INTRODUCTION:

The United States Food and Drug Administration (USFDA) is a federal agency of the Department of Health and Human Services. The Food and Drug Administration is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation's food supply, cosmetics, and products that emit radiation. All over the world, the USFDA is known as the most stringent and efficient pharmaceutical regulatory authority. The FDA also has responsibility for regulating the manufacturing, marketing, and distribution of tobacco products to protect public health and to reduce tobacco use by minors.¹

The FDA also plays a significant role in the nation's counterterrorism capability. Many warning letters are issued in the reference of impurities found in drugs.²

Federal regulation of drugs came into being as early as 1848. With the addition of new laws, federal public health protection was formed in 1906.³

To gain approval, a pharmaceutical company must undergo multiple inspections and audits by the FDA, which are generally very demanding in nature. FDA inspections are conducted for four reasons: (1) Pre-approval inspection (PAI) prior to drug product approval;⁴ (2) routine cGMP inspection; (3) post-approval and surveillance; and (4) cause audit. During an inspection, if any non-compliance is observed, the investigator issues the non-compliance observation on form-483 (Objectionable conditions cited by the FDA on Form No. 483) and that is why the observations are popularly known as 483 observations.⁵Within 15 business days, the manufacturer must respond, explaining the reason for the noncompliance, the impact on product quality, and the appropriate corrective action taken to avoid recurrence. If the response is not satisfactory, non-compliance observations are critical in nature, having a direct impact on product quality, patient safety, and data integrity, the FDA issues alert letters to the manufacturers. This letter is known as a “Warning Letter” (WL).^6,7

A “Warning Letter” is an official message or notification from the US FDA to a manufacturer or other organization that has violated some rule in regulatory activity. The purpose of a warning letter is to make it clear to the recipient that they must take the necessary corrective actions required to get to the root of the problems and thus rectify them. The FDA also provides some directions, guidance, and a time frame for the recipient to formulate a plan to take the necessary corrective actions and inform the FDA of these plans. After the FDA completes an evaluation of the corrective actions executed by the company, it may issue a close-out letter to the company. The adequacy of the corrective actions undertaken by the company is judged by a follow up inspection by the same office that sent the warning letter in the first place.⁸

As the issuance of a warning letter can harm the reputation of a company, the FDA must be sure before issuing a warning letter. To determine whether a warning letter must be issued, center officials and program office directors generally consider the following factors:

· Evidence discovered, or observations confirming, that a company, product (s), or individual violates a regulation or law, such that failure to take adequate and prompt corrective action may result in FDA enforcement action.

· The observed violation (s) is/are deemed to be of significant regulatory significance.

· The issuance of a warning letter is appropriate and in incompliance with FDA’s policy, as mentioned in Compliance Policy Guides.

· There are reasonable expectations that the recipient will take prompt and appropriate corrective actions. This study was carried out to determine the number of warning letters issued to Indian pharmaceutical companies and analyse differences in the types and nature of violations.⁸

1. Introduction of Inspection:^9,10

The FDA conducts inspections and surveys of controlled establishments to determine if businesses are following all relevant regulations and laws. The FDA conducts border inspections of production facilities, clinical testing locations, laboratories that perform animal or microorganism tests, and import controlled goods. Inspections are also conducted at foreign facilities that produce or process FDA goods for export to the United States. For any of the following purposes, inspections may be carried out as follows:

· Pre-authorization inspections

· Post-approval inspections

· Routine inspections

· For cause inspections

· Follow–up inspections

· Form 483

2. Overview of Warning Letter Process:¹⁰

The process of a warning Letter starts with inspections by companies or FDA investigations. After the company has been inspected, the inspector will submit the inspection comments on form 483 to the firm and forward the establishment inspection report (EIR) to the FDA, which will be checked and forwarded to the company. The official action indicated regulatory/administrative steps in the EIR is illustrated in Figure 1, which could be shown as a Warning Letter.

An inquiry is essentially a data collection operation. Complaint inquiries, health fraud investigations, substance tampering investigations, and catastrophe investigations are all examples of FDA investigations. Investigations differ from inspections in that no Form 482, or notice of inspection, is normally given.

2.1 Warning Letter Process:

Figure 1. FDA Processes to a warning letter

2.2 Types of Warning Letter: ¹¹

· General FDA Warning Letters

· Tobacco Retail Warning Letters

· Drug Marketing and Advertising Warning Letters (and Untitled Letters to Pharmaceutical Companies)

· Warning Letter Close-Out Letter Program (applies to letters issued on or after Sept. 1, 2009)

4. Method:

The objective of this article is to know the types of warning letters issued and to know the major violations in case of drugs from warning letters.

4.1 Data Collection:

Data were collected from the warning letters available on the FDA’s public database.

The “Search and Export Warning Letters to Excel” function was used to download an Excel Spreadsheet containing all the warning letters issued from 2019 to 2021. Letters were screened manually.

4.2 Determination of Variables:

The gathered data were analyzed based on the following variables:

· Dates on which the warning letters were issued

· Company name

· Issuing office

· Number of violations

· Subject of warning letter

· Nature of violation

4.3 Data Entry:¹²

Data from the warning letters were segregated according to the following determined variables.

Sample size:

All the warning letters issued from January 2019 to August 2021 are attached. Publicly available FDA letters sent to pharmaceutical companies from 2019 to 2021 were reviewed. The total number of warning letters issued from January 2019 to August 2021, was 1569.

The total number of warning letters issued in 2019, was 483.

The total number of warning letters issued in 2020, was 633.

The total number of warning letters issued in 2021 till August month, was 453.

A total of 1569 warning letters were reviewed from January 2019 to August 2021 and out of which 678 were related to drugs and pharmaceuticals.

4.4 Sample Inclusion and Exclusion Criteria:¹²

Only Warning letters related to Drugs were included in the sample. Warning Letter related to Food, Tobacco, Medical Devices, and cosmetics were excluded.

Table 1: Sample size distribution from 2019 to 2021

Year	Total Warning Letters	Warning Letters Related to Drug
2019	483	218
2020	633	304
2021 (Till August)	453	156

5. RESULT AND DISCUSSION:

A total of 1569 warning letters were issued to pharmaceutical companies from 2019 to 2021. Of those 678 warning letters were issued related to drugs. A fluctuating trend of increase and decrease in the total number of warning letters related to drugs issued from 2019 – 2021 can be observed.

Figure 2: % No. of Warning letters in 2019 to 2021

5.1 Warning Letter – Country wise:

Figure 3: Warning Letter – country wise (2019)

From Figure 3, it is observed that the United States (168), India (20), and China (13) were issued the most warning letters by the US FDA in 2019. Followed by Canada (3), Singapore (2), South Korea (2), Australia (2), Ireland (1), Spain (1), France (1), Taiwan (1), Turkey (1), Costa Rica (1), Bahamas (1), and Trinidad and Tobago (1) have the least number of warning letters issued by the US FDA in 2019.

Figure 4: Warning Letter – Country wise (2020)

From Figure 4, it is observed that the United States (232), India (16), China (13), Canada (9), and Mexico (15) were issued the most warning letters by the US FDA in 2020. Followed by South Korea (3), United Kingdom (3), Germany (1), Denmark (1), Ireland (1), Bulgaria (1), Romania (1), Puerto Rico (1), Israel (1), Japan (1), Singapore (1), Russia (1), Indonesia (1), Pakistan (1), New Zealand (1) have the least number of warning letters issued by US FDA in 2020.

Figure 5: Warning letter – Country wise (2021- Till August month)

From Figure 5, it is observed that the United States (113), Mexico (27), and China (6) were issued the most warning letters by the US FDA in 2021. Followed by Turkey (3), India (2), Canada (2), Colombia (1), Japan (1), and Australia (1) have the least number of warning letters issued by the US FDA in 2021- Till August month.

5.2 Observation cited in warning letters:

All the cited observations in the warning letters from 2019 to 2021 were reviewed and categorized as listed below in Table 2.

Table 2: Observations cited in warning letter (2019-2021)¹³

Nature of Observation	Total number of observations
Poor Quality System	89
Breach of Data Integrity	36
Inadequate Stability Program	51
Inadequate Written Procedure	112
Poor Laboratory Control	21
Poor Production Control	30
Inadequate Cleaning Validation	45
Inadequate Control for Computerized System	15
Inadequate Component Testing	53
Inadequate Testing of Active Ingredient	50
Inadequate Investigation	61
Poor System to Prevent Contamination or Mix-up	18
Failed to Use Equipment	13
Inadequate Laboratory Record Data	16
Inadequate process validation	38

5.3 Subject of warning letters issued by US FDA in 2019- 2021:

Table 3: Subject of Warning Letters in 2019-2021¹³

Subject of Warning letters	Total
Adulterated	290
CGMP for finished pharmaceuticals	159
CGMP for API	21
Misbranded	460
Unapproved	381
Label	181
Cannabidiol (CBD) product	28
Unapproved and Misbranded Opioid	28
False and Misleading claim	9
Deficiencies in practice for producing sterile drug product	46
Compounding pharmacy	43
One New Subjects observed in 2020 and 2021
Unapproved and Misbranded product related to COVID – 19	156

The Food, Drug, and Cosmetic Act, Section 502, lists several reasons why a drug might be misbranded, the most common of which are a false or misleading name, incorrect label contents, prominent label details, insufficient instructions of use, and a notice on the label or misleading container.¹⁰

A medicine is considered adulterated if it contains wholly or in part any dirty, putrid, or decomposed material, according to section 501 of the Food, Drug, and Cosmetic Act. Also, if the processes, equipment, analytical method or controls used in the manufacturing, processing, packaging, or keeping of medication do not adhere to or are not performed under cGMP^14,15 and a quality by design (AQBD).¹⁶Furthermore, whether the drug’s strength varies from, or its consistency or purity falls below, the official compendium’s requirements, or if the drug has been filled with or substituted to minimize its quality or strength.¹⁷Most of the adulterated citations in the topic of warning letters were discovered in 2019, but the number of adulterated citations in the topic of warning letters has decreased since then.¹⁰

The relevance of analytical technique validation and system appropriateness testing is emphasized in several FDA Warning Letters. The US FDA recently visited BBC Group Limited, a medication manufacturing plant in China, from March 22 to March 26, 2021. Significant violations of current good manufacturing practice (cGMP) guidelines for finished pharmaceuticals were discovered during the inspection. One of the issues that was brought up was the validation of analytical test methods.¹⁸ There are numerous warning letters related with impurities identified in the medicine, such as genotoxic impurity, metal impurity, and carcinogenic impurity.^19,20

In the years 2020 and 2021, one new subject – unapproved and misbranded Corona Virus Disease 2019 (COVID–19) products – was observed. During the global outbreak of respiratory disease caused by a novel coronavirus, some websites offered misleading products, product names, product pages, and product packages that claimed to mitigate, prevent, treat, diagnose or cure COVID-19.²¹The US FDA took urgent measures to prevent consumers from purchasing unapproved and misbranded products and issued 128 warning letters in 2020 and 28 warning letters in 2021 till August month to such websites and producers.

Opioid addiction and abuse have resulted in a major public health epidemic in the United States, with a high mortality toll. Tramadol and oxycodone are among the opioids for sale. Consumers face substantial hazards due to the simple availability of opioids on the internet. The US FDA appealed to the websites offering those products to immediately cease the sale in a string of 18 Warning letters issued in 2020 and 3 Warning letters issued in 2021.

Aside from the above-mentioned subjects, the warning letter included minorly specified subjects with ten or fewer citations. Even though violations related to Bioresearch Monitoring, such as protocol noncompliance and insufficient case history information in 2019 to 2021. Only 10 Warning letters were sent to the Clinical Investigation. Due to a failure to meet the milestone date for completion of the Post Marketing Requirement (PMR), only 1 letter was given.

Figure 7: Subject of warning letters issued by US FDA in 2019 to 2021

5.4 21 CFR Part 211 Violations for Drugs and Formulations:

Figure 8: 21 CFR Part 211 Violations for Drugs and Formulations (2019)

From the above figure 8, it is observed that violations of section 211.22 are observed 51 times. It represents the responsibilities of the quality control unit. It says that there the quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. ^22,23

Violation of section 211.165 was observed 46 times. It represents the testing and release for distribution. Violation of section 211.192 was observed 39 times. It represents the Production record review. It says that any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentage established in master production and control records) or the failure of a batch or any of its component to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.

Violation of section 211.100 was observed 38 times. It represents the written procedures. It says that there should be a written procedure for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they are represented to possess. Violation of section 211.67 was observed 27 times. It represents the cleaning validation. Violation of section 211.84 was observed 24 times. It represents testing and approval or rejection of components, drug product containers, and closures.

Figure 9: 21 CFR Part 211 Violations for Drugs and Formulations (2020)

From the above figure 9, it is observed that violations of section 211.22 are observed 24 times. Violation of section 211.84 was observed 23 times. It represents testing and approval or rejection of components, drug product container, and closure. Violation of section 211.165 was observed 22 times. It represents the testing and release for distribution. Violation of section 211.100 was observed 20 times. It represents the Written procedures. It says that there shall be a written procedure for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they are represented to possess.

Violation of section 211.166 was observed 18 times. It represents stability testing. Violation of section 211.192 was observed 18 times. It represents the production record review. Violation of section 211.113 was observed 13 times. It represents Control of Microbial contamination. It says that there must be appropriate written procedures to prevent microbial contamination in the drug product. This procedure shall include validation of all aseptic and sterilization processes. Violation of section 211.42 was observed 13 times. It represents design and construction features. It says any building for production must be a suitable size for proper operations, space for equipment and the areas must be defined to prevent cross-contamination.^22,23

Figure 10: 21 CFR Part 211 Violations for Drugs and Formulations (2021)

From the above figure 10, it is observed that violations of sections 211.165 and 211.166 are observed 9 times. Violation of section 211.84 was observed 7 times, Violation of section 211.22 was observed 6 times. Violation of sections 211.100 and 211.192 was observed 4 times. Violation of section 211.67 was observed 3 times.

In the years 2019 to 2021, violations of sections 312.20, 312.40, 312.60, 312.50, 312.66, 312.57, and 312.62 have been observed for 3, 3, 4, 1, 1, 1, and 1 times, respectively. Section 312.20 represents an investigational new drug application. Section 312.40 represents general requirements for use of an investigational new drug in a clinical investigation. Section 312.60 represents the general responsibilities of investigators. Section 312.66 represents an assurance of IRB review. Section 312.57 represents recordkeeping and record retention. Section 312.62 represents investigator recordkeeping and record retention.

6. Close-Out Letter:

Once the agency has completed an evaluation of corrective actions undertaken by a firm in response to a warning letter, the FDA can issue a warning letter close-out letter, or simply called a close-out letter. A close-out letter may be issued when, based on the FDA’s evaluation, the firm has taken corrective action to address the violations contained in the warning letter.

A close-out letter will not be issued based on representations that some action will or has been taken. The corrective actions must have been made and verified by FDA. Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection. If the warning letter contains violations that by their nature are not correctable, then no close-out letter will be issued.⁹

Just 65 warning letters out of 678 WL have issued close-out letters based on the received close-out response in 2019 to 2021.²⁴

7. CONCLUSION:

The present review article describes what a warning letter (WL) is, Different observations, and violations cited in warning letters from the years 2019 to 2021. China and India received the most FDA warning letters in 2019 after the United States. Mexico received the most warning letters in 2020 and 2021, after the United States. Misbranding, labeling difficulties, the selling of unapproved drugs, and internet marketing with false or misleading claims are the most common violations for online pharmacies. Violations for API, drugs, and formulations include adulteration, misbranding. It also includes a few false or misleading claims. In the years 2020 and 2021, the FDA will concentrate its efforts on prescription medications, such as those associated with the COVID-19 epidemic that were misbranded and sold on the internet without FDA approval. The FDA’s investigations into such products must continue in order to protect the public. A Warning Letter is only a notice; it does not obligate FDA to take any enforcement action and is not required before FDA takes action. A Warning Letter, on the other hand, is not closed out until all of the violations have been resolved, and sending a warning letter close-out letter to the FDA can take years. As a result, it’s better to avoid receiving warning letters. The number of warning letters issued will be reduced if the company corrects the unacceptable conditions during the inspection and replies to form 483s within the time limit and the proper corrections and promised corrections.

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Received on 12.02.2022 Modified on 16.03.2022

Asian J. Pharm. Res. 2022; 12(4):295-301.

DOI: 10.52711/2231-5691.2022.00048