Over-the-Counter Drugs: Regulatory Analysis of Warning Letters Between Fiscal Years 2015–2019

Abstract

Background

According to 21 Code of Federal Regulation (CFR) Part 211, Over-the-Counter (OTC) drug manufacturers must establish and follow current good manufacturing practices (cGMP) to produce quality products while meeting regulatory standards. The warning letters issued by the U.S. Food and Drug Administration (FDA) reveal quality inadequacies that may impact the safety and effectiveness of these products. This study provides an analysis of warning letters and cited violations to identify the most common areas of quality issues and to understand the FDA’s current thinking on regulatory expectations.

Methods

Warning letters between U.S. fiscal years (FY) 2015–2019 were analyzed by the following steps: extraction of CFR violations, categorization of violations, trend analysis of data, and interpretation of results.

Results

A total of 116 OTC warning letters and for comparison purposes 561 prescription (Rx) warning letters were analyzed in this study. OTC drug violations relating to product and process controls significantly increased, while violations relating to labeling decreased over the years. Despite these changes in violation numbers, the number of violations increased in most categories, highlighting a continual increase of quality inadequacies.

Conclusion

The quality issues are mostly seen in cGMP violations specifically in the drug product, process, and laboratory controls. Most significant violation changes are also seen in drug product and process controls. The overall number of violations in OTC drugs has been increasing in the past 5 years and the analysis results provide a projection for continued increases in violations. Although this study provides an overall quality analysis of OTC warning letters and cited violations, more studies are required to understand the risk to consumers using OTC drug products due to the trends associated with these observations.

Introduction

In recent years, a modernization of Over-the-Counter (OTC) drug regulations has been initiated to assess emerging safety issues and to accommodate drug innovation [1]. Due to the expansion of scientific innovation, current OTC drugs have become more challenging to review and regulate with the initial OTC drug regulation system [1]. This regulatory gap between the OTC drug regulation and currently marketed products is seen through the violations captured in issued warning letters. Many violations related to current good manufacturing practices (cGMP), labeling, and quality controls are reported in the warning letters. Understanding these violations and assessing quality inadequacies from the OTC drug manufacturers are critical because they can highlight safety and effectiveness issues that may negatively impact OTC drug consumers. The identification and analysis of violations also gives critical insight on the FDA’s current thinking in the implementation of drug regulations and provides suggestions to OTC manufacturers for strengthening their quality systems to produce safe and effective OTC drugs.

Overview of the Over-the-Counter Drugs

Over-the-Counter (OTC) drugs, also known as nonprescription drugs, are drugs that are found to be safe and effective for direct consumer usage. OTC drugs are available without a prescription and there are more than 300,000 OTC products marketed in the United States [2]. An average of 60,000 products are sold each year covering more than 80 therapeutic categories including acne, analgesics, heartburn, sleeping aids, and allergy.

According to the FDA’s Office of Non-Prescription Drugs (ONPD), the benefits of OTC drugs include low potential for misuse and abuse, greater weight of benefits versus risks, ease of self-diagnosis, adequacy in labeling, and availability of safe and effective drug products without a health professional [3]. The availability of OTC drugs also leads to savings of $146 billion each year for the U.S. Healthcare system [4]. The price difference between OTC drugs and Rx drugs and unrequired clinical visits to buy OTC drugs are the primary reasons for these savings [4]. These characteristics reflect how OTC drugs play a vital role in today’s health care system.

OTC Drug Monograph

The OTC drug monograph is the regulatory standard published in the Federal Register for OTC drugs [5]. It is a “recipe book” that covers categories of acceptable active ingredients, formulations, indications of use, doses, and labeling of OTC products. The drug is considered Generally Recognized As Safe and Effective (GRASE) and not misbranded once it is manufactured in compliance with the final monograph. Any marketed drug not manufactured in accordance with the requirements of the OTC drug monograph is considered a “new drug” [6]. The OTC drug monograph and the general GRASE requirements for OTC drugs can be found in 21 Code of Federal Regulation (CFR) Part 330 [7]. For each monograph, the GRASE active ingredients including dosage strength and form are listed. Specific labeling requirements such as indications, warnings, and directions for use are also listed within the monograph.

NDA vs OTC Drug Monograph

Any OTC drug that does not meet monograph requirements is considered a “new drug” and requires a New Drug Application (NDA) to be marketed [8, 9]. The NDA was created by the Federal Drug and Cosmetic (FD&C) Act in 1938 to ensure the safety and effectiveness of OTC drugs. The extensive amount of data such as pre-clinical and clinical results, identification of active ingredients and materials, studies on the drug’s impact on the body, and plans of manufacturing, processing, and packaging are required in an NDA [9].

One of the significant differences between the NDA process and an OTC drug monograph is the requirement for pre-market approval. Because the ingredients listed in the final monograph have been previously reviewed and considered GRASE, any additional review for the drugs within an OTC drug monograph is unnecessary. With this, the general process timeline (from the development of the OTC drug to its availability to the market) of an OTC drug monograph is significantly shorter than an Rx-to-OTC Switch, thus giving incentives to OTC drug manufacturers to follow the OTC drug monograph for production [10].

OTC drugs also differ from Rx drugs in their post-marketing surveillance requirements. For Rx drugs, the Office of Surveillance and Epidemiology (OSE) maintains post-marketing surveillance systems to identify adverse events for already marketed products. The requirements on post-marketing reporting of adverse drug experience is defined in 21 CFR 214.80 [11]. For OTC drugs, however, the regulation relating to post-marketing requirements is not clearly defined in the CFR and adverse event reporting is not required for OTC drugs subject to monographs. This indicates the difference in the pharmacovigilance expectations between OTC and Rx drugs.

Labeling requirements for OTC drugs are included within the OTC drug monograph (21 CFR 330–355). The general format and content requirements such as drug facts, uses, warnings, and directions are included in 21 CFR 201.60 [12]. Unlike OTC drugs, the labeling for Rx drugs are reviewed and approved during the NDA process. More extensive information is needed for Rx drugs as a pre-approval labeling requirement due to the uncertainty of safety and effectiveness of the new drug. Most labeling violations for Rx drugs are related to misprint of labels on primary packaging or container closure system. The voluntary recalls due this type of mislabeling are announced to the public through FDA’s MedWatch: Safety Information and Adverse Event Reporting Program [13]. The labeling requirements for Rx drugs are covered in 21 CFR 201.50 (Subpart B) include but not limited to prescribing information, use in a specific population, risk summary, and pre-clinical and clinical studies [14].

Warning Letters

Warning letters are issued by the U.S. Food and Drug Administration (FDA) to notify of significant regulatory violations of the FD&C Act made by manufacturers [15]. The warning letter is important because it identifies the need for prompt corrective action and gives the opportunity for drug manufacturers to take voluntary actions before enforcement action is initiated [15]. Enforcement action includes recalls, seizures, injunctions, administrative detention, and civil monetary penalties [16].

Before the issuance of the warning letter, an inspection is conducted by the FDA investigator. Any observations made during the inspection are recorded in the FDA Form 483 [17]. Specific inspections and enforcement actions can also be found in the FDA’s Data Dashboard [18]. Once the manufacturers receive the Form 483, they are encouraged to respond to the FDA with the appropriate corrective action plan within 15 working days [19]. If this requirement is unmet due to unresponsiveness or an insufficient response, a warning letter is issued as an escalation from the 483 [17]. The warning letter is far more serious than a Form 483 and the manufacturer’s implementation of corrective action is required by law.

Materials and Methods

To identify and evaluate quality inadequacies in OTC drugs, this study incorporated the following steps: extraction of CFR violations, categorization of violations, trend analysis of data, and interpretation of results. To carry out these steps, a regulatory database was created by obtaining all OTC drug specific warning letters. Currently the only publicly available warning letters from the U.S. FDA warning letter site cover fiscal years 2015 to 2019 [20]. A total of 116 OTC drug warning letters were issued by the FDA during these years. Cited CFR regulations, observations from the inspections, and general product information was extracted from these warning letters.

Violations with similar themes were categorized into four major categories (quality unit, labeling, drug product and process controls, and laboratory controls) by the specific CFR associated with each category. Each category was further dissected into violation groups by the frequency of violations made each year. A database containing all of this information can be found in Supplemental Materials. The trend analysis was performed by converting violation frequencies into percentages and by comparing results between the years within each category.

A total of 561 Rx warning letters were also collected and violations were extracted to compare the quality inadequacies between OTC and Rx drugs [20]. Three out of four of the same violation categories were used for Rx drugs to make appropriate comparisons between the two groups. Due to the difference in labeling requirements for Rx drugs, the evaluation of Rx drug labeling violations was omitted from this study.

Results

A total of 116 OTC warning letters were analyzed in this study. Starting from FY 2015 to 2019, the number of warning letters were 5, 11, 26, 39, and 35, respectively. A total of 561 Rx warning letters were collected to make a comparison to the number of OTC warning letters. The number of Rx warning letters from FY 2015 to 2019 was 73, 142, 136, 109, and 101, respectively. A gradual increase then slight decrease from FY 2018 is seen in OTC warning letters while a gradual decrease starting from FY 2016 is seen in Rx warning letters. The overall comparison is shown in Fig. 1.

Fig. 1.

Number of warning letters FY2015–FY2019

A total number of 556 violations were cited within the 116 OTC warning letters collected for this study. From FY 2015 to 2019, the number of violations was 22, 24, 118, 185, and 204, respectively. A total number of 4163 violations were counted within the 561 Rx warning letters. From FY 2015 to 2019, the number of Rx drug violations was 1036, 1023, 835, 684, and 585, respectively. A gradual increase in OTC violations is seen over the past 5 years while a gradual decrease is seen in Rx violations. The overall comparison is shown in Fig. 2.

Fig. 2.

Number of violations FY2015–FY2019

According to the FDA, the Office of Pharmaceutical Quality (OPQ) initiated a program with CDER in FY2017 to provide “One Quality Voice” regarding facility evaluation and inspections [21]. This program improved the inspection coverage to ensure quality of manufacturing processes of OTC drugs and aimed to inspect all previously uninspected sites by the end of FY2019 [21]. It can be predicted that both the shift in the FDA’s thinking on quality expectations as well as the execution of inspection focus are the reasons for these results.

Violations by Category

Violations pertaining to each category were evaluated to make further comparisons between OTC and Rx drugs. Violation categories from each year were calculated into a percentage to display the relative proportions to the total number of violations. For Rx drugs, the labeling category was excluded from this analysis due to the difference in labeling requirements from OTC drugs. The categorical analysis is shown in Figs. 3, 4, 5, 6, and 7. The table including the violation counts is provided in Supplemental Table 1.

Fig. 3.

FY2015 violations by category

Fig. 4.

FY2016 violations by category

Fig. 5.

FY 2017 violations by category

Fig. 6.

FY 2018 violations by category

Fig. 7.

FY 2019 violations by category

Overall, the OTC drug violations from each category greatly varied each year while Rx drug violations generally stayed consistent. Out of 4 categories, the labeling category and drug product and process controls category showed the greatest proportional change with 25% decrease and 37% increase, respectively.

OTC Violation Category Trend Analysis

A trend analysis of OTC drug violations was done to examine the past performance of the OTC manufacturers and to identify patterns to predict FDA’s regulatory expectations. The overall trend analysis is shown in Fig. 8.

Fig. 8.

OTC trend analysis

As previously mentioned in the overall violation results section, the overall number of violations in OTC drugs gradually increased from FY2015 to FY2018. While the greatest increase in violation categories (drug and product and process controls and laboratory controls) occurred between FY2016 and FY2017, the greatest decrease (labeling) also occurred during those years. The separation of points (FY2018) also indicated that the number of violations in each category significantly differed from previous years. Based on trending points in FY2019, it can be predicted that violations in 2 out of 4 violation categories (laboratory controls and general quality violations) may continue to increase in FY2020.

OTC Violation Group Analysis

More extensive analysis was done to further identify specific violations relating to each category. These specific violations were sorted into violation groups and the violation differences between the fiscal years were observed. The group analysis is shown in Figs. 9, 10, 11, and 12. The table including the violation counts is provided in Supplemental Table 1.

Fig. 9.

OTC general quality

Fig. 10.

OTC labeling

Fig. 11.

OTC drug product and process controls

Fig. 12.

Laboratory controls

A total of 106 general quality violations were cited in OTC warning letters from FY2015 to FY2019. Out of 106 violations, most cited violations were related to electronic record (VG6; 27 violations; 25%) with greatest increase (2 to 14 violations) occurring between FY2017 and FY2019. The least cited violations were related to approving and rejecting procedures or specifications (VG3; 1 violation; 1%).

A total of 72 labeling violations were cited within the warning letters and most violations were related to misbranding of the OTC drugs (VG3; 21 violations; 29%). The greatest increase (4 to 12 violations) also occurred in this group between FY 2018 and FY 2019. The least amount of violations was related to expiration date issues (VG4; 8 violations; 11%) with no violations cited in FY 2018.

A total of 196 drug product and process control violations were cited within the warning letters and most violations were related to failure of component verifications (VG2; 62 violations; 32%) with the greatest increase in violations (7 to 29 violations) occurred between FY2017 and FY2018. The least cited violations for this category were failure to make an appropriate report for deviation procedures (VG5; 10 violations; 5%). This category also contained the largest number of violations (n = 196) compared to other categories. These results indicated that most changes in violations occurred in drug product and process controls.

A total of 179 laboratory control violations were cited within the OTC warning letters and most-cited violations were related to lack of a stability program (VG2; 69 violations; 39%). The greatest increase (11 to 26 violations) also occurred in this group between FY2018 and FY 2019. The least number of cited violations were related to laboratory controls involved in packaging and labeling operations (VG3; 2 violations; 1%).

Discussion

Examining the differences in quality issues involved in both drug types is critical to understand the regulatory expectations of ensuring the safety and effectiveness of these drugs. Due to the difference in the market approval process for OTC and Rx drugs, the violations seen within the warning letters also varied greatly. Each violation category for Rx drugs generally stayed consistent during the FY 2015–2019. More than 50% of these violations were related to laboratory controls while more than 20% of violations were related to drug product and process controls each year. The rest of the violations (average of 14%) were related to general quality issues. According to the FDA, the quality control laboratory serves as one of the most important functions in pharmaceutical production and control [22]. It is important for manufacturers to set appropriate laboratory controls as any out-of-specification results from laboratory errors can lead to product failures, which can impact the quality of the drug product [22]. Therefore, this higher number of laboratory control violations indicates that the FDA’s expectations of manufacturers meeting laboratory control requirements are critical.

Unlike Rx drugs, each violation category showed notable differences in OTC drugs. Over the years, the number of drug product and process control violations increased significantly reaching 45% (from 8%) in FY 2018. While laboratory control violations and general quality violations stayed consistent (average of 20% to 30%), the labeling violations decreased significantly from 32 to 7%. These results are interesting because the increasing violations reflect the need for fundamental cGMP compliance for OTC manufacturers. Setting the appropriate production and process controls during the manufacturing process is important because it helps manufacturers to increase their ability to produce products repeatedly and reproducibly while meeting quality standards [23]. It is evident that there is an increasing emphasis on the regulation of production and process controls for OTC drugs.

General Quality Violations

General quality violations were issued to OTC manufacturers for violations that are not specifically related to manufacturing operations. Out of all violations, 19% (n = 106) of these violations were related to general quality issues. Among the six violation groups, violations relating to electronic records had the greatest increase. With the advancement of technology in recent years, the FDA’s intent on a narrow interpretation of 21 CFR Part 11 was announced through the Guidance Document for Electronic Records. While this regulation clarified previous confusion regarding the usage of the electronic record, the FDA’s exercise of enforcement on record regulations increased [24]. This may have been the reason for the increasing number of violations in the electronic records group. As OTC manufacturers adopt this new technology, it is the manufacturer’s responsibility to set critical controls that meet the FDA’s quality standards guidelines.

Other violation groups such as the quality control unit, general written procedures, records, and reports, and cleaning, sanitizing and maintenance showed consistency in violations with 24%, 21%, and 23%, respectively. These results showed that there is a lack of fundamental cGMP understanding in OTC manufacturers and this recognition is critical as cGMP is the main regulatory standard for ensuring pharmaceutical quality [25]. The strict adherence to cGMPs is important not only during the production of the drug but also during the building of quality systems to assure the safety and effectiveness of drug products.

Labeling Violations

For OTC drug manufacturers, following the standardized format for OTC labeling is critical due to its direct availability to the consumers. Since OTC labeling is intended for safe and effective usage of OTC drugs, it must contain accurate information [26]. Previous studies by Aikin et al. and Chatterjee et al. also highlighted this importance with results suggesting that overstatement of efficacy and omission of risk claims can affect viewer perception of the drug’s efficacy, risks, and benefits [27, 28].

In our study, misbranding of the product was most common (29%) compared to other violation groups and showed a significant difference between the years. Often, these misbranding violations included OTC labels making therapeutic claims without any scientific support. The OTC monograph specific violations were cited along with the unapproved new drug violations. The monograph contains GRASE ingredients and any deviations from the monograph classify the OTC drug as an unapproved new drug. This correlation was supported by a similar number of violations cited for both violation group (14 unapproved new drug violations; 13 monograph specific violations).

Drug Product and Process Control Violations

The violation category related to drug product and process controls contained the most violations when compared to other categories (35% n = 196). Within this category, most of the violations were specifically related to material component verification. According to 21 CFR 211.84, the OTC manufacturers are required to conduct a test to verify the identity of each component of the drug product. This is required to ensure the material components’ conformity with specifications for purity, strength, and quality. Based on the results of this study, there is an increase in observations of materials used by OTC manufacturers that do not meet quality standards. Even though it is difficult to accurately determine the overall quality level of currently marketed OTC drug products, the increased number of observations of lack of quality systems regarding material verifications is concerning.

Our study results also indicated a lack of representative sampling (24%) of OTC drug products. Determining a representative sample is critical since it is intended to portray the overall quality of the batch produced. It is also important for OTC manufacturers to test appropriate representative samples for approval and rejection of the products [29].

The number of violations varied greatly in four out of six groups (representative sample, component verification, control procedures and validation, and procedures for deviations) in this category. A significant decrease was seen in procedures for deviations and control procedures and validation groups while a significant increase was seen in representative sample and component verification. This result indicated that out of four categories, most quality inadequacies are present in drug product and process controls.

Laboratory Control Violations

Thirty-two percent (n = 176) of all OTC violations were related to the laboratory control category and most of these violations were due to the lack of a stability program. The stability program is an essential requirement of cGMP because it determines the expiration date and storage conditions for the drug product [30]. The shelf-life duration and expiration dates must be supported by the stability testing results and it is the OTC manufacturer’s responsibility to establish the appropriate stability program for the product. However, our study results indicate that a significant number of current OTC manufacturers do not have appropriate stability programs in place. Compared to other violation groups, VG1 (testing and releasing for distribution) contained the second most violations (25%). Inspections found that some OTC manufacturers released lots before proper testing for distribution. This final testing before release is critical to identify any deviations and to make an investigation on those deviations. The gradual increase in number of violations indicated that a number of current OTC manufacturers also do not meet laboratory controls for this group.

Conclusion

This study provides insight into the quality inadequacies relating to current marketed OTC drugs through the evaluations of warning letters issued by the FDA. The results from this study indicate that significant quality inadequacies have been observed in OTC drugs. The quality issues are mostly seen in cGMP violations specifically in the drug product, process, and laboratory controls. Most significant violation changes are also seen in drug product and process controls. The overall number of violations in OTC drugs has been increasing in the past 5 years and the analysis results provide a projection for continued increases in violations unless OTC manufacturers move to address these issues.

Different regulatory and pharmacovigilance expectations in quality system are seen through regulation differences between OTC and Rx drugs. More specifically, the changes in quality expectations of OTC drugs are seen through the increased number of inspections by the FDA. While this study provides an overall quality analysis of OTC warning letters and cited violations, more studies should be conducted to understand the risk to consumers using OTC drug products due to the trends associated with these observations.