FDA Domestic and Foreign Oversight Protocols and Violation Responses

April 12, 2023 - The United States Food and Drug Administration (FDA) has been criticized repeatedly for shortcomings and flaws in its oversight protocols. Understanding the current regulations that the FDA follows for assessing drug manufacturing facilities and its response to violations may provide insight into areas for improvement and further evaluation.

Although the FDA uses information from other organizations, such as the US Pharmacopeia (USP), the regulations have not managed to catch all flaws, leading to many complications. In addition to the expenses associated with improper oversight, cracks in the oversight procedures can contribute to recalls, drug shortages, patient fatalities, and more.

Recent Insight into Manufacturing Process Oversight

Recent recalls of eyedrops across the US have prompted FDA officials to evaluate manufacturing facilities and their sterility. The recalls include artificial tears from Global Pharma Healthcare, ophthalmic solutions from Apotex Corp, and soothing drops manufactured by Pharmedica USA.

These recalls were triggered by a CDC investigation into Pseudomonas aeruginosa, an ocular infection that causes ocular discharge, eye pain, redness, foreign body sensation, and other symptoms. Some infections throughout this outbreak led to enucleation and permanent blindness.

In light of these recalls — and that most of them were likely byproducts of manufacturing flaws — the FDA inspected the Global Pharma facilities in India, citing ten violations, including incomplete sterilization processes. Further information from the FDA revealed that there were cracks and scratches in rooms that were supposed to be sterile, unestablished test methods, inappropriate use of equipment, inadequate cleaning, and unkempt records, among others.

The jaw-dropping inspection littered with manufacturing violations and adulteration has left many wondering what’s next. How will the FDA respond to these violations? What can be done to prevent breaches to this extent? Evaluating the current global and domestic oversight procedures is essential to answer these questions.

Understanding the FDA’s Role

The FDA is a complex organization responsible for monitoring prescription drugs, pharmaceutical quality, operating procedures, and collaborating with other government health organizations, including the HHS and CDC, for managing public health concerns.

Although it is more known for regulating and approving drug products based on data from clinical trials, the FDA is also responsible for monitoring food, cosmetics, biological products (managed by the Center for Biologics Evaluation and Research), veterinary medicine, and more.

The Federal Food, Drug, and Cosmetic Act of 1938 is a component of the Code of Federal Regulations (CFR), authorizing the FDA to evaluate all FDA-regulated products and continue overseeing manufacturing practices even after a drug has an approved application.

While multiple FDA guidance documents detail the protocols its Office of Compliance follows for regulation, the FDA has received repeated criticism for its lack of quality oversight. Exploring the protocols to ensure product quality after market approval is critical to understanding the recall process and the consequences of violating the protocols.

A congressional testimony delivered on June 1, 2020, by Judith A. McMeekin, PharmD, Associate Commissioner for Regulatory Affairs, before the United States Senate Committee on Finance, detailed the FDA oversight process for foreign manufacturing companies.

According to the testimony, “FDA laboratories test for drug quality, using testing standards set by the United States Pharmacopeia, or standards submitted in marketing applications, or methods developed by FDA.”

Data from the FDA Center for Drug Evaluation and Research (CDER) Site Catalog notes that as of May 2020, only 26% of active pharmaceutical ingredient (API) manufacturing for the US human drug market is done domestically. Additionally, only 46% of the finished dosage form (FDF), or finished product form, manufacturing of human drugs was in the US as of 2020.

As a result of expanded global manufacturing, the FDA had to adapt its analysis of pharmaceutical production to globalize its drug inspection program.

“For drugs that are not subject to premarket approval requirements, manufacturers may not be subject to FDA inspection before such products are shipped to or distributed in the US,” stated McMeekin in the testimony.

While the FDA has the authority to conduct a premarket evaluation of any foreign prescription drugs through New Drug Applications (NDAs) and other prescription drugs, the organization cannot preemptively evaluate other foreign products. Among the products not subject to premarket approval are supplements, OTC monographs, and APIs used for pharmaceutical compounding.

“FDA may be required to engage in more challenging and resource-intensive efforts to identify and respond to any problems that arise subsequently; however, patients may have already been exposed to the drugs,” added McMeekin.

FDA Inspections

The testimony delivered by McMeekin divided global and domestic inspections into three categories: pre-approval, surveillance, and for-cause inspections. While the protocols may differ slightly depending on the facility's type, location, and management systems, the general premise is the same.

McMeekin says pre-approval inspections are “conducted as part of the review of an application to market a new brand or generic drug.”

Once a facility has been approved, the FDA is authorized to conduct regular surveillance inspections to monitor the process and quality of manufacturing, ensuring that it follows current good manufacturing practices (CGMP). According to the testimony, domestic inspections are often unannounced.

Conversely, foreign inspections are often announced in advance “partly due to logistics such as arranging travel and access to facilities, securing visas, and partly because of the high costs of conducting foreign inspections.” While McMeekin clarifies that announcements vary depending on the facility and its history of unapproved practices, scheduled inspections are less likely to provide a comprehensive and accurate evaluation of the facility.

When a manufacturer has the opportunity to prepare for an inspection, they will likely put extra time and effort into maintaining or creating the illusion of following CGMP requirements, leading to potentially false analyses.

The final category of inspections is for-cause inspections, initiated when the FDA identifies or receives a report of manufacturing violations, including a deviation from CGMP regulations. These can be announced or unannounced but are intended to collect additional information on the potential violation.

Despite the protocols and guidelines in place, a 2016 report identified nearly 1,000 foreign manufacturing facilities that had never been inspected. Although these flaws have been corrected, they indicate a more significant oversight issue at the FDA.

FDA Import Program

The FDA Import Program regulates and enforces actions by international manufacturers who import products into the US.

While the FDA cannot necessarily monitor all components of manufacturing internationally, once a product enters the US, the organization has the authority to evaluate it, even after it is incorporated into the domestic market.

By importing products under FDA jurisdiction into the US, international manufacturers enter a contract with the FDA, authorizing it to examine or collect samples from products to test for safety. The FDA has jurisdiction over inspecting a product’s label or conducting a field examination. Additionally, they can collect samples for testing and analysis in FDA labs.

Inspection Classifications

Once an inspection has been completed, FDA officials can classify the check as no action indicated, voluntary action indicated, or official action indicated.

No action indicated (NAI) implies a quality system and facility. In other words, the facility passed the inspection without any significant problems that warrant further action. Voluntary action indicated (VAI) is a classification for facilities with some complications but nothing leading the FDA to enforce administrative or regulatory changes. Finally, official action indicated (OAI) suggests an inspection failure in which regulatory or administrative actions are recommended and must be taken.

Data from an FDA evaluation of foreign and domestic inspection outcomes found that 93% of inspections in the US yielded NAI or VAI outcomes, considered acceptable outcomes. Comparatively, 98% of European Union (EU) inspections were satisfactory. Chinese and Indian manufacturing inspections were adequate 91% and 86% of the time, respectively. Global manufacturing inspections in other parts of the world pass roughly 91% of the time.

What Happens When a Facility Fails Inspection?

When a manufacturer receives an OAI outcome, they may be subject to multiple regulatory actions by the FDA. In addition to the warning letters, injunctions, and seizures for domestic manufacturers who receive an OAI outcome, international manufacturers with an OAI may receive an import alert.

Warning Letters

One of the most common ways the FDA issues notices regarding violated regulations is through warning letters. Generally, FDA Warning Letters are sent to manufacturers after a violation is found or reported to identify the error, emphasize the need for correction, and provide directions and a timeframe for planning revisions.

According to the FDA, companies are expected to run their correction plans by the organization to ensure adequate corrections. The organization also monitors the changes until they have returned to the appropriate standards.

The FDA also issues other warning letters, including drug marketing, advertising, and close-out letters. The Close-Out Letter Program is sent out after the FDA has completed its evaluation and the appropriate corrections have been made.

“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,” said the FDA website.

Detaining International Products

Beyond examining or analyzing the safety and efficacy of a particular product, the FDA is licensed to detain and conduct hearing on products as they see fit. Any product that violates FDA laws and guidelines, including contamination, safety issues, misbranding, manufacturing under unsanitary conditions, and items restricted for sale, can be detained.

Once a product is detained, the responsible party is issued a notice regarding a hearing. Throughout the hearing, the FDA and the manufacturer will provide evidence or testimony of product safety. An FDA compliance officer will be required to decide on the product.

Import Alerts and Import Refusals

The FDA may also issue an import alert, in which global products are detained without a physical examination due to a history of violations and noncompliance. Import alerts help prevent products that violate FDA standards from being distributed in the US.

Taking import alerts one step further, FDA officials also can issue import refusals if a product does not meet the appropriate standards.

Injunctions

Domestically, FDA officials have a more significant hand in regulating and enforcing standards across multiple products. According to the FDA website, beyond issuing warning letters, it can also conduct seizures of contaminated or misbranded products to remove them from the market.

Depending on the extent of the violation and previous actions, the FDA may also request an injunction from the court to prevent the manufacturer or company from future violations.

Criminal Prosecution

Some violations may be subject to criminal prosecution, as Section 301 of the Federal Food, Drug, and Cosmetics Act clarifies. Misdemeanor convictions may apply to unintentional violations, resulting in fines or up to one year of imprisonment. The maximum penalties may be as expensive as $500,000. Furthermore, intentional violations may be considered felony offenses, with fines and up to three years of prison.

The general guidelines for maximum fines are listed below:

• $100,000 for a misdemeanor by an individual that does not result in death
• $2000,000 for a misdemeanor by a corporation that does not result in death
• $250,000 for a felony by an individual or a misdemeanor by an individual that results in death
• $500,000 for a felony by a corporation or a misdemeanor by a corporation that results in death

Although it is unclear what repercussions Global Pharma will face, the flaws have illuminated the need for more FDA oversight and additional regulatory measures to prevent future public health issues.