f there is a surefire way to arouse the concerns of Food and Drug Administration inspectors, try this: take a notebook listing manufacturing problems, place it in plastic bags along with other paperwork, and toss them in a nearby scrap yard where the inspectors can find them.
Here’s another approach: leave “unofficial notebooks,” which are used to track manufacturing activities, lying around an office so the inspectors can read how bacteria is present in the water system, but become puzzled when the problem is not cited in official company records.
These were just two of several “serious breaches” of good manufacturing practices the FDA cited in a Dec. 23, 2015, warning letter sent to Cadila Healthcare, one of India’s largest drug makers. The letter followed agency inspections of two manufacturing plants in India between August and December 2014.
What else concerned the FDA?
There were problems with the potency of warfarin made at one plant and Cadila agreed to temporarily suspend production. But after running tests, the company resumed production in November 2014. Yet in June 2015, Cadila acknowledged to the FDA that problems with some lots of warfarin were subsequently found, but had been shipped anyway.
Meanwhile, nine consumer complaints were lodged by way of pharmacies and distributors over potential product mix-ups. But while Cadila conceded some drugs were made on adjacent production lines, the company never completed its investigation. Were mix-ups caused by inadequate cleaning, unsuitable equipment, material flow, or something else? Cadila didn’t know, which made it hard to fix the problem.
There’s more. Several batches of active pharmaceutical ingredients failed an analysis, but Cadila never explored why this occurred. The drug maker also failed to prevent unauthorized access or changes to data. FDA inspectors noted a lab manager could delete data from software and, in fact, one file was deleted. But an audit trail function was never activated and Cadila did not have records of any changes.
For its part, Cadila issued a statement to the Bombay Stock Exchange last week to maintain that it takes “quality and compliance matters very seriously … and is working hard to ensure that the commitments made to the FDA are fully completed.” The drug maker also insisted its products are safe and effective and that no products shipped to the United States are made with ingredients from the plant where the analyses failed.
“This has a theme found in a lot of warning letters, especially warning letters issued to Indian companies,” said Vince Suneja, chief executive of TwoFour Insight Group, a consulting firm that works with Indian drug makers. “There’s a failure to properly investigate problems and a lack of adequate controls for data.”
Indeed, as we have noted previously, this is only the latest instance in which the FDA has scolded an Indian drug maker or ingredients supplier for quality control problems. Over the past several years, in fact, there has been mounting concern over the safety of the pharmaceutical supply chain after the agency cited several companies for production failures.
The most notable example was Ranbaxy Laboratories, which is now owned by Sun Pharmaceutical. The drug maker has been a poster child for manufacturing problems. Last year, Ranbaxy paid a $500 million fine to US authorities as part of a settlement that included pleading guilty to two charges of violating drug safety laws that, for example, involved manipulating data.
Several companies have also been hit with so-called import alerts in which the FDA bans products made at a specific facility. The crackdown, however, has alarmed Indian drug makers. They have complained the FDA has singled them out for especially tough inspections, which occur too frequently and haphazardly, depriving them of the opportunity to make substantive changes.
The ongoing problems prompted several congressional lawmakers last month to ask the US Government Accountability Office to review FDA oversight of foreign manufacturing plants.
Last year, the FDA began considering a new approach to inspecting manufacturing facilities in India. The plan is to “allow our inspectors to document where a firm’s quality management system exceeds what would be required to meet regulatory compliance,” FDA officials wrote in a blog post. “To put it simply: the inspections can yield also carrots, and not just sticks.”
The FDA has also begun working with the Indian government to bolster domestic oversight. Right now, the agency has three inspectors who work in the country, but others regularly travel there as well, so the total number varies. India’s drug makers, however, are angry over the FDA scrutiny, which has led to a series of import alerts that ban products from being shipped to the US.