Security and safety, like beauty, are in the eye of the beholder, especially in the time of a politicized pandemic.

“The U.S. drug supply chain is safe, and the supply chain is secure,” Judith McMeekin, associate commissioner for regulatory affairs at the FDA, testified before the Senate Finance Committee Tuesday.

Sen. John Cornyn (R-Texas) immediately responded, “Did you say our supply chain is secure?” He noted that most of the active pharmaceutical ingredients (APIs) needed to make the drugs used in the U.S. are produced overseas, with many of them coming from China. Just as China hoarded personal protection equipment, it could hoard those critical drug supplies, he said, adding, “Am I wrong?”

The locus of manufacturing was just one of the concerns raised at the oversight hearing that was supposed to focus on the FDA’s inspections of foreign drug manufacturing facilities. McMeekin’s assurance of the security of the supply chain followed a litany, from both Republicans and Democrats, of questionable drugs allowed into the U.S. over the years.

Committee Chair Chuck Grassley (R-Iowa) referenced the 2007-2008 heparin scandal in which hundreds of people died due to a toxin in the API, multiple quality problems with India’s Ranbaxy Laboratories Ltd. that came to light years ago and ongoing problems with high levels of N-nitrosodimethylamine, a probable carcinogen, in certain classes of drugs.

Ranking Member Ron Wyden (D-Ore.) voiced quality concerns raised by the FDA’s efforts to stem COVID-19-related drug shortages. He pointed out that the agency, which has stopped most domestic and foreign inspections during the pandemic, allowed the import of hydroxychloroquine from a plant in Pakistan that has never been inspected and from a plant in India that is on import alert.

Given the safety and security concerns about the nation’s drug supply chain, Wyden said, “It makes sense to look for ways to build up our drug manufacturing capacity in the U.S.” However, he took issue with a recent Biomedical Advanced Research and Development Authority (BARDA) contract that would do just that, saying the company awarded the $354 million contract, Phlow Corp., of Richmond, Va., has no experience manufacturing drugs and no facilities in which to manufacture them.

Under the BARDA contract, Phlow and its partners – Civica Rx, AMPAC Fine Chemicals and the Medicines for All Institute – are to provide U.S.-based capacity to produce essential APIs and chemical compounds necessary for the APIs, as well as the finished drugs.

Currently, 26% of facilities manufacturing APIs and 46% of the facilities producing finished dosage forms (FDFs) for the U.S. market are located in the U.S., according to the FDA. In comparison, 26% of API facilities and 19% of FDF facilities manufacturing for the U.S. are in the EU, 13% of the API facilities and 7% of the FDF plants are in China, and 19% of the API facilities and 10% of the FDF plants are in India. However, those numbers don’t tell the whole story, as they reflect the number of facilities, not the volume or numbers of APIs and FDFs being produced, and they don’t show how many of those are sole sources for U.S. drugs.

The percentages also don’t reflect the production of raw materials used to make the APIs, as the FDA doesn’t regulate those facilities, Rosemary Gibson, a senior adviser on health care at the Hastings Center, said at last week’s National Press Foundation’s webinar on medical trade wars. She added that the U.S. is dependent on China for producing those materials.

Inspection challenges

Aside from questions about the security risk of relying on other countries for critical drugs and ingredients, the globalization of the U.S. medicine chest continues to create regulatory challenges for the FDA, especially when it comes to inspections.

Since 2015, the FDA has been conducting more foreign inspections than domestic ones. But there are problems and inequities with how those inspections are being done, according to the Government Accountability Office (GAO). All domestic inspections, except pre-approvals, are unannounced, but foreign facilities are usually given up to 12 weeks’ advance notice of an FDA inspection, the GAO said in a report released Tuesday.

Referencing those findings, Grassley told the FDA witnesses at the Finance hearing that announced visits undermine the ability of field inspectors to do their job. “Twelve weeks is plenty of time to doctor up a facility to make sure that it passes,” he said.

Mark Abdoo, associate commissioner for global policy and strategy at the FDA, clarified that the agency does surprise for-cause inspections overseas. And the GAO found that the amount of notice was much shorter for foreign inspections conducted by in-country FDA investigators, with that notice ranging from none to up to five days.

However, only 27% of the FDA inspections conducted in China in fiscal 2018 and 10% of those conducted in India were done by agency investigators based in those countries. All the other inspections involved U.S.-based investigators and generally had 12 weeks’ advance notice.

The long lead time in announcing those inspections is due in part to making travel arrangements, securing visas and scheduling the investigators, according to the FDA.

The advance notice isn’t the only concern the GAO raised. In her testimony at the hearing, the GAO’s Mary Denigan-Macauley said FDA investigators often have to rely on English-speaking employees at the facilities being inspected to translate documents and to communicate with other workers. In one instance, an investigator had to use a phone translation app. Using company translators can create conflicts of interest and, if that person doesn’t know the technical language needed, it can make it harder to communicate with staff.

The GAO report blames some of the inspection weaknesses it identified in fiscal 2018 on FDA staffing issues. It noted that in December 2019, the FDA was in the process of filling 26 of the 58 vacancies it had in its inspection staff.

The FDA said it anticipates filling all its pharmaceutical investigator vacancies this year, adding that its mutual recognition agreement with the EU has enabled it to focus more of its investigator work force on higher-risk facilities around the world.

Hiring staff and sending investigators into the field are two different issues though, as it takes 18 months to two years of training before a new investigator is fully proficient. And when it comes to filling positions at its offices in other countries, the FDA has to negotiate agreements with the host countries about the number of investigators who can permanently be attached to a foreign office.

Despite the challenges, the FDA has made progress in its foreign inspections. For instance, the agency has addressed the 963 foreign facilities that had never been inspected as of December 2016. By the end of fiscal 2019, it had had inspected 496, about 52%, of those facilities and determined that 361 facilities, 37%, didn’t need to be inspected because they had gone out of business, weren’t servicing the U.S. market or had been registered with the FDA erroneously. Another 52, or 5%, had refused inspection; 34, or 4%, were inaccessible because of travel warnings and other issues; and 20, or 2%, had no imported drug shipments to the U.S.

No Comments