Featured Product
This Week in Quality Digest Live
FDA Compliance Features
Taran March @ Quality Digest
The Olympus CIX100 inspection system enables 21 CFR Part 11 compliance
Wade Schroeder
Gleaning best practices from regulatory standards
Adrian Hernandez
Current manufacturing oversight in the United States and overseas is hampered by staff shortages and limited funding
Del Williams
Tubular cable conveyors can be flushed with water, rinsed, and sanitized without disassembly
Jon Speer
How to do it in real time

More Features

FDA Compliance News
First trial module of learning tool focuses on ISO 9001 and is available now
Free education source for global medical device community
Good quality is adding an average of 11 percent to organizations’ revenue growth
Further enhances change management capabilities
Creates adaptive system for managing product development and post-market quality for devices with software elements
VQIP allows for expedited review and importation for approved applicants that demonstrate safe supply chains
An invite from Alcon Laboratories
Intended to harmonize domestic and international requirements
Pharma quality teams will have performance-oriented objectives as well as regulatory compliance goals

More News

FDA Compliance

The FDA’s Weak Drug Manufacturing Oversight Is a Potentially Deadly Problem

Current manufacturing oversight in the United States and overseas is hampered by staff shortages and limited funding

Published: Wednesday, August 4, 2021 - 12:01

T

he U.S. Food and Drug Administration (FDA) regularly inspects manufacturing facilities to ensure that drugs meet rigorous quality standards. These standards are vital to protect patients from drugs that are incorrectly dosed, contaminated, or ineffective.

But over the past few years, tens of millions of doses of prescription and over-the-counter drugs have failed FDA quality expectations. This includes the ongoing 2018 recall of thousands of batches of popular blood pressure, diabetes, and acid reflux medications containing the probable carcinogen NDMA.

For perspective, the number of individual tablets and capsules for prescription and over-the-counter drugs entering the United States each year is counted in the trillions.

A setback for Johnson & Johnson’s Covid-19 vaccine occurred with the U.S. Food and Drug Administration’s (FDA) order on June 11, 2021, to discard 60 million doses that failed to meet quality and safety guidelines. A Baltimore manufacturing facility run by Emergent BioSolutions had been producing Covid-19 vaccines for both J&J and AstraZeneca, and inadvertently mixed up ingredients from the two companies.

Manufacturers may still backslide while the pandemic continues to put inspections on the back burner. As a pharmacist and physician team investigating drug, device, and dietary supplement safety, we are concerned about the current level of manufacturing oversight in the United States and overseas. To protect consumers, the FDA needs to strike a balance between quickly getting lifesaving drugs out to market and rigorously ensuring their safety.

FDA’s overseas oversight fell under the radar

During the past 30 years, U.S. pharmaceutical companies have laid off tens of thousands of U.S. manufacturing workers and moved their drug manufacturing overseas. The main reasons for this outsourcing include cheaper labor, looser environmental regulations, and less oversight. Meanwhile, pharmaceutical companies in India and China captured a greater share of the U.S. generic drug market. As of May 2020, 74 percent of facilities manufacturing active ingredients and 54 percent of those manufacturing finished drugs for the United States were located overseas.

Until 2007, the FDA focused almost entirely on inspecting U.S.-based manufacturing plants for drug quality. Foreign plants, on the other hand, were on the honor system: The FDA trusted their own internally generated paperwork as proof of compliance.

The folly of this system came to light in 2004, when a whistleblower alerted the FDA that Ranbaxy Corp., one of the largest generic drug companies in the world, was fabricating its drug test reports. Ranbaxy ultimately paid a $500 million fine in 2013 for knowingly producing substandard drugs for the U.S. market since their first FDA approval in 1998.

The drug inspection overhaul of 2007 to 2019

After the Ranbaxy fiasco, the FDA increased foreign manufacturing inspections from 333 in 2007 to 966 in 2019. The proportion of foreign manufacturing plants that had never had an FDA inspection shrank from 64 percent in 2010 to 16 percent in 2019. Of those, the FDA also found that 37 percent didn’t need inspection because they either went out of business, were no longer supplying drugs to the United States, or weren’t selling drugs to the United States in the first place.

As inspections increased, so did the number of serious drug-safety issues that came to light. Dozens of Indian manufacturing facilities were barred from shipping drugs to the United States after the FDA discovered they were manipulating and omitting quality test results and had unsanitary production conditions. Similar findings resulted from inspections of Chinese manufacturing facilities, including the company behind numerous blood pressure drug recalls in 2019.

Decreasing oversight at U.S. manufacturing facilities

One reason the FDA had less oversight of overseas facilities was limited funding. Before the 2012 Generic Drug User Fee Amendment, the FDA was primarily funded by user fees from pharmaceutical, vaccine, and medical device manufacturers. The amendment imposed a $15,000 surcharge on each foreign manufacturing facility to cover the added expense of conducting onsite inspections overseas.

Despite increased inspection funding, the FDA remained stymied by an inability to fill job vacancies for both U.S. and overseas-based inspectors. These vacancies are especially prevalent in India and China, where 33 percent and 30 percent of available overseas-based inspector jobs, respectively, remained unfilled according to the most recent data available, November 2019.

The 2012 FDA Safety and Innovation Act removed the legal requirement to inspect U.S. manufacturing facilities every two years. This was partly so the FDA could shift its domestic workforce to foreign inspections and ensure that all facilities worldwide met the same target criteria. Domestic inspections subsequently decreased from 1,122 in 2007 to just 698 in 2019. Currently, the FDA inspects foreign and domestic manufacturing facilities every five years, or more frequently when serious issues are identified.

Although the decrease in domestic inspections may have given the FDA more bandwidth for foreign oversight, this may have also pressured FDA officials to gloss over quality issues.

For example, the U.S. Office of Special Counsel discovered in March 2021 that FDA administrators had downplayed whistleblower concerns about serious quality issues in U.S. vaccine manufacturing facilities from 2017 to 2018.

Similarly, a 2020 FDA inspection had already identified numerous facility and manufacturing issues in Emergent BioSolution’s Baltimore facility. Had these findings been immediately addressed, cross-contamination with the Johnson & Johnson Covid-19 vaccine would have been less likely. But none of these issues were deemed serious enough to halt production. They were instead allowed to be gradually resolved as production continued.

How has Covid-19 affected foreign inspections?

The gap between foreign and domestic inspections has widened during the course of the Covid-19 pandemic. Because international travel shut down after March 2020, the FDA conducted only three overseas inspections, and 52 in the United States.

The effects of the pandemic on inspections may be long-lasting. As of 2020, 13 percent of foreign manufacturers have never had an inspection since doing business with the United States. Another 17 percent have not been inspected for more than five years. With current staffing levels, it will likely take a long time to remedy the backlog.

What does it all mean for consumers?

Until the FDA has sufficient personnel to conduct rigorous onsite inspections, consumers don’t have many options. Because many states allow or mandate automatic substitution of products the FDA deems bioequivalent, consumers have limited ability to specify which manufacturer’s version they would like to receive at the pharmacy counter.

U.S. consumers can have much more confidence that the drug products they receive today are of higher quality than those from the early 2000s. But the loss of tens of millions of Covid-19 vaccine doses due to poor manufacturing oversight underscores the value of prospective inspections and the risks that reducing domestic inspections pose.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Discuss

About The Authors

Adrian Hernandez’s picture

Adrian Hernandez

Adrian Hernandez is an associate professor of comparative effectiveness and outcomes research at the University of Connecticut.

C. Michael White’s picture

C. Michael White

C. Michael White is a distinguished professor and head of the Department of Pharmacy Practice at the University of Connecticut.