Manipulating data, destroying documents, altering staff training records, retesting samples and only recording those that pass – drug companies have been caught doing all these things.
The only thing stopping them: the element of surprise in the hands of strong regulators. The regulators may still be vigilant, but the pandemic put the brakes on unannounced inspections. Restoring them could save lives.
When prescription drug manufacturing largely migrated to China and India in the 1990s and early 2020s, major regulatory agencies were unprepared for the shift. Instead of inspections, they mostly relied on the manufacturers’ honour system.
Even though 54 percent of finished products and 74 percent of active ingredients were manufactured outside the United States in 2010, the US Food and Drug Administration (FDA) conducted only 440 inspections of offshore factores, compared with 1148 inspections of US factories..
Unannounced inspections continued in the US, but overseas manufacturers were given notice, allowing them time to clean house or alter documents. Regulators worried about international relations and logistical issues such as lining up translators.
The results were less than ideal.
It took a whistleblower to alert the FDA that Ranbaxy Laboratories, one of the largest generic-medicine manufacturers in the world, was allegedly falsifying drug quality data and manufacturing drugs it knew had impurities and would not maintain their expected shelf life. In 2013, with 1600 documented issues, Ranbaxy pled guilty and paid a US$500-million penalty to the US government to resolve false-claims allegations, good-manufacturing-practice violations and making false statements to the FDA. This was nearly a decade after the World Health Organization withdrew three Ranbaxy antiretrovirals due to the appearance of fraudulent data in 2004.The FDA stepped up its oversight in 2007, and by 2019 annual foreign manufacturing inspections were up to 966, shrinking the number of plants never inspected to 16 percent.
But drug manufacturing quality issues persist.
Millions of pills or vials of injectable medication have been recalled because of impurities or contaminants, or issues with product dissolution. Cancer-causing nitrosamines have been found in some commonly used blood pressure (valsartan, losartan, irbesartan), blood-sugar reducer (metformin), acid reducer (ranitidine, nizatidine), smoking cessation (varenicline) and muscle spasm (orphenadrine citrate) products in the US. They get into the products when manufacturers use contaminated solvents and catalysts (agents that drive the chemical reactions needed to produce active ingredients). European and FDA rules call for manufacturers of active ingredients to test for nitrosamines and for manufacturers using these active ingredients to create final products to test them as well. But there can still be a disconnect between the rules and how well the facilities follow them.
One of the major producers of the nitrosamine-contaminated active ingredients valsartan and losartan was Zhejiang Huahai Pharmaceuticals, a company with a history of quality issues. When the FDA inspected the company in 2017, it found the manufacturer had not disclosed that drug batches had failed to meet US quality standards and instead erroneously recorded passing grades.
The pandemic all but shut down inspections of foreign manufacturers, with only three FDA overseas inspections from March 2020 to the end of the year.
Both the European Medicines Agency (EMA) and the FDA have piloted remote inspections to continue providing oversight. In April 2022 the FDA was set to restart more routine foreign inspections, but both the EMA and FDA are looking to retain aspects of their remote inspection process.The EMA is clear that these remote inspections are not a sufficient substitute for in-person inspections.
For the past several years the major regulatory agencies have been collaborating, so that if one inspects a facility, the results are shared and redundancy is reduced.
Meanwhile, FDA laboratory analysis on active ingredients and finished products has occurred at a low level from 2013 and continues to this day (but with no disclosure of findings since 2017). In 2013, just 55 products were analysed for cause (customer or health-professional complaints or adverse events) and 12 were randomly assessed. In 2015 and 2017, the number of products analysed for cause fell to 15 and eight, respectively, while the number randomly sampled increased to 40 and 55.
Much progress has been made from the 1990s to the present in terms of the number of inspections of manufacturing plants in India and China, remote inspections, regulatory cooperation across countries, and the initiation of limited laboratory testing of the products themselves. Many facilities had to be taken offline and revamped to meet quality standards and other companies voluntarily took their facilities offline to pre-emptively revamp them.
But the COVID-19 pandemic has set regulators back in terms of in-person inspections, they need more unannounced inspections, and they need more inspectors who can speak the local language so they are not beholden to the companies to provide them. Greater use of laboratory verification of product quality would also boost the incentive for manufacturers to adhere to quality standards.
(Dr C. Michael White is Distinguished Professor and Chair of Pharmacy Practice at the University of Connecticut. He has written more than 470 published research articles assessing the safety and effectiveness of prescription and over-the-counter drugs, substances of abuse, and dietary supplements, including articles in JAMA, Annals of Internal Medicine and The Lancet.)
