From 2019 to 2023, the FDA issued a total of 3,096 warning letters. As reflected in Fig. 1, the FDA issued, 485, 640, 687, 688, and 596 warning letters in the years 2019, 2020, 2021, 2022, and 2023, respectively. From 2019 to 2023, the FDA conducted 56,913 inspections, with 16,293 inspections in 2019, 7,952 in 2020, 6,855 in 2021, 11,843 in 2022, and 13,970 in 2023.

By office, the Center for Tobacco Products (CTP) issued the highest number of warning letters each year, with 263 letters in 2022 alone, accounting for 38% of total issuances in 2022. A majority of these letters (99.24%) contained both adulterated and misbranding keywords. Figure 2 outlines the number of warning letters issued by the office for the five-year period.

FDA warning letter distribution by office and year. Other/Unlabeled/NA letters include letters without an office or in collaboration with other non-FDA regulatory bodies[12, 14, 24,25,26,27,28,29,30]

The average warning letter issuance rate, or the number of warning letters issued as a fraction of inspections, was 5.44% or 5.44 warning letters per 100 inspections from 2019 to 2023. During 2020 and 2021, there was a drastic reduction in inspection volume, leading to higher rates of warning letter issuance as a fraction of inspections, as seen in Fig. 3. The change in the warning letter-to-inspection ratio was calculated for every year, followed by measuring the rate of change from 2019 to 2023. The rate of change in the warning letter issuance was 43%, from 2.98 to 4.27 warning letter issuances per 100 inspections from 2019 to 2023, respectively. Additionally, the rates for devices and drugs were .72 per 100 inspections and 2.97 per 100 inspections in 2019, rising to 1.72 and 6.93 per 100 inspections in 2023, respectively. Graphed within Fig. 3 are these ratios of warning letters to inspections for every year using the relative change formula, for example, \(\frac \times 100 \approx 43\)%. From 2019 to 2023, rates of warning letter issuance against all inspections for the agency, devices, and drugs increased at 43%, 141%, and 134%, respectively.

The keyword analysis for the seven surveyed keywords revealed fluctuations in the amount of keyword usage. COVID-19 went from 0% in 2019 to 5.58% in 2023 with a high of 25.83% of letters containing the keyword in 2020. Both the Misbranded and Adulterated keywords were present in over 60% of warning letters issued each year from 2019 to 2023. For the year 2022, the FDA issued 685 warning letters. Misbranding and adulteration violations were the largest keyword findings, with 62% and 67%, respectively, for 2022. 99.24% of warning letters issued by the Center of Tobacco contained both adulterated and misbranding keywords, with similar Figures for all years surveyed. Figure 4 demonstrates the keyword frequency fluctuations for the period, particularly in 2020 and 2021. 20 out of the top 25 referenced codes increased in frequency from 2020 to 2023. The record year 2019 had a significant variance in code frequency, notably due to formatting changes to tobacco letters. From 2019 to 2023, 16 out of the top 25 most frequently featured codes saw increases. For codes that grew in frequency from 2020 to 2023, they did so at an average rate of 85%. This was calculated from Fig. 6 by taking the 20 codes that had a positive change in frequency from 2020 to 2023 and calculating the average percent change in the appearance frequency, which in this case was an 85% change, from a frequency of 16% in 2020 to 26% in 2023. The growth rate for all 25 top codes from 2020 to 2023 was 64%. For the five decreasing codes from 2020 to 2023, the average rate of decrease was -22%. The five codes that did not increase were FD&C Act 505(a), FD&C Act 301(d), 21 U.S.C. 331(d), FD&C Act 801(a)(3), and 21 U.S.C. 381(a)(3). These five codes from Fig. 6 were not included in the 85% growth rate calculation, as they exhibited negative growth. However, they are part of the overall analysis, contributing to the total growth rate of 64% for all 25 codes from 2020 to 2023. These five codes only describe two areas as well, observable in Table 1. FD&C Act 801(a)(3) and 21 U.S.C. 381(a)(3) describe adulterated or misbranded products, while FD&C Act 505(a), FD&C Act 301(d), and 21 U.S.C. 331(d) all describe interstate commerce [31]. These rates underscore the overall increase in the frequency of the top 25 cited violation codes.

There are multiple references for the same regulation, often a CFR reference and a U.S.C. reference. For example, when defining tobacco, the center of tobacco will often state, ”Under section 201(rr) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. §321(rr)), these products are tobacco products because they are made or derived from tobacco and intended for human consumption” [32]. These codes are located in Fig. 5 as the second and third most cited codes between 2019 and 2023. This can be attributed to the fact that FD&C Act 201(rr) is formally codified under the section 21 U.S.C. §321(rr). The method of sourcing data did not account for this type of legal understanding. Therefore, similar instances were recorded within Table 1.

Figure 5 and Table 1 shows 9/25 of the top violations pertain to misbranding or adulteration, 11/25 of the codes refer to tobacco legislation and 5/25 codes refer to interstate commerce. FD&C Act 505 does not belong to any prior category but pertains to the section of legislation that covers new drugs and devices. Many codes are cited together; FD&C Act 505(a) and FD&C Act 301(d) are overarching references for 21 U.S.C. 355(a) and 21 U.S.C. 331(d), respectively. Similar to the prior tobacco example, ’these products are unapproved new drugs sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a)’ [33]. There were several instances of overlapping code definitions. For example, two codes related to the failure to register an establishment, while in another case, three codes overlapped, covering interstate commerce, misbranding, and adulteration. Additionally, two codes pertained to both tobacco and misbranding. Figure 5 is ranked by total code volume for 2020, with the volume for each subsequent year stacking upon the 2020 count. The cumulative ranking over the four years closely mirrors the 2020 ranking, with only minor deviations, specifically FD&C Act 505, which would rank higher based on their cumulative total. The purpose of Fig. 6 is to demonstrate the deviation of this code. The figure normalizes the volume of each code for the given year over the total warning letters issued within that year. For instance, FD&C Act 901(b) was cited 212, 273, 258, and 241 times in 2020, 2021, 2022, and 2023, respectively. As indicated by the warning letter volume in Fig. 1, a total of 640, 687, 688, and 596 warning letters were issued in 2020, 2021, 2022, and 2023, respectively. Thus, as a percentage of total warning letters issued, FD&C Act 901(b) appeared in 33%, 40%, 38%, and 40% of letters for 2020, 2021, 2022, and 2023, respectively.

Warning Letter Issuance as a percentage of inspections per year

Keywords graphed as a percent of warning letters from 2019 to 2023

Top 25 codes extracted from warning letters, sorted by rank based on the 2020 volume, with each subsequent year stacked accordingly

Top 25 codes graphed as a ratio of the total count of each code to the total number of warning letters issued per year from 2020 to 2023