Drug Regulators Turn to Zoom-Style Plant Inspections During the Pandemic
(Bloomberg Businessweek) -- For the past year the pandemic has brought a halt to in-person inspections of many pharmaceutical manufacturing facilities around the world. With a backlog of more than 1,000 audits to clear, the U.S. Food and Drug Administration is facing pressure to embrace something it’s long eschewed: virtual inspections of foreign drug plants.
Inspectors from some Western nations, including the U.K. and Japan, plus the Council of Europe have tried alternatives to in-person audits, such as assessments that use head-mounted cameras, mobile Wi-Fi hotspots, web conferencing, and confidential document-sharing tools. Although they’ve been pleased to continue the global flow of medicine production during the pandemic, some inspectors admit that on-site audits allow better scrutiny, including the ability to conduct surprise inspections, ask questions in real time, and fully review sterile conditions inside facilities.
Still, the FDA on April 14 published general guidelines that could pave the way for the wider use of remote factory evaluations of things like safety and whether the ingredients used are of the strength level claimed. The agency said the remote inspection guidelines could be used “for the duration of the Covid-19 public health emergency.” FDA officials have held talks with international counterparts who’ve already conducted virtual inspections in places such as India, according to a person familiar with the matter, who asked not to be named because the deliberations weren’t public.
About 40% of facilities producing pharmaceuticals that are shipped to the U.S. are in China and India. But the FDA has been reluctant to rely on the type of remote monitoring of foreign plants recently used by the U.K. and the European Directorate for the Quality of Medicines and HealthCare (EDQM) because of past problems with some international manufacturing facilities. Millions of blood pressure pills with active ingredients produced in Asia, for instance, have been recalled in recent years because they were tainted with carcinogens. In 2013, India’s Ranbaxy Laboratories Ltd. pleaded guilty to the manufacture and distribution of adulterated drugs, and paid a $500 million penalty to the U.S. Department of Justice, after widespread data manipulation was found at two of its factories.
The FDA’s preference for in-person plant audits as a way to spot wrongdoing or potential quality lapses—such as the soiled uniforms and overflowing toilet drains its inspectors found in another Indian plant in 2013—is having a big impact for manufacturers. “It definitely has created a slowdown in the movement of medicines,” says Sireesha Yadlapalli, a senior director in India at the U.S. Pharmacopeia, a more than 200-year-old organization that creates standards for the global industry. The inspection pause also “has the potential to erode trust” in foreign plants that had won approvals years before but are not now undergoing periodic reinspections to make sure they’re still meeting standards, she says.
Although manufacturers rarely welcome the tense, meticulous factory audits from Western agencies that act as gatekeepers to some of the most lucrative drug markets, they complain that the disruption caused by the pandemic has created a backlog of more than 1,000 such reviews, which is hurting their business.
Almost a dozen factories run by three of the biggest Indian pharmaceutical companies were waiting to resolve warning letters and official action requests slapped on their plants by the FDA before the Covid‑19 outbreak, according to a report in January by AllianceBernstein LP. A delayed facility tour has also held up U.S. approval of a biosimilar version of the cancer treatment Avastin that’s being produced by Bengaluru-based Biocon Ltd.
One regulator exploring remote inspections is the EDQM. From November to February the regulator ran three virtual test inspections at Indian plants and toured the facilities using mobile phone and tablet cameras. “It could become an additional pillar” of supervision, says manufacturing practices inspector Cristina Baccarelli. She’s part of a team that typically visits 40 pharmaceutical production facilities a year but has been grounded since April 2020, when the EDQM curtailed overseas travel.
The U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) has conducted more than 750 inspections since last April, including an unspecified number that have been done remotely. This year it audited the Serum Institute of India Pvt Ltd., the world’s largest vaccine maker, which is supplying Britain and most of the developing world with millions of doses of AstraZeneca Plc’s Covid shot.
“We intend to continue with a hybrid approach of both remote and on-site activities post-pandemic,” says Paula Walker, a unit manager for inspection operations at the MHRA. Remote inspections, she says, have enabled the agency to continue its mission “of ensuring patient and public health, and security of the supply chain during the pandemic.”
Such approaches are dogged with challenges: patchy internet speeds, particularly in remote regions; equipment that isn’t standardized; and, perhaps most crucially, the lack of the element of surprise, a key tool in policing an industry that has a history of manufacturing fraud. “It is not easy to substitute certain elements of on-site inspections, such as body language interpretation, direct and immediate interaction with all operators, quick and unpredicted changes of the inspection agenda,” Baccarelli says.
Virtual approaches also aren’t well suited for certain areas, such as sterile facilities, Walker says. And the USP’s Yadlapalli says data assurance is harder and access is limited, with inspectors unable to look into trash cans for shredded documents or, in extreme cases, sleuth out fake “show” facilities. “Those types of deep dives are hard,” says Yadlapalli, who predicts post-pandemic use of remote technology will probably be limited to checking on established low-risk manufacturers. “There are some definite challenges.”
Although the FDA is only now issuing expanded guidance for virtual plant audits, it’s adapted to the pandemic by using “additional tools such as remote interactive evaluations, record requests, and leveraging information from trusted regulatory partners,” says a spokesperson for the agency.
The FDA has also conducted a few “mission critical” in-person visits, including some in India, since January, the spokesperson says. But the agency’s overseas offices are short-staffed, and inspections are considered only for companies producing Covid-related treatments or drugs that are in short supply. The scale of the oversight is daunting, with 550 FDA-approved plants in India that need to be monitored, the most outside the U.S., according to the Indian Pharmaceutical Alliance.
Unless the FDA—which typically conducts about 1,500 domestic and international surveillance trips annually—somehow speeds up the pace of inspections, the agency will face bottlenecks for years to come. Pandemic restrictions could potentially increase the number of plants going more than five years without an audit, the U.S. Government Accountability Office warned in a report in March.
As those holdups linger, anxious Indian drugmakers are continuing to lobby the FDA to start virtual evaluations. At an online industry event in February, an executive from Mumbai-based Lupin Ltd., which is waiting for multiple plants to be inspected, asked an FDA official why the agency wasn’t following the lead of other nations’ regulators. “We get that question a lot,” responded Christopher Middendorf, an inspector who’s based in India. The FDA is “considering all options. Nothing is off the table.”
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