  2. See Conducting Remote Regulatory Assessments, Questions and Answers, Draft Guidance for Industry, July 2022, https://www.fda.gov/media/160173/download.
  3. In fiscal year 2021, CDER conducted 133 BIMO RRAs. See FDA Bioresearch Monitoring (BIMO) Fiscal Year 2021 Metrics, https://www.fda.gov/media/156517/download.
  4. See Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, Guidance for Industry, April 2021. During the pandemic, CDER conducted remote interactive evaluations using livestreamed video of operations as well as remote, live interactions with facility personnel to assess manufacturing facilities named in marketing applications, https://www.fda.gov/media/147582/download.
  5. See Regulatory Procedures Manual, Section 4-1-8 (“Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection.”) (emphasis added), https://www.fda.gov/media/71878/download.
  6. FDORA Section 3612 adds new Section 704(a)(5) to the FDCA concerning the authority to conduct BIMO inspections.
  7. See e.g., United States – European Union Amended Sectoral Annex For Pharmaceutical Good Manufacturing Practices (GMPs), Article 11, https://ustr.gov/sites/default/files/IssueAreas/Manufacturing/20170119%20Pharma%20MRA
    %20US%20EU%20%28FINAL%29.pdf    .
  8. See Frequently Asked Questions – [U.S./EU] Mutual Recognition Agreement, Question 13, https://www.fda.gov/media/103391/download.
  9. As of May 2020, only two percent of EU based drug manufacturing facilities were classified as OAI as compared to seven percent of U.S. based facilities. See FDA Testimony before the U.S. Senate Committee on Finance (Judith McMeekin), June 1, 2020, Figure 6, https://www.finance.senate.gov/imo/media/doc/02JUN2020.FDAJNT.STMNT.pdf.
  10. See House Committee on Appropriations Report 116-446, Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Bill FY21, p. 86, https://www.congress.gov/116/crpt/hrpt446/CRPT-116hrpt446.pdf.

FDA Drug Manufacturing Oversight During COVID-19: The GAO Report on the Inspections Backlog and Steps FDA is Taking to Address It

This article was originally published in the Summer 2021 issue of FDLI’s Update magazine. The full issue can be dowloaded using the link at right.

To date, restrictions put in place in light of the COVID-19 pandemic continue to impact the ability of the Food and Drug Administration (FDA or the agency) to inspect drug manufacturing facilities, which has generated a growing backlog of inspections, as well as a range of backlog-related concerns expressed by both the pharmaceutical industry (Industry) and Congress. Consequentially, on March 4, 2021, a Subcommittee of the U.S. House of Representatives’ Committee on Appropriations held a hearing to better understand the inspections backlog and what could be done to address it.

The focus of this hearing was the January 28, 2021 report by the Government Accountability Office (GAO) entitled COVID-19: Critical Vaccine Distribution, Supply Chain, Program Integrity, and Other Challenges Require Focused Federal Attention (the GAO Report).[1] The GAO Report provides insight into the depth of inspectional challenges faced by FDA during COVID-19, as well as possible next steps the agency could take to address these challenges. Testimony given by GAO Health Care Director Mary Denigan-Macauley at the hearing offered an update to the earlier more detailed findings conveyed in the GAO Report.[2] In addition, GAO more recently reiterated the importance of the GAO Report recommendations regarding FDA drug manufacturing inspections through release of a new document called Priority Open Recommendations to the Department of Health and Human Services (HHS) (Priority Recommendations).[3] In this latest update, GAO acknowledged that while FDA has made some improvements in its inspection planning process, FDA must continue to ensure that its inspection plans for future years “identify, analyze, and respond to the issues presented by the backlog of inspections that could jeopardize the goal of risk-driven inspections.”[4]

Since publication of the GAO Report and corresponding congressional testimony, FDA has released two other noteworthy documents related to inspections. First, on April 14, 2021, FDA released a guidance entitled Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, which introduced a new tool for conducting remote inspectional work during the pandemic.[5] Second, on May 5, 2021, FDA issued its Resiliency Roadmap for FDA Inspectional Oversight to provide further transparency around adaption of the agency’s inspectional work during the pandemic.[6]

In this article, we first review GAO’s most recent findings on the state of the inspections backlog and its causes. We then review GAO’s recommendations to FDA on addressing the backlog and FDA’s response to those recommendations. Last, we review recent FDA efforts to address the backlog and potential permanent changes FDA may make going forward regarding oversight of drug manufacturing facilities.

GAO’s Findings on the State of the Drug Manufacturing Inspections Backlog and its Impact on FDA Oversight

In March 2020, as the spread of COVID-19 became an established threat around the world, FDA suspended most foreign[7] and domestic[8] inspections of facilities that manufacture drugs intended for the U.S. market, continuing only with its “mission critical” activities. In July 2020, on-site, prioritized domestic inspections resumed, but only on a limited basis (i.e., depending on the local risk of COVID-19 infection), meaning that the agency’s on-site inspections capability remained very limited.[9]

Even before the current pandemic, GAO had existing “long-standing concerns about FDA’s ability to oversee the increasingly global pharmaceutical supply chain.”[10] GAO reported that prior to COVID-19, FDA conducted pre-approval, surveillance, and for-cause inspections at all facilities that manufacture drugs intended for the U.S. market, amounting to about 1,600 inspections of approximately 4,200 facilities each year. Close to 60% of these facilities were located overseas, a third of which were in China and India.[11] Given the backlog created by COVID-19, the GAO Report made clear that FDA now faces an even bigger challenge in overseeing the global pharmaceutical supply chain.

GAO Found a Sizeable Backlog of FDA Inspections

Notably, FDA’s inspection metrics for 2020 pale in comparison to the same metrics reported in previous years. GAO reported that FDA was unable to complete more than 1,000 of its planned inspections in Fiscal Year (FY) 2020,[12] leaving the total number of inspections of foreign and domestic facilities 56% lower than each of the previous two fiscal years.[13] For domestic facilities, FDA conducted 52 inspections between March and October 1, 2020, but conducted about 400 inspections during the same time period in each of the two previous years. Foreign facilities experienced an even more drastic decrease, with FDA conducting only three inspections between March and October 1, 2020, compared to more than 600 inspections during the same time period in each of the previous two years.[14]

GAO Found That the Inspections Backlog May Lead to Future Delays in Drug Approvals 

In addition to quantifying the backlog, GAO expressed concerns that the agency will face challenges in carrying out its preapproval and surveillance oversight responsibilities in the future if the inspections backlog remains unaddressed. Specifically, the GAO Report noted that while FDA has not yet experienced serious delays in meeting user fee goal dates, the impact on approvals from delayed inspections may become more evident in the future.[15]

While FDA reported that it was operating above its 90% on-time action performance goal for approval decisions as of November 2020, the GAO Report noted that the inspections pause had not yet had a significant impact on the agency’s drug approval performance, because preapproval inspections typically occur months in advance of approval. Additionally, GAO noted that two of the Industry associations it spoke with expressed concern about this issue. Consequentially, GAO concluded that “[a] continued pause in preapproval inspections may lead to future delays in FDA drug approvals.”[16] 

GAO Found That the Inspections Backlog May Require FDA to Alter Its Risk-Based Inspection Model for Surveillance Inspections

FDA conducts surveillance inspections according to a risk-based model that prioritizes the highest risk facilities for inspection in any given fiscal year, based on mandatory factors (sites that have never before been inspected or have not been inspected within the last five years) and other risk-based factors such as type of drug manufactured, length of time since last inspection, and previous compliance history.[17] As noted above, FDA was unable to complete more than 1,000 of the approximately 1,500 planned surveillance inspections for FY20. These inspections will roll over into the site selection model for future fiscal years; thus, GAO found that the backlog could potentially threaten FDA’s “strategic goal of shifting toward exclusively risk-driven surveillance inspections” if the agency does not make changes to the model.[18]

GAO Found That FDA’s Current Use of Alternative Tools is Not a Comprehensive Solution to Addressing the Inspections Backlog

GAO also noted that to keep up with some of its inspectional work during COVID-19, FDA adopted a range of alternative tools, such as use of inspections conducted by foreign regulators, use of statutory authority to request and review facility records remotely, and use of sampling and testing drug products imported from foreign manufacturers. GAO reported that despite FDA’s vastly expanded use of such tools, this was not enough to avoid a backlog of mandatory on-site inspections. The GAO Report discussed each of these alternative tools and the concerns related to their longer-term utility.

FDA Use of Information From Inspections Conducted by Foreign Regulators

The first tool reviewed by GAO was use of information from inspections conducted by foreign regulators. GAO reported that FDA found information from inspections conducted by foreign regulators statutorily satisfies FDA inspectional requirements in some instances, but not in all. For example, inspections conducted in Europe by the 28 European regulators privy to the Mutual Recognition Agreement (MRA) have been deemed an acceptable substitute for an FDA inspection. Additionally, in light of COVID-19, FDA expanded recognition to inspections conducted outside of Europe by European regulators under the MRA, but only for 19 out of the 28 European regulators. No framework similar to the MRA exists to extend formal recognition of inspections conducted by regulators among the Pharmaceutical Inspection Cooperation Scheme (PIC/S), including Australia, Canada, Japan, and South Africa. Thus, information from inspections conducted outside of Europe by the other nine European regulators and by PIC/S members can only be used for purposes of “surveillance-level oversight” to inform the risk-based site selection model and are not acceptable substitutes for an FDA inspection. Moreover, like FDA, all relevant foreign regulators have also slowed their foreign inspection programs during COVID-19, limiting the ability of any regulatory authority to engage in on-site inspections. 

Furthermore, FDA is most in need of information about facilities located in China and India; FDA conducted more inspections than any other foreign regulator in those countries prior to COVID-19. These countries, however, are not party to the MRA or other reliance agreements. Thus, although information from European and certain other foreign regulator inspections can substitute for FDA inspections, this information is either not available or does not qualify as a sufficient substitute for all needed inspections.

FDA Use of Records Requests “in Advance of or In Lieu of” an Inspection

The second tool reviewed by GAO, and the tool on which FDA relied most heavily during the pandemic, was use of FDA’s authority to request records from facilities “in advance of or in lieu of” an inspection under Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). A records request is not an inspection, but FDA was able to satisfactorily assess the compliance status of many facilities named in drug product applications by reviewing their records, and thus, was able to meet many user fee goal dates. However, FDA told GAO that “only FDA in-person inspections and European regulator reports can satisfy the Agency’s statutory requirements for surveillance reports.”[19] GAO concluded that this tool has limited capability in mitigating the backlog of surveillance inspections, unless FDA’s statutory authority is expanded or interpreted to include use of records requests as a true substitute for surveillance inspections (as opposed to merely providing supplemental information in advance of such an inspection to inform FDA’s risk-based site selection model).

FDA Use of Information from Sampling and Testing of Product Obtained at the U.S. Border

The last tool reviewed by GAO was FDA’s sampling and testing of drug products obtained at the U.S. border. GAO noted that FDA adjusted use of this tool during the pandemic to specifically target high risk drugs manufactured at foreign facilities where inspections had been postponed. Significantly, FDA pointed out that sampling and testing alone will not confirm if a manufacturing facility is meeting quality standards. Thus, this tool can only supplement an FDA inspection, but can never act as a substitute for one. 

GAO’s Recommendations to FDA for Improving Its Drug Manufacturing Oversight

The GAO Report made two recommendations intended to help FDA adapt its inspections program to most effectively carry out its drug manufacturing oversight responsibilities.

GAO Recommendation to Assess Use of Alternative Inspection Tools

GAO recommended that FDA “fully assess the agency’s alternative inspection tools and consider whether these tools or others could provide the information needed to supplement the agency’s regular inspection activities or help meet its drug oversight objectives when inspections are not possible in the future.”[20] Although listed second in the GAO Report, this recommendation captured the interest of Industry and Congress.

GAO observed that while FDA has substantially increased its use of Section 704(a)(4) records request authority, “the agency has not yet finalized a policy for how it can use this information to supplement its inspection activities.”[21] Note, however, that on January 29, 2021, one day after the GAO published its report, FDA issued revised guidance outlining its new interim process for communicating issues identified following a Section 704(a)(4) records request issued “in advance of or in lieu of” a pre-approval inspection.[22] The revised guidance also provides information about FDA’s expanded recognition practice under the MRA, as discussed earlier, which includes use of European regulators’ inspection reports for facilities located outside of Europe.

GAO also noted that “FDA has not assessed whether inspections conducted by PIC/S members are equivalent to FDA inspections.”[23] GAO did not explicitly address any of the difficulties FDA would face in trying to implement a mutual recognition framework with those authorities. However, the report acknowledged that such an assessment would not be a quick solution, noting that it took FDA five years to complete a capability assessment of each European regulator in order to establish the MRA in the first place. We also note that in addition to the five-year timeline that accrued when conducting capability assessments in initial development of the MRA, the MRA also required a years-long negotiation between FDA and European regulators before assessments could even begin. Thus, while there may be agreement as to the concept, establishing additional mutual recognition agreements with other regulators could take many years to implement.

Most significantly, GAO recommended that FDA assess whether there are “additional tools” the agency should be using, specifically pointing to virtual inspections. GAO reported that four of five Industry associations it spoke with mentioned successful implementation of virtual inspections by foreign regulators, explaining that these regulators have used a range of virtual technologies to remotely conduct facility inspections. FDA reported to GAO that “the agency is in the process of assessing the potential use, including its authority to use, other tools to serve as supplements to FDA inspections, including using remote video and other remote and live interactions with establishment staff and records to evaluate drug manufacturing operations.”[24]

GAO Recommendation to Develop a Plan for Addressing the Inspections Backlog

Second, GAO recommended that FDA ensure “inspection plans for future fiscal years identify, analyze, and respond to the issues presented by the backlog of inspections that could jeopardize its goal of risk-driven inspections.”[25] In particular, GAO explained that FDA should adapt the risk-based model it uses to select inspection sites in order to loosen its definition or prioritization of “mandatory surveillance inspection.” FDA’s model, as of the date of the GAO Report, defined never-inspected facilities or facilities not inspected within the past five years as “mandatory surveillance inspections” because they present significant risks to pharmaceutical quality.[26] Historically, FDA has prioritized mandatory surveillance inspections and used its remaining resources for inspections of other high risk facilities identified through the risk-based model. [27] In its report, GAO expressed concern that unless more resources are allocated to the drug inspection program, the backlog of mandatory surveillance inspections would “dominate” FDA’s surveillance inspection program, creating a situation where other high risk facilities would not be inspected.[28] 

Recent FDA Efforts Aimed at Addressing the Drug Manufacturing Inspections Backlog and Possible Longer-Term Oversight Changes

FDA made clear in its response to GAO that it would consider both recommendations as it assesses how to address the inspections backlog, although its ongoing pandemic response, and preexisting statutory and resource limitations, continue to burden implementation of significant change. Significantly, since release of the GAO Report in January and GAO congressional testimony in March, FDA has issued two documents that provide further transparency around how it will address inspectional concerns highlighted in the GAO Report. We review those documents below.

FDA Announces a New Tool Called Remote Interactive Evaluations

On April 14, 2021, FDA released a guidance entitled Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, introducing a new tool for conducting remote inspectional work during the pandemic.[29] In the guidance, FDA describes a Remote Interactive Evaluation (RIE) as “any combination of [various remote] interactive tools” used to evaluate a drug or biologic manufacturing facility.[30] RIEs apply to all drug inspection programs, including pre-approval or pre-licensing inspections; post-approval, routine surveillance inspections; follow-up and compliance inspections; bioresearch monitoring (BIMO) inspections; and inspections of 503B outsourcing facilities.

Importantly, however, RIEs are not outright inspections, and thus, the start and close of an RIE will not trigger issuance of FDA Form 482s and Form 483s. RIEs are instead intended to provide information to meet user fee commitments, update FDA’s relevant internal databases, and inform the risk-based surveillance inspection site selection model. FDA will follow several similar inspection procedures in carrying out an RIE, such as holding closeout meetings and providing a written list of observations in which the facility will have 15 business days to respond. FDA will also issue final “remote interactive evaluation reports” in closing out an RIE.[31]

RIEs are meant to complement other remote tools used by FDA during the pandemic. For example, an RIE may precede a request for information, possibly under Section 704(a)(4), in order to most efficiently conduct the RIE.[32] Additionally, FDA will apply “risk management tools” to determine the need to conduct an RIE, similar to its approach taken with respect to other types of evaluations throughout the pandemic.[33]

FDA’s adoption of virtual technologies as a component of RIEs and other remote evaluations is encouraging news for Industry, which sees this approach as a more meaningful way to address the inspections backlog. However, since FDA caveated in discussions with GAO, as well as in the RIE guidance, that any remote evaluation is not a substitute for an on-site inspection under its current statutory authority, questions still remain as to how the agency will manage the inspections backlog in the longer-term. These questions will likely persist across Industry until more information is provided.

FDA Publishes Its Resiliency Roadmap for FDA Inspectional Oversight Moving Forward

On May 5, 2021, FDA issued a report entitled Resiliency Roadmap for FDA Inspectional Oversight (the Resiliency Roadmap).[34] This report, which covers inspectional activities for all FDA-regulated commodities, provides updated information regarding FDA’s inspectional activities during the pandemic and a roadmap for how it intends to prioritize its inspectional work as the pandemic continues.

Of particular interest, FDA provided updated statistics regarding delayed applications. According to the Resiliency Roadmap, FDA received more than 13,500 applications for all medical product approval/authorization between March 2020 and March 2021, and determined that of those applications, approximately 600 needed inspectional oversight of some type before action could be taken on the application.[35] FDA reported that only 48 drug products were delayed solely because a GMP inspection could not be conducted. FDA noted that only six of the 48 delayed products were considered mission critical and that it had scheduled the inspections for those six mission critical products to occur by September 30, 2021.[36]

FDA also reported on its queue of for-cause domestic inspections that are follow-up compliance actions after a previous domestic inspection resulted in “official action indicated” (OAI) classification. FDA reported that it was able to complete 90% of these OAI follow-up inspections in FY20 and noted that it had 79 OAI follow-up inspections still to be conducted for human and animal drug domestic facilities in FY21.[37] However, FDA did not provide any statistics related to the number of OAI follow-up for-cause inspections in its queue for foreign inspections.

For surveillance inspections, FDA indicated that it was able to use remote tools to provide oversight on the relative risk of some establishments. As a result, when reassessing facility risk to create the surveillance site selection list for FY21, some facilities that were included in the FY20 model are no longer included in the FY21 model.[38] FDA did report that it had 857 remaining surveillance inspections for drug facilities planned for FY21, with the majority being domestic facilities.[39]

In addition to providing inspectional statistics during the pandemic, the Resiliency Roadmap also includes an outline of FDA’s plans for conducting inspections going forward, while noting that these plans will depend heavily on the course of the COVID-19 pandemic. In general, FDA will first conduct mission critical inspections (Tier 1) and then prioritize PAI/PLI inspections and for-cause inspections (Tier 2).[40] Lower priority inspections that do not meet these criteria (Tier 3) may be postponed, which could include some routine surveillance inspections. FDA said that it will continue to use risk-based measures going forward, with longer intervals occurring between non-priority surveillance inspections. FDA is clear that the volume of surveillance work presents a significant challenge even in the best case scenario, and that as a result, FDA will continue to use remote alternative tools whenever possible.[41]

Notably, the workload estimates focus on domestic inspections and the small number of foreign inspections that can be accomplished by in-country FDA investigators, assuming that FDA will continue to prioritize mission critical foreign inspections, but that travel restrictions and other limitations will prevent FDA travel for foreign routine surveillance inspections. FDA also assumes that foreign authorities will conduct 25% of remaining medical product inspections.[42]

Conclusion

In sum, the GAO Report captured concerns about the impact of the pandemic on FDA’s inspections backlog and the risk it poses to the agency’s oversight capabilities in the foreseeable future. Congressional testimony, as well as mounting calls from Industry, set the stage for FDA’s recent adoption of certain additional oversight tools, as well as its longer range plans for use of other tools with more complex implementation requirements. FDA has made significant progress in implementing the GAO recommendations with its use of more innovative inspection alternatives, such as RIEs and the increased transparency provided in the Resiliency Roadmap. GAO subsequently acknowledged that FDA made some improvements, but reiterated its concern that FDA should continue to prioritize addressing inspection delays caused by the pandemic. Thus, while FDA’s adoption of some additional tools to address the inspection backlog has been positively received, all eyes still will remain on FDA as it moves forward with implementing its use of these new tools and potentially adopts newer approaches to its drug manufacturing oversight in the future.

[1] GAO Report, “COVID-19: Critical Vaccine Distribution, Supply Chain, Program Integrity, and Other Challenges Require Focused Federal Attention” (January 2021), available at https://www.gao.gov/assets/gao-21-265.pdf. This report was the GAO’s fifth installment in its series of reports to fulfill the mandate imposed by the CARES Act to monitor and report on the federal response to the coronavirus pandemic (COVID-19).

[2] Statement of Mary Denigan-Macauley, Testimony before the Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Agencies, Committee on Appropriations, House of Representatives, “Drug Safety: FDA’s Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog” (March 2021), available at https://www.gao.gov/assets/720/712761.pdf.

[3] GAO, “Priority Open Recommendations to the Department of Health and Human Services” (May 2021), available at https://www.gao.gov/assets/gao-21-527pr.pdf.

[4] Id.

[5] FDA Guidance, “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency” (April 2021), available at https://www.fda.gov/media/147582/download.

[6] FDA Report, “Resiliency Roadmap for FDA Inspectional Oversight” (May 2021), available at https://www.fda.gov/media/148197/download?utm_medium=email&utm_source=govdelivery.

[7] See supra note 1 at 150, citing “Coronavirus Disease 2019 Update: Foreign Inspections” (March 2020), available at https://www.fda.gov/news-events/press-announcements/coronavirus-disease-2019-covid-19-update-foreign-inspections.

[8] See supra note 1 at p. 151, citing “Coronavirus Update: FDA Focuses on Safety of regulated Products While Scaling Back Domestic Inspections” (March 2020), available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-focuses-safety-regulated-products-while-scaling-back-domestic#:~:text=Today%2C%20we’re%20announcing%20that,domestic%20routine%20surveillance%20facility%20inspections.

[9] Id., citing “Coronavirus Update: FDA prepares for resumption of domestic inspections with new risk assessment system” (July 2020), available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-prepares-resumption-domestic-inspections-new-risk-assessment-system.

[10] Id. at p. 148.

[11] Id. at p. 149.

[12] Id. at 155.

[13] Id. at p. 149.

[14] Id. at p. 151.

[15] Id. at p. 154–55.

[16] Id. at p. 155.

[17] Id.

[18] Id.

[19] Id. at p. 154.

[20] Id. at Executive Summary.

[21] Id. at p. 157.

[22] FDA Updated Guidance, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers” (January 2021), available at https://www.fda.gov/media/141312/download.

[23] See supra note 1 at p. 157.

[24] Id.

[25] Id. at Executive Summary.

[26] Id. at p. 155.

[27] Id.

[28] Id. at p. 156.

[29] See supra note 5.

[30] Id.

[31] Id.

[32] Id.

[33] Id.

[34] See supra note 6.

[35] The 13,500 applications included human drugs, animal drugs, devices, biologics, BIMO, and tobacco. FDA did not breakdown the number of applications by commodity.

[36] See supra note 6 at p. 8.

[37] Id. at p. 9.

[38] Id. at p. 11.

[39] Id. at p. 12.

[40] Id. at p. 13–15.

[41] Id.

[42] Id.

FDA Inspectional Activities During COVID-19

Greenleaf Regulatory Landscape Series

On March 10, 2020, following the global emergence of the novel coronavirus (SARS-CoV- 2) and spread of COVID-19 disease, the Commissioner of the Food and Drug Administration (FDA or the Agency) suspended most foreign inspections of facilities that manufacture FDA- regulated products. The following week, domestic surveillance inspections, if not deemed “mission-critical,” were postponed as well. These policies were extended in subsequent months, with prioritized, pre-announced domestic inspections only resuming in July 2020. As the pandemic progressed, these travel restrictions and on-site limitations led to a growing backlog of regulatory inspections. Regulators responded by undertaking various alternative approaches to inspectional work to ensure the continued supply of quality medicines to patients, and to mitigate the creation of drug shortages.

Timeline of On-Site Inspection Policies at FDA During COVID-19

Under Section 704(a)(4) of the Food, Drug, and Cosmetic Act (FDCA), FDA can “in advance of or in lieu of an inspection” request records or information to determine whether inspection of a drug manufacturing facility is needed. Note: Section 704(a)(4) does not apply to other FDA inspection types (e.g., the Bioresearch Monitoring Program (BIMO), good clinical practice (GCP) inspections, medical device manufacturing facility inspections, etc.). Leveraging this authority, FDA began utilizing 704(a)(4) records requests to enable abbreviated on-site inspections so that the risk of exposure to COVID-19 was otherwise reduced. By August 2020, Elizabeth Miller, Assistant Commissioner for Medical Products and Tobacco Operations at FDA, said that 424 records requests to drug manufacturers had been made during the pandemic – 111 in the pre-approval space and 313 in the post-approval, good manufacturing practice (GMP) space. Miller added that another 123 records requests to biologics manufacturers had been made during the same time frame. Additionally, FDA made use of flexibilities established under the Mutual Recognition Agreement (MRA) for products evaluated by the European Union (EU), as well as information from inspections occurring outside the EU provided by the Pharmaceutical Inspection Co-Operation Scheme (PIC/S).

On August 19, 2020, FDA published final guidance, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers,” which closely followed previously posted guidance from April 2020 and continued “mission-critical” inspections, which had been on-going throughout the pandemic, as well as prioritized, domestic inspections based on a case-by-case risk analysis. Although the new guidance did not indicate whether FDA would begin to lean into virtual technologies as a supplement to 704(a)(4) records requests and/or on-site inspection requirements, foreign regulators demonstrated interest in implementing virtual approaches to their inspectional activities early on in the pandemic. For example, health authorities in the UK, EU, and Singapore piloted various virtual practices and tools as supplements to standard GMP inspections.

Foreign Health Authorities’ Adoption of Virtual Inspectional Activities

In November 2020, speculation grew as to whether FDA would begin conducting some form of virtual GMP assessments or inspections, similar to its foreign counterparts. Brian Hasselbalch, the Deputy Director of the Office of Policy for Pharmaceutical Quality at the Center for Drug Evaluation and Research (CDER), confirmed that guidance “on remote evaluations using interactive video or other types of interactive tools and techniques” is under development. Hasselbalch said that such a document will describe the role these types of interactions are to play in the Agency’s decision making with respect to pending applications, surveillance activities, and possibly even for-cause inspections. He added that manufacturers with pending applications involving facilities, or plans to submit such applications, should begin to equip themselves with necessary streaming technologies.

Despite indications that FDA is planning to utilize virtual technologies in some form, it is unclear what this will mean for inspection requirements under the FDCA. When implementing a virtual approach to inspectional work, the Agency has to work within its Section 704 authority and ensure this authority reaches across various product areas (e.g., drugs, biologics, and medical devices). Importantly, there is a distinction between a virtual assessment, where the Agency would rely on virtual tools to facilitate a 704(a)(4) records request (e.g., by following up on a records request with live streaming of the facility, etc.), and otherwise allowing an actual virtual inspection, where an inspector would present an FDA Form 482 and could issue an FDA Form 483. The approach taken by FDA will depend on whether it interprets a virtual inspection to count as a statutorily required inspection under Section 704 of the FDCA, although the Agency’s stance on this has not been made clear. Irrespective of FDA’s allowance of virtual inspection, or mere virtual assessments as part of 704(a)(4) records request, it seems inevitable that further incorporation of various virtual tools and technologies is approaching, especially as COVID-19 continues to impact regulatory operations and oversight around the world.

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